INSTRUCTIONS FOR USE

CUPIN IV

QUPEN IV

Trade name of the drug: Kupin IV.

Active ingredient (INN) : paracetamol

Dosage form : solution for infusion

Compound :

Every 100 ml of solution contains:

active substance : paracetamol – 1.0 g;

excipients : mannitol, anhydrous sodium phosphate, hydrochloric acid, water for injection.

Description : transparent colorless liquid without foreign inclusions of sediment.

Pharmacotherapeutic group : analgesics and antipyretics.

ATX code : N02BE01

Pharmacological properties.

Paracetamol is a non-narcotic analgesic from the group of para-aminophenols. Has an analgesic and antipyretic effect. The drug blocks cyclooxygenase I and II mainly in the central nervous system, affecting the centers of pain and thermoregulation. The lack of influence on the synthesis of prostaglandins in peripheral tissues determines the absence of a negative effect on water-salt metabolism (sodium and water retention) and the mucous membrane of the gastrointestinal tract.

The analgesic effect after intravenous use occurs within 5-10 minutes after administration. The maximum analgesic effect is observed 60 minutes after administration and lasts 4-6 hours. The antipyretic effect is observed 30 minutes after administration and lasts for at least 6 hours.

Pharmacokinetics

Suction

The pharmacokinetics of paracetamol is linear up to 2 g after a single administration and after repeated administration within 24 hours.

The bioavailability of paracetamol after an infusion of 500 mg — 1 g of paracetamol is similar to that observed after an infusion of 1 g and 2 g of procetamol (corresponding to 500 mg and 1 g of paracetamol, respectively). The maximum plasma concentration (Cmax ₎ of paracetamol is observed at the end of a 15-minute intravenous infusion of 500 mg — 1 g of paracetamol and is about 15 mcg / ml and 30 mcg / ml, respectively.

Distribution

The volume of distribution of paracetamol is approximately 1 l/kg.

Paracetamol does not bind significantly to plasma proteins.

Following an infusion of 1 g paracetamol, a significant concentration of paracetamol (1.5 μg/ml) was observed in the cerebrospinal fluid 20 minutes after infusion.

Metabolism

Paracetamol is metabolized primarily in the liver through the following 2 main metabolic pathways: conjugation with glucuronic acid and sulfuric acid. The latter route is rapidly saturated in doses exceeding therapeutic ones. A small portion (less than 4%) is metabolized by cytochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in the urine after conjugation with cysteine and mercapturic acid. However, during a massive overdose, the amount of this toxic metabolite increases.

Removal

Metabolites of paracetamol are excreted mainly in the urine. 90% of the administered dose is eliminated after 24 hours, mainly in the form of glucuronide (60-80%) and sulfate (20-30%) conjugates. Less than 5% is excreted unchanged. The plasma half-life is 2.7 hours and the total clearance is 18 L/hour.

Newborns, infants and children.

The pharmacokinetic parameters of paracetamol observed in infants and children are similar to those observed in adults, with the exception of the plasma half-life, which is slightly shorter (1.5-2 hours) than in adults. In neonates, the plasma half-life is longer than in infants, being 3.5 hours. Neonates, infants, and children under 10 years of age excrete significantly fewer conjugates as glucuronides and more as sulfates than adults.

Indications for use

Paracetamol infusion is indicated for the short-term treatment of moderate pain, especially after surgery and for the short-term treatment of fever when intravenous administration is clinically justified by the immediate need for the treatment of pain or pyrexia and/or when other routes of administration are not possible.

Directions for use and dosage

Dosage based on patient weight (see dosage chart below)

Patient weight	Dose per administration	Volume per injection	Maximum volume of paracetamol (10 mg/ml) per administration based on group weight upper limits (ml)**	Maximum daily dose***
≤ 10 kg *	7.5 mg/kg	0.75 ml/kg	7.5 ml	30 mg/kg
> 10 kg to ≤ 33 kg	15 mg/kg	1.5 ml/kg	49.5 ml	60 mg/kg, not more than 2 g
> 33 kg to ≤ 50 kg	15 mg/kg	1.5 ml/kg	75 ml	60 mg/kg, not more than 3 g
>50 kg with additional risk factors for hepatotoxicity	1 g	100 ml	100 ml	3 g
> 50 kg without additional risk factors for hepatotoxicity	1 g	100 ml	100 ml	4 g

*Premature neonates : Safety and efficacy data are not available for preterm neonates.

**Patients who weigh less require smaller volumes.

The minimum interval between repeated administrations should be at least 4 hours. No more than 4 doses should be administered per day .

The minimum interval between repeated doses in patients with severely impaired renal function should be at least 6 hours.

*** Maximum daily dose: The maximum daily dose, as presented in the table above, is the dose for patients not receiving other paracetamol-containing products and should be adjusted accordingly when taking such products.

Serious renal impairment:

When using paracetamol in patients with severe renal impairment (creatinine clearance ≤ 30 ml/min), it is recommended to increase the minimum interval between each dose to 6 hours.

In adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low glutathione reserves in the liver), dehydration:

The maximum daily dose should not exceed 3 g.

Mode of application

Cupin IV is administered as a 15-minute intravenous infusion.

