Paracetamol b. braun 10 mg/ml

INSTRUCTION FOR MEDICAL USE OF THE MEDICINAL PRODUCT PARACETAMOL B. BRAUN 10 mg/ml

Composition:

Active substance: paracetamol;

1 ml of solution contains 10 mg of paracetamol;

Excipients: mannitol (E 421); sodium citrate dihydrate; acetic acid, glacial; water for injections.

Pharmaceutical form. Infusion solution.

Main physicochemical properties: clear, colorless solution ranging to pale pink-orange in color (perception may vary), free from particles.

Theoretical osmolarity 305 mOsmol/L; pH 4.5 – 5.5.

Pharmacotherapeutic group. Analgesics and antipyretics.

ATC code N02B E01.

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

Paracetamol B. Braun 10 mg/mL provides onset of analgesia within 5–10 minutes after initiation of infusion. Peak analgesic effect is achieved within 1 hour, and the duration of this effect typically lasts 4–6 hours.

Paracetamol B. Braun 10 mg/mL reduces elevated temperature within 30 minutes after initiation of infusion, with the antipyretic effect lasting for at least 6 hours.

Pharmacokinetics

Adults

Absorption

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

The bioavailability of paracetamol after infusion of Paracetamol B. Braun 10 mg/mL at doses of 500 mg and 1 g is comparable to that after infusion of 1 g and 2 g of propacetamol (containing 500 mg and 1 g of paracetamol, respectively). The maximum plasma concentration (Cmax) of paracetamol observed at the end of a 15-minute intravenous infusion of 500 mg and 1 g of Paracetamol B. Braun 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, a significant concentration of paracetamol (approximately 1.5 µg/mL) was observed in cerebrospinal fluid starting from the 20th minute after infusion.

Metabolism

Paracetamol is primarily 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 to a reactive intermediate metabolite (N-acetylbenzoquinoneimine), which under normal conditions is rapidly detoxified by reduced glutathione and excreted in urine following conjugation with cysteine and mercapturic acid. However, in cases of severe 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, predominantly as glucuronide conjugates (60–80%) and sulfate conjugates (20–30%). Less than 5% is excreted unchanged. The elimination half-life in plasma is 2.7 hours, and total clearance is 18 L/h.

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 neonates, the plasma elimination half-life is longer than in older children, approximately 3.5 hours. In neonates and children up to 10 years of age, significantly less glucuronide conjugates and more sulfate conjugates are excreted compared to adults.

Table 1

Age-related pharmacokinetic values

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

Age	Body weight (kg)	CLstd/Foral (l × h-1 × 70 kg-1)
40 weeks post-conception	3.3	5.9
3 months postnatal	6	8.8
6 months postnatal	7.5	11.1
1 year postnatal	10	13.6
2 years postnatal	12	15.6
5 years postnatal	20	16.3
8 years postnatal	25	16.3

*CLstd — population clearance estimate

Special patient categories

Renal impairment

In cases of severe renal dysfunction (creatinine clearance 10–30 mL/min), elimination of paracetamol is slightly slowed, 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 dysfunction 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 elderly patients are not altered. There is no need to adjust the dosage of the drug in these patients.

Clinical characteristics.

Indications.

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

Short-term treatment of fever.

For intravenous administration, clinically justified by the immediate need for pain or hyperthermia treatment, and/or when other routes of administration are not available.

Contraindications.

Hypersensitivity to paracetamol, propacetamol hydrochloride (a paracetamol precursor), or to any of the excipients.

Severe hepatic impairment.

Interaction with other medicinal products and other forms of interactions.

• Probenecid causes an almost twofold reduction in paracetamol clearance by inhibiting its conjugation with glucuronic acid. When paracetamol is used concomitantly with probenecid, consideration should be given to reducing the paracetamol dose.
• Salicylamide may prolong the elimination half-life of paracetamol.
• Caution is required when using paracetamol concomitantly with substances that induce enzymes (see section "Overdose").
• Concomitant use of paracetamol (4000 mg daily for at least 4 days) with oral anticoagulants may lead to minor changes in INR (International Normalized Ratio) values. In such cases, enhanced INR monitoring should be performed throughout the period of concomitant use and for 1 week after discontinuation of paracetamol treatment.
• Caution is advised when paracetamol is used concomitantly with flucloxacillin, as co-administration has been associated with metabolic acidosis with a high anion gap, particularly in patients with risk factors (see section "Special warnings and precautions for use").

