Paradin

INSTRUCTIONS FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARADYN

Composition:

Active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

Excipients: glucose monohydrate; acetic acid; sodium acetate trihydrate; sodium citrate dihydrate; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: colorless or slightly yellowish (pale) solution.

Pharmacotherapeutic group.

Analgesics and antipyretics. ATC code N02BE01.

Pharmacological properties.

Pharmacodynamics.

The precise mechanism of the analgesic and antipyretic effects of paracetamol has not yet been fully established; it may involve both central and peripheral actions.

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

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

Pharmacokinetics.

Adults

Absorption

After single or repeated administration within 24 hours at doses up to 2 g, the pharmacokinetics of paracetamol are linear.

The bioavailability following intravenous infusion of 500 mg or 1 g paracetamol is equivalent to that after administration of 1 g or 2 g of propacetamol (containing 500 mg or 1 g of paracetamol, respectively). Maximum plasma concentration (Cmax) is achieved at the end of a 15-minute infusion of 500 mg or 1 g paracetamol, reaching 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. A significant concentration (approximately 1.5 µg/mL) was detected in cerebrospinal fluid 20 minutes after infusion following administration of 1 g paracetamol.

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 fraction (less than 4%) is metabolized by cytochrome P450 enzymes 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 significantly.

Elimination

Paracetamol metabolites are primarily excreted in urine. Within 24 hours, approximately 90% of the administered dose is eliminated by the kidneys, 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.

Neonates, infants, and children

The pharmacokinetics of paracetamol in infants and 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. Compared to adults, neonates, infants, and children up to 10 years of age exhibit significantly reduced glucuronidation capacity.

Table 1

Pharmacokinetic parameters according to age (standardized clearance,*

CLstd/Foral (L•h⁻¹•70 kg⁻¹))

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

Special patient groups

Patients with renal impairment

In 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 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 dosing interval 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 (see section "Posology and method of administration").

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 any of the excipients of the medicinal product. Severe hepatocellular insufficiency.

Interaction with other medicinal products and other forms of interaction.

Probenecid causes an almost twofold reduction in paracetamol clearance by inhibiting its conjugation with glucuronic acid. When paracetamol is used concomitantly with probenecid, the need to reduce the paracetamol dose should be considered.

Salicylamide may prolong the elimination half-life of paracetamol.

Caution is required when paracetamol is used concomitantly with enzyme-inducing medicinal products. These medicinal products include, but are not limited to, barbiturates, isoniazid, carbamazepine, rifampicin, and ethanol (see section "Overdose").

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

Caution should be exercised when paracetamol is used concomitantly with flucloxacillin, as their simultaneous 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.

Warning

As soon as possible, it is recommended to continue treatment using oral forms of analgesics.

To avoid overdose, it is necessary to ensure that other prescribed medicinal products do not contain paracetamol or propacetamol.

Exceeding the recommended doses may lead to serious liver function disorders. Clinical signs and symptoms of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are usually observed only 2 days after administration of the drug, with peak severity typically occurring on days 4–6. Antidotal treatment should be initiated as soon as possible (see section "Overdose").

This medicinal product contains less than 1 mmol of sodium (23 mg) per container, i.e. it is practically sodium-free.

Paracetamol may cause serious skin reactions. Patients should be informed about early signs of serious skin reactions, and administration of the drug should be discontinued at the first appearance of skin rash or any other signs of hypersensitivity.

Metabolic acidosis with a high anion gap (HAGMA) due to pyroglutamic acidosis has been reported in patients with severe underlying conditions such as severe renal impairment, sepsis, or marasmus, or other causes of glutathione deficiency (e.g., chronic alcoholism), who have been treated for prolonged periods with therapeutic doses of paracetamol or a combination of paracetamol and flucloxacillin.

In suspected cases of HAGMA due to pyroglutamic acidosis, immediate discontinuation of paracetamol and close monitoring of the patient are recommended. Measurement of urinary 5-oxoproline levels may be useful in identifying pyroglutamic acidosis as the underlying cause of HAGMA in patients with multiple risk factors.

If flucloxacillin treatment continues after discontinuation of paracetamol, careful monitoring for signs of HAGMA is recommended, as flucloxacillin may perpetuate the clinical picture of HAGMA (see section "Interaction with other medicinal products and other forms of interaction").

As with all infusion solutions presented in glass vials, careful monitoring of the infusion process is required, with particular attention at the end of the infusion (see section "Method of administration and dosage").

The drug should be used with caution in patients with:

− hepatocellular insufficiency, Gilbert’s syndrome;

− severe renal impairment (see sections "Pharmacological properties" and "Method of administration and dosage");

− chronic alcoholism;

− nutritional depletion (reduced hepatic glutathione reserves due to chronic undernutrition, anorexia, bulimia, or cachexia);

− dehydration;

− glucose-6-phosphate dehydrogenase deficiency (risk of hemolytic anemia).

Use during pregnancy or breastfeeding.

