Pride

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PRAID® (PRIDE)

Composition:

Active ingredient: paracetamol;

1 ml of solution contains: paracetamol – 10.0 mg;

Excipients: sorbitol (E 420), sodium hydrogen phosphate dihydrate, sodium hydroxide, diluted hydrochloric acid, water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical characteristics: clear, colorless or slightly yellow liquid.

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

Pharmacological properties.

Pharmacodynamics.

The exact mechanism of the analgesic and antipyretic effects of paracetamol is not fully established; it may have both central and peripheral actions.

Praid® provides pain relief within 5–10 minutes after administration. The peak analgesic effect is achieved within 1 hour, and the duration of this effect usually lasts 4–6 hours.

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

Pharmacokinetics.

Absorption

After single administration of up to 2 g of the drug and after repeated administration within 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). The 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 (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: glucuronide conjugation and sulfate conjugation. 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-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 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/hour.

Children

The pharmacokinetics of paracetamol in infants and children is practically 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. Compared to adults, children under 10 years of age show significantly reduced glucuronidation and increased sulfation.

Pharmacokinetic parameters according to age

(standardized clearance, * CLstd/Foral (L•h⁻¹•70 kg⁻¹))

Table 1

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

Special patient groups

Patients with renal impairment

In patients with severe renal impairment (creatinine clearance 10–30 mL/min), elimination of paracetamol is slightly prolonged, and the elimination half-life ranges from 2 to 5.3 hours. The elimination rate of glucuronide and sulfate metabolites in patients with severe renal impairment is three times slower than in healthy volunteers. Therefore, in patients with severe renal impairment, the minimum interval between doses should be at least 6 hours (see section "Dosage and administration").

Elderly 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-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. Severe hepatocellular insufficiency.

Interaction with other medicinal products and other forms of interaction.

Probenecid reduces paracetamol clearance by half by inhibiting its conjugation with glucuronic acid; therefore, when used concomitantly with probenecid, the dose of paracetamol should be reduced.

Salicylates may increase the elimination half-life of paracetamol.

Caution should be exercised when co-administering the medicinal product with enzyme-inducing agents (barbiturates, isoniazid, carbamazepine, rifampicin, ethanol, and others) (see section "Overdose").

Concomitant use of paracetamol (4 g daily for at least 4 days) with oral anticoagulants may lead to minor changes in the international normalized ratio (INR). In such cases, INR should be monitored during treatment and for 1 week after discontinuation of Praid®.

Caution should be exercised when paracetamol is used concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with an increased anion gap due to pyroglutamic acidosis, particularly in patients with risk factors (see section "Special precautions").

Special precautions for use.

Caution is required when prescribing and administering PRAID® to avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), which may lead to accidental overdose and fatal outcomes.

It is recommended to switch to oral formulations of paracetamol as soon as such administration becomes feasible.

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

The risk of liver injury increases when PRAID® is administered at doses exceeding the recommended ones.

Clinical signs of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) typically first appear approximately two days after drug administration, peaking at 4–6 days. Administration of an antidote should be initiated as soon as possible (see section "Overdose").

As with all intravenous solutions in glass vials (bottles), monitoring of the infusion procedure is necessary, particularly toward the end of the infusion (see section "Dosage and administration").

Cases of high anion gap metabolic acidosis (HAGMA) due to 5-oxoprolinuria (pyroglutamic acidosis) have been reported in patients with severe underlying conditions such as 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, paracetamol should be discontinued immediately and careful monitoring of the patient should be 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.

Use with caution in patients with:

• Hepatocellular insufficiency;
• Severe renal impairment (see sections "Pharmacokinetics" and "Dosage and administration");
• Chronic alcoholism;
• Depleted hepatic glutathione reserves due to chronic undernutrition, anorexia, bulimia, or cachexia;
• Dehydration.

This medicinal product contains 2.54 mmol (or 58.39 mg) of sodium per 100 mL dose. Caution is advised when administering to patients on a sodium-controlled diet.

This medicinal product contains sorbitol (E 420). If you have been diagnosed with an intolerance to certain sugars, you should consult your doctor before taking this medicinal product.

Use during pregnancy or breastfeeding.