Special precautions for use.

RISK OF MEDICATION ERRORS Exercise caution to avoid dosing errors due to confusion between milligram (mg) and milliliter (mL), which may result in accidental overdose and death (see section "Dosage and Administration").

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

To avoid the risk of overdose, it is necessary to check whether other medicinal products being administered contain paracetamol or propacetamol. Dosage may require adjustment (see section "Dosage and administration").

Administration of the medicinal product in doses exceeding the recommended ones poses a risk of severe liver damage. Clinical signs and symptoms of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) usually become apparent only 2 days after administration of the medicinal product, with peak severity typically occurring on days 4–6. Antidote treatment should be initiated as soon as possible (see section "Overdose").

Paracetamol should be used with caution in:

• hepatic impairment;
• severe renal impairment (creatinine clearance ≤ 30 mL/min, see sections "Dosage and administration" and "Pharmacokinetics");
• chronic alcoholism;
• chronic malnutrition (low hepatic glutathione stores);
• dehydration;
• genetically determined deficiency of G-6-PD (favism), due to the possible development of hemolytic anemia caused by reduced glutathione availability following paracetamol administration.

Caution is recommended when using paracetamol concomitantly with flucloxacillin due to an increased risk of metabolic acidosis with a high anion gap, especially in patients with severe renal impairment, sepsis, malnutrition, and other sources of glutathione deficiency (e.g., chronic alcoholism), as well as in those receiving maximum daily doses of paracetamol. Close monitoring, including measurement of urinary 5-oxoproline, is recommended.

This medicinal product contains less than 1 mmol of sodium (23 mg) per 100 mL in the vial, i.e., it is practically sodium-free.

Use during pregnancy or breastfeeding.

Pregnancy

A large body of data on use in pregnant women indicates no malformations or fetotoxicity/neonatal toxicity. Epidemiological studies on neurological development in children exposed to paracetamol in utero have shown inconclusive results. If clinically indicated, paracetamol may be used during pregnancy; however, it should be used at the lowest effective dose, for the shortest possible duration, and with the least possible frequency.

Breastfeeding

After oral administration, paracetamol passes into breast milk in small amounts. No adverse effects in newborns have been reported. Therefore, Paracetamol B. Braun 10 mg/mL can be used in women who are breastfeeding.

Ability to influence reaction speed when driving or operating machinery.

No significant effect.

Method of Administration and Dosage

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

The 50 ml vial is intended only for children with body weight above 10 kg and up to 33 kg.

The 10 ml ampoule is intended only for full-term newborns, infants, and children with body weight up to 0.10 kg.

Dosage

The dose to be administered and the vial size depend exclusively on the patient's body weight. The volume administered must not exceed the specified dose. If necessary, the required volume should be diluted in an appropriate infusion solution prior to administration or administered using a syringe pump.

Paracetamol B. Braun 10 mg/ml may be used undiluted, or, if necessary, diluted in 9 mg/ml (0.9%) sodium chloride solution for infusion or in 50 mg/ml (5%) glucose solution for infusion, or in a combination of both solutions at a ratio of 1/10 paracetamol (one part of Paracetamol B. Braun 10 mg/ml solution to nine parts of diluent). For shelf life after dilution, see section "Shelf Life".

Table 2

Dosage according to patient's body weight

Ampoule 10 ml
Patient body weight	Dose per administration	Volume per administration	Maximum volume of the medicinal product Paracetamol B. Braun 10 mg/ml per administration depending on the upper limit of patient's body weight (ml)***	Maximum daily dose**
≤ 10 kg*	7.5 mg/kg	0.75 ml/kg	7.5 ml	30 mg/kg

Bottle 50 ml
Patient body weight	Dose per single administration	Volume per single administration	Maximum volume of Paracetamol B. Braun 10 mg/ml per single administration depending on the upper limit of patient's body weight (ml)***	Maximum daily dose**
> 10 kg, but ≤ 33 kg	15 mg/kg	1.5 ml/kg	49.5 ml	60 mg/kg (not more than 2 g)

Bottle 100 ml
Patient body weight	Dose per single administration	Volume per single administration	Maximum volume of Paracetamol B. Braun 10 mg/ml per single administration depending on the upper limit of patient body weight (ml)***	Maximum daily dose**
> 33 kg, but ≤ 50 kg	15 mg/kg	1.5 ml/kg	75 ml	60 mg/kg (no 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 newborns:

Data on safety and efficacy in premature newborns are lacking (see section "Pharmacokinetics").