Pregnancy

Clinical experience with intravenous administration of paracetamol is limited. However, epidemiological data on therapeutic doses of oral paracetamol indicate no adverse effects on pregnancy or fetal/neonatal health. Epidemiological studies on the neurological development of children exposed to paracetamol in utero have yielded inconclusive results. When clinically indicated, paracetamol may be used during pregnancy, but it should be administered at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breastfeeding period

After oral administration, paracetamol is excreted in breast milk in small amounts. No adverse reactions in infants have been reported during breastfeeding while using paracetamol. Therefore, paracetamol may be used in women who are breastfeeding.

Ability to affect reaction speed when driving vehicles or operating machinery.

No data available.

Dosage and Administration.

Intravenous route of administration

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

The 50 ml vial is intended only for full-term newborns, infants, young children of preschool age, and children with body weight up to 33 kg.

Dosing

Table 2

Dosing according to patient's body weight

*Preterm neonates: safety and efficacy data of the medicinal product in preterm neonates are lacking (see section "Pharmacokinetics").

**Patients with lower body weight require smaller volumes. The minimum interval between doses 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.

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

Renal impairment

In patients with renal impairment, the minimum interval between each administration of the medicinal product should be observed as follows:

Hepatic insufficiency

In patients with chronic or compensated active liver disease, hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low hepatic glutathione stores), dehydration, Gilbert's syndrome, or body weight less than 50 kg, the maximum daily dose should not exceed 3 g (see section "Special precautions for use").

Elderly patients

Dose adjustment in elderly patients is generally not required.

Method of administration

To avoid dosing errors due to confusion between milligrams (mg) and milliliters (ml), careful calculation of doses is essential when prescribing and administering Paradin, infusion solution. Such confusion may lead to accidental overdose and even fatal outcomes. When writing prescriptions, the total dose should be indicated both in milligrams and milliliters.

Paracetamol solution is administered by intravenous infusion over 15 minutes.

Patients with body weight ≤ 10 kg:

• The Paradin container should not be hung for infusion due to the small volume of medication to be administered.
• The required volume should be withdrawn from the container and may be administered undiluted or diluted (one part of the preparation to nine parts of diluent) in 0.9% sodium chloride solution or 5% glucose solution 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 must not exceed 7.5 ml.
• Dosing recommendations must be strictly followed.

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

As with any other infusion solution supplied in containers containing air, careful monitoring of the infusion process is required regardless of the administration method, with particular attention at the end of the infusion. This caution at the end of the infusion is especially relevant for central venous infusions and aims to prevent air embolism.

Children.

The 100 ml container is intended only for children with body weight above 33 kg. The 50 ml container is intended only for full-term newborns, infants, toddlers, and children with body weight above 10 kg and up to 33 kg.

Safety and efficacy data for use in preterm neonates are lacking.

Overdose.

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 receiving enzyme inducers. Overdose may be fatal in these cases.

Symptoms appear within the first 24 hours and include nausea, vomiting, anorexia, pallor, and abdominal pain.

Overdose of 7.5 g or more of paracetamol administered as a single dose in adults or 140 mg/kg body weight as a single dose in children causes hepatic cytolysis, which may lead to complete and irreversible necrosis resulting in hepatocellular insufficiency, metabolic acidosis, and encephalopathy, potentially progressing to coma and fatal outcome.

Concurrently, increased 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 damage usually become apparent initially after 2 days and peak at 4–6 days.

Treatment:

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

Adverse reactions.

As with all paracetamol-containing products, adverse reactions to the drug occur very frequently (≥ 1/10), frequently (from ≥ 1/100 to < 1/10), uncommonly (from ≥ 1/1000 to < 1/100), rarely (from ≥ 1/10000 to < 1/1000), very rarely (< 1/10000), and frequency not known (cannot be estimated from the available data).

They are described below:

*Very rare cases of hypersensitivity reactions have been reported, ranging from mild skin rashes or urticaria to anaphylactic shock, requiring discontinuation of treatment.

**Post-marketing experience with concomitant use of paracetamol and flucloxacillin; usually in the presence of risk factors (see section "Special precautions for use").

***Very rare cases of serious skin reactions have been reported, which require discontinuation of treatment.

Description of selected adverse reactions

Metabolic acidosis with high anion gap

Cases of metabolic acidosis with high anion gap due to pyroglutamic acidosis have been observed during paracetamol use in patients with risk factors (see section "Special precautions for use"). Pyroglutamic acidosis may occur due to low glutathione levels in these patients.

Shelf life. 18 months. Once opened, the solution must not be stored.

Storage conditions.

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

Keep out of reach of children.

Incompatibilities.

Paradine must not be mixed with other medicinal products.

Packaging.

50 ml or 100 ml in a bag; bag in a protective package made of metallized foil; 1 or 12 packages in a cardboard box.

Prescription category. Prescription only.

Manufacturer. Infomed Fluids S.R.L.

Manufacturer's address and place of business. 50 Bulevardul Teodor Pallady, Sector 3, Bucharest, 032266, Romania.