Pregnancy

Clinical experience with intravenous administration of paracetamol is limited. However, epidemiological data on the use of therapeutic doses of oral paracetamol indicate no adverse effects on pregnancy or fetal/neonatal health.

Prospective data on overdose during pregnancy do not suggest an increased risk of fetal malformations.

Reproductive toxicity studies with intravenous paracetamol in animals have not been conducted. Oral administration studies in animals have not demonstrated fetotoxic effects.

Paracetamol may be used during pregnancy if clinically necessary, but only after careful benefit-risk assessment. In such cases, recommended dosage and treatment duration must be strictly followed.

Breastfeeding period

After oral administration, paracetamol is excreted in breast milk in small amounts. No adverse effects in infants have been reported during breastfeeding while paracetamol is used. Therefore, this medicinal product can be used during breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

No effect.

Administration and dosage.

Administer intravenously.

For adults, adolescents, and children with body weight over 33 kg, use the solution in 100 mL vials.

Dosage depends on the patient's body weight.

Table 2

• 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 doses in patients with severe renal impairment should be at least 6 hours.

Maximum daily dose: The maximum daily dose is intended for patients who are not receiving other medicinal products containing paracetamol and should be appropriately adjusted if such products are taken.

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 (see section "Pharmacokinetics").

Patients with hepatic insufficiency, chronic alcoholism, chronically undernourished patients (low hepatic glutathione stores), and dehydrated patients

The maximum daily dose should not exceed 3 g (see section "Special precautions for use").

Method of administration

WARNING! To avoid dosing errors due to confusion between milligrams (mg) and milliliters (mL), doses must be carefully calculated when prescribing and administering the medicinal product PRAID®, infusion solution. Such confusion may lead to accidental overdose and even fatal outcomes. When writing prescriptions, both the total dose in milligrams (mg) and the total volume of the dose in milliliters (mL) must be clearly indicated.

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

Patients with body weight ≤ 10 kg

• The vial of the medicinal product PRAID® 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 drawn from the vial using a syringe and administered either 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 preparation (including 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.

For all infusion solutions in glass vials (bottles), it is important 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 particularly necessary during central intravenous administration to prevent air embolism.

Children

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

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

Overdose

The risk of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) increases in elderly patients, young children, patients with liver disease, chronic alcoholics, patients with alimentary dystrophy, and those taking enzyme-inducing drugs. In these cases, overdose may be fatal.

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, and in children with a dose of 140 mg/kg body weight. This leads to hepatic cytolysis, which may result in complete and irreversible necrosis, leading to hepatic failure, metabolic acidosis, encephalopathy, potentially progressing to coma and patient death. Within 12–48 hours, levels of liver transaminases (alanine aminotransferase (ALT), aspartate aminotransferase (AST)), 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;
• Determination of plasma paracetamol concentration as soon as possible after overdose, before starting treatment;
• Intravenous or oral administration of the antidote, N-acetylcysteine (NAC), preferably within 10 hours of overdose. NAC may also be administered later than 10 hours after overdose, but treatment duration will be longer;
• Symptomatic treatment;
• Liver function tests must be performed before starting 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. In some cases, liver transplantation may be required.

Adverse reactions

As with other medicinal products containing paracetamol, adverse reactions occurred rarely (≥ 1/10000 − < 1/1000) and very rarely (< 1/10000); see Table 3.

Table 3

In clinical trials, frequent adverse reactions at the injection site (pain and burning) were reported.

Rarely, hypersensitivity reactions were observed: from simple rash or urticaria to anaphylactic shock, which required discontinuation of treatment.

Cases of erythema, redness, itching, and tachycardia have also been reported.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

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

Reporting suspected adverse reactions

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

Shelf life. 2 years.

Do not use the medicinal product after the expiry date stated on the packaging.

Storage conditions.

Store at a temperature not exceeding 25°C.

Keep out of reach and sight of children.

Incompatibilities.

Pryd® should not be mixed with other solutions except those specified in the section "Dosage and administration".

Packaging.

50 ml or 100 ml in a vial. 1 vial per carton.

Prescription status. Prescription only.

Manufacturer.

JSC "Farmak".

Manufacturer's address and place of business.

74, Kyrylivska Street, Kyiv, 04080, Ukraine.