Patients weighing ≤ 10 kg:

The glass bottle/bag of paracetamol infusion should not be suspended as an infusion due to the small volume of drug that must be administered to this population

The volume to be administered must be removed from the vial or bag and can be administered undiluted or diluted (in 1 to 9 volumes of diluent) in 0.9% sodium chloride solution or 5% glucose solution and administered as a 15-minute infusion. Use the diluted solution within one hour of preparing it (the infusion time is included).

A 5 or 10 ml syringe should be used to measure the dose appropriate to the child’s weight and volume required. However, it should never exceed 7.5 ml per dose

The user must be informed about the product to select the optimal dose.

Side effects

As with all paracetamol-containing products, adverse drug reactions are rare (>1/10000, <1/1000) or very rare (<1/10000) and are described in the Table below:

Organ systems	Rarely > 1/10000, < 1/1000	Very rarely < 1/10000
Are common	Malaise	Hypersensitivity reactions
Cardiovascular	Hypotension
Liver	Elevated levels of liver transaminases
Platelets/Blood		Thrombocytopenia, leukopenia, neutropenia

Frequent injection site adverse reactions were reported during clinical trials (pain and burning).

Very rare cases of hypersensitivity reactions, ranging from simple skin rash or hives to anaphylactic shock, have been reported and require discontinuation of treatment.

There were no cases of erythema, redness, itching or tachycardia.

Contraindications

Cupin IV infusions are contraindicated:

patients with hypersensitivity to paracetamol or procetamol hydrochloride (precursor to paracetamol) or to any component of the drug;
in cases of severe hepatocellular failure.

Carefully

Cupin IV should be used with caution in cases of:

hepatocellular failure,
severe renal dysfunction (creatinine clearance ≤ 30 ml/min),
chronic alcoholism,
chronic malnutrition (low liver glutathione reserve),
dehydration.

Drug interactions

Probenecid causes an almost 2-fold decrease in the clearance of paracetamol, inhibiting its conjugation with glucuronic acid. When used simultaneously with probenecid, a dose adjustment of paracetamol is necessary.

Salicylamide may increase the half-life t _1/2 of paracetamol.

Attention should be paid to the concomitant use of enzyme-inducing substances.

Concomitant use of paracetamol (4 g per day for at least 4 days) with oral anticoagulants may result in a slight change in INR values. In this case, intensive monitoring of INR values should be carried out during the period of concomitant use and for at least a week after stopping treatment with paracetamol.

special instructions

It is recommended that appropriate oral analgesic treatment be used as quickly as possible.

To avoid the risk of overdose, other drugs used should be checked for paracetamol and procetamol. None of the drugs used should contain either paracetamol or procetamol.

Doses higher than recommended carry the risk of very serious liver damage. Clinical symptoms and signs of liver damage (including fulminant hepatitis, liver failure, cholestatic hepatitis, cytolytic hepatitis) usually first appear after two days of taking the drug, with a peak usually after 4 to 6 days. Antidote treatment should be started as soon as possible.

Use during pregnancy and lactation

Pregnancy

Clinical experience with intravenous paracetamol is limited. However, epidemiological data from the use of oral therapeutic doses of paracetamol do not show adverse effects on pregnancy or fetal/newborn health. Prospective data from pregnant women exposed to overdose do not show an increased risk of malformations.

Reproductive studies with intravenous paracetamol have not been performed in animals. However, studies using the oral route have shown no malformations or fetotoxic effects.

However, paracetamol infusions should only be used during pregnancy after a careful assessment of benefits and risks. In this case, the recommended dosages and duration of treatment must be strictly observed.

Lactation

After oral administration, paracetamol is excreted into breast milk in small quantities. No side effects were observed in breastfeeding infants.

Therefore, paracetamol infusion can be used in nursing women.

Impact on the ability to drive vehicles and operate machinery

Unknown.

The drug should be stored out of the reach of children and not used after the expiration date.

Overdose

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

Symptoms usually appear within the first 24 hours and include: nausea, vomiting, anorexia, pallor, abdominal pain. An overdose of 7.5 g or more of paracetamol in a single dose in adults and 140 mg/kg body weight in a single dose in children causes hepatic cytolysis, probably inducing complete and irreversible necrosis, resulting in hepatocellular failure, metabolic acidosis and encephalopathy, which can lead to coma and death. At the same time, an increase in the level of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed along with a decrease in the level of prothrombin time, which can appear from 12 to 48 hours after administration.

Clinical symptoms of liver damage are usually evident initially after two days, and reach a maximum after 4 to 6 days.

Emergency measures

Immediate hospitalization.

Before starting treatment, take a blood tube to quantify the concentration of paracetamol in plasma, as quickly as possible after an overdose.

Treatment includes administration of the antidote, N-acetylcysteine, intravenously or orally, if possible within 10 hours. N-acetylcysteine may, however, provide some degree of protection even after 10 hours, but in these cases long-term treatment is required.

Symptomatic treatment.

Liver tests should be performed at the start of treatment and repeated every 24 hours. In most cases, liver transaminases return to normal within one to two weeks, with complete restitution of liver function. In very severe cases, however, a liver transplant may be necessary.

Release form

A clear, colorless solution filled in 100 ml LDPE FFS bottles, appropriately marked and equipped with a white LDPE cap, sealed in a PP bag.

Storage conditions

QUPEN IV

Price on Request

QUPEN IV

Price on Request