** Maximum daily dose:

The maximum daily dose indicated applies to patients who are not receiving other medicinal products containing paracetamol; otherwise, the daily dose must be appropriately adjusted, taking into account the use of such medicinal products.

*** Patients with lower body weight require smaller volumes.

The minimum interval between administrations should be at least 4 hours. The minimum interval between administrations for patients with severe renal impairment should be at least 6 hours.

No more than 4 doses should be administered within 24 hours.

Severe renal impairment

When administering paracetamol to patients with severe renal dysfunction (creatinine clearance ≤ 30 mL/min), it is recommended to reduce the dose and extend the minimum interval between each administration to 6 hours (see section "Pharmacokinetics").

Adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low hepatic glutathione stores), dehydration

The maximum daily dose should not exceed 3000 mg (see section "Special precautions").

Administration method

Exercise caution when prescribing and administering Paracetamol B. Braun 10 mg/ml to avoid dosing errors due to confusion between milligrams (mg) and milliliters (ml), which may lead to accidental overdose and death. Ensure appropriate dose and administration. When writing prescriptions, indicate both the total dose in milligrams and the total volume in milliliters. Ensure that the dose is measured and administered accurately.

For intravenous use.

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

Patients with body weight ≤ 10 kg

The required volume should be withdrawn from the vial/ampoule and diluted in 0.9% sodium chloride solution (9 mg/mL) or 5% glucose solution (50 mg/mL), or a combination of both, to a 1/10 dilution of paracetamol (one-tenth of the volume of the Paracetamol B. Braun 10 mg/mL medicinal product solution in nine-tenths of the diluent) and administered over 15 minutes.

To measure the dose according to the child's body weight and desired volume, a 5 mL or 10 mL syringe should be used. However, the volume must never exceed 7.5 mL per dose.

To ensure correct dosing, the user must refer to the information provided in the product information.

Paracetamol B. Braun 10 mg/mL may be diluted with 0.9% sodium chloride solution (9 mg/mL) or 5% glucose solution (50 mg/mL), or a combination of both, to a 1/10 dilution of paracetamol (one-tenth of the volume of the Paracetamol B. Braun 10 mg/mL medicinal product solution in nine-tenths of the diluent). The diluted medicinal product must be used within 1 hour after preparation, including the infusion time.

The resulting solution is intended for single use only. Any unused solution should be discarded.

Before administration, the solution should be visually inspected for the presence of particles and discoloration. The solution should only be used if it is clear, colorless to pale pink-orange (perception may vary), free of particles, and the vial and its cap are undamaged.

As with any other infusion solution supplied in vials containing air, care must be taken to monitor the infusion carefully regardless of the method of administration; particular attention is required at the end of the infusion. This caution at the end of the infusion is especially relevant when administering the infusion into central veins, aiming to prevent air embolism.

Children.

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

The 50 mL vial is intended only for children with body weight greater than 10 kg and up to 33 kg.

The 10 mL ampoule is intended only for full-term newborns, infants, and children with body weight up to 10 kg.

Overdose.

Symptoms

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

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.

Overdose from a single dose of 7.5 g or more of paracetamol in adults or a single dose of 140 mg/kg body weight 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 death. Concurrently, elevated levels of liver transaminases (AST, ALT), lactate dehydrogenase, and bilirubin, along with decreased prothrombin levels, may appear 12–48 hours after administration. Clinical signs of liver damage typically first appear after two days and peak at 4–6 days.

Treatment

Immediate hospitalization.

A blood sample for plasma paracetamol analysis must be taken as soon as possible after overdose, and prior to initiating treatment.

Treatment includes administration of the antidote N-acetylcysteine (NAC) by intravenous or oral route, if possible, within 10 hours of overdose. However, NAC may still provide some protective effect even after 10 hours, but in such cases prolonged NAC treatment should be administered.

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 recovery of normal liver function. However, in very severe cases, liver transplantation may be required.

Adverse reactions.