Axapara

INSTRUCTION
for medical use of medicinal product

AXAPARA
(AXAPARA)

Composition:

active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

excipients: mannitol (E 421), disodium phosphate dihydrate, sodium hydroxide, hydrochloric acid concentrated, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear colourless 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

AXAPARA 10 mg/ml 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 effect typically lasts 4–6 hours.

The medicinal product reduces elevated temperature within 30 minutes after the start of infusion, with the antipyretic effect lasting at least 6 hours.

Pharmacokinetics.

Adults

Absorption

The pharmacokinetics of paracetamol is linearly dose-dependent up to 2 g, both after single administration and repeated administration within 24 hours.

Bioavailability of paracetamol after infusion of 500 mg and 1 g of paracetamol 10 mg/ml is comparable to the bioavailability after infusion of 1 g and 2 g of propacetamol (containing 500 mg and 1 g of paracetamol, respectively). Maximum plasma concentration of paracetamol (Cmax) observed at the end of a 15-minute intravenous infusion of 500 mg and 1 g of paracetamol 10 mg/ml 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, significant concentrations of paracetamol (approximately 1.5 µg/ml) were observed in cerebrospinal fluid starting from 20 minutes after infusion.

Metabolism

Paracetamol is mainly metabolized in the liver via two primary 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 portion (less than 4%) is metabolized by cytochrome P450 into a reactive intermediate metabolite
(N-acetylbenzoquinone imine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine following conjugation with cysteine and mercapturic acid. However, in 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, predominantly as glucuronide conjugates (60–80%) and sulfate conjugates
(20–30%). Less than 5% is excreted unchanged. The plasma half-life is 2.7 hours, and total clearance is 18 L/hour.

Children

Pharmacokinetic parameters of paracetamol in children are similar to those observed in adults, except for a slightly shorter plasma half-life (1.5 to 2 hours) compared to adults. In newborns, the plasma half-life of paracetamol is longer than in older children, approximately 3.5 hours. Newborns and children under 10 years of age excrete significantly less glucuronide and more sulfate conjugates than adults.

Table 1

Pharmacokinetic values by age (standardized clearance,
*CLstd/Foral (L·h⁻¹·70 kg⁻¹))

*CLstd – estimation of the patient group regarding CL (clearance).

Special patient categories

Renal impairment

In cases of severe renal dysfunction (creatinine clearance 10–30 mL/min), elimination of paracetamol is slightly prolonged, 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 geriatric patients are not altered. There is no need to adjust the dosage regimen in this patient group.

Clinical characteristics.

Indications.

Short-term treatment of moderate pain, particularly postoperative pain.

Short-term treatment of fever.

Intravenous administration is clinically justified in cases of urgent need for pain relief or hyperthermia treatment, and/or when other routes of administration are not feasible.

Contraindications.

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

Severe hepatocellular insufficiency.

Special safety precautions.

Extreme caution must be exercised when prescribing and administering the medicinal product Axapara to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose and fatal outcomes. Prescriptions must clearly state the total dose in milligrams and the corresponding volume in milliliters.

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

Interaction with other medicinal products and other forms of interaction.

• Probenecid causes nearly a twofold reduction in paracetamol clearance by inhibiting its conjugation with glucuronic acid. When paracetamol is used concomitantly with probenecid, dose reduction of paracetamol should be considered.
• Salicylamide may prolong the elimination half-life of paracetamol.
• Caution is required when paracetamol is used concomitantly with enzyme-inducing substances. These include, among others, barbiturates, isoniazid, carbamazepine, rifampicin, and ethanol (see section "Overdose").
• Concomitant use of paracetamol (4000 mg daily for at least 4 days) with oral anticoagulants may result in minor changes in international normalized ratio (INR) values. Enhanced INR monitoring should be performed during concomitant treatment and for 1 week after discontinuation of paracetamol therapy.
• Caution is required when paracetamol is used concomitantly with flucloxacillin, as co-administration has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions for use").

Special precautions for use.

Long-term or frequent use of the medicinal product is not recommended. Appropriate oral analgesic therapy should be initiated as soon as this route becomes feasible.

To avoid the risk of overdose, check whether other administered medicinal products contain paracetamol or propacetamol. Dosage adjustments may be necessary (see section "Dosage and administration").

Doses exceeding the recommended amounts may lead to severe liver function impairment.

Clinical signs and symptoms of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) typically appear approximately 2 days after administration, with peak severity usually occurring 4–6 days later. Antidotal treatment should be initiated as soon as possible (see section "Overdose").

Paracetamol should be used with caution in the following conditions:

• hepatocellular insufficiency, Gilbert’s syndrome;
• severe renal impairment (creatinine clearance ≤ 30 mL/min) (see sections "Pharmacokinetics" and "Dosage and administration");
• chronic alcoholism;
• chronic malnutrition (low hepatic glutathione stores);
• dehydration;
• genetically determined glucose-6-phosphate dehydrogenase deficiency, which may lead to hemolytic anemia due to reduced glutathione availability following paracetamol administration.

Paracetamol may cause serious skin reactions. Patients should be informed about early signs of serious skin reactions. The medicinal product must be discontinued immediately at the first signs of skin rash or any other symptoms of hypersensitivity.

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in critically ill patients, such as those with severe renal impairment or sepsis, or in patients with poor nutrition or other sources of glutathione deficiency (e.g., chronic alcoholism), who were treated with therapeutic doses of paracetamol over prolonged periods or in combination with flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, immediate discontinuation of paracetamol and close patient monitoring are recommended. Measurement of urinary 5-oxoproline levels may help identify pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

If flucloxacillin is continued after discontinuation of paracetamol, it is advisable to confirm the absence of HAGMA, as the clinical picture of HAGMA may persist (see section "Interaction with other medicinal products and other forms of interaction").

As with all infusion solutions in glass vials, the infusion procedure should be monitored, particularly towards the end of the infusion (see section "Dosage and administration").

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

Use during pregnancy or breastfeeding.

Pregnancy

Clinical experience with intravenous paracetamol is limited. However, epidemiological data on the use of oral therapeutic doses of paracetamol do not indicate adverse effects during pregnancy or effects on fetal/newborn health.

Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results.

Paracetamol during pregnancy should be used only after careful benefit-risk assessment, at the lowest effective dose, for the shortest duration, and with the lowest possible frequency.

Breastfeeding period

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

Ability to influence reaction speed when driving or operating machinery.

No effect.

Method of administration and dosage.

The medicinal product is administered intravenously.

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

Dosage

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

Table 2

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

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

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

Patients with severe renal impairment

When prescribing 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, patients with 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.

Route of administration

WARNING! To avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose and even fatal outcomes, it is recommended to specify both the total dose in milligrams and the total dose in milliliters when prescribing.

Paracetamol solution is administered as a 15-minute intravenous infusion.

Patients with body weight ≤ 10 kg

• The vial should not be hung for infusion due to the small volume of medicinal product to be administered.
• The required volume of the medicinal product should be withdrawn from the vial using a syringe and administered undiluted or diluted in 0.9% sodium chloride solution or 5% glucose solution at a ratio of one part medicinal product to nine parts diluent, and infused over 15 minutes.

The diluted solution must be used within 1 hour after dilution, taking into account the infusion time.

• A 5 mL or 10 mL syringe should be used to measure the required dose according to the child's body weight. However, this dose should not exceed 7.5 mL.
• Dosing recommendations must be strictly followed.

To withdraw the solution, use a 0.8 mm needle (21 gauge) and pierce the stopper vertically at the designated site.

For all infusion solutions in glass vials (bottles), monitoring of the procedure, especially at the end of the infusion, should be performed regardless of the route of administration. Monitoring at the end of the infusion is particularly important in central intravenous administration to prevent air embolism.

Prior to administration, the medicinal product should be visually inspected for the presence of particles and discoloration. It is intended for single use only. Any unused portion should be discarded.

The diluted solution should be visually inspected before use; do not use if particulate matter or precipitate is observed.

After dilution, chemical and physical in-use stability of the solutions was maintained for 48 hours at 23°C.

To avoid microbiological contamination, the product should be used immediately.

Children

The 100 mL vial is intended only for children with body weight greater than 33 kg.

Due to lack of safety and efficacy data, the medicinal product is not used in premature infants.

Overdose.

Symptoms

There is a risk of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis), particularly in elderly patients, young children, patients with liver disease, chronic alcoholism, chronic malnutrition, and patients receiving enzyme inducers. Overdose may be fatal in these cases.

Symptoms usually 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 absent.

Regardless of the presence or severity of possible liver function disturbances, acute renal failure may develop in cases of overdose.

An overdose of 7.5 g or more of paracetamol administered at once in adults or 140 mg/kg body weight administered at once in children causes liver cytolysis, which may lead to complete and irreversible necrosis, resulting in hepatocellular failure, metabolic acidosis, and encephalopathy, potentially leading to coma and fatal outcomes. Concurrently, elevated levels of liver transaminases (AST, ALT), lactate dehydrogenase, and bilirubin occur together with decreased prothrombin levels, which may appear 12–48 hours after administration. Clinical signs of liver injury usually become apparent initially after two days and peak at 4–6 days.

Treatment

Immediate hospitalization.

Before starting treatment and as soon as possible after overdose, a blood sample should be taken for plasma paracetamol analysis.

Treatment includes administration of the antidote N-acetylcysteine (NAC) either intravenously or orally, if possible, within 10 hours of overdose. However, NAC may provide some degree of protection even after 10 hours, but in these cases, prolonged NAC treatment should be prescribed.

Symptomatic treatment

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

Adverse reactions.

As with other medicinal products containing paracetamol, the frequency of occurrence of the adverse reactions listed below is defined as follows: common

(≥ 1/100 − < 1/10), rare (> 1/10,000 − < 1/1,000), very rare (< 1/10,000), and frequency not known (cannot be estimated from available data).

Table 3

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

**During the post-marketing period, when paracetamol was used concomitantly with flucloxacillin; usually in the presence of risk factors (see section "Special Warnings and Precautions for Use").

***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 very important. It allows continuous monitoring of the benefit-risk balance of the medicinal product. Healthcare professionals should report any suspected adverse reactions via the national pharmacovigilance system.

Shelf life.

2 years.

Storage conditions.

Store at a temperature not exceeding 30 °C.

Do not freeze.

Keep out of reach of children.

Incompatibility.

The medicinal product Aksapara must not be mixed with other medicinal products except those specified in the section "Method of administration and dosage".

Prescription status.

Prescription only.

Packaging.

100 ml in a vial, 1 vial in a cardboard pack.

Manufacturer.

Axa Parenterals Ltd./Axa Parenterals Ltd.

Manufacturer's address.

Plot No. 936, 937 & 939, Vill. Kishanpur, Jamalpur, Roorkee-247667, Distt. Haridwar, Uttarakhand, India.

Marketing Authorization Holder.

Axa Parenterals Limited.

Address of the Marketing Authorization Holder.

Plot No. 936, 937 & 939, Vill. Kishanpur, Jamalpur, Roorkee-247667, Distt. Haridwar, Uttarakhand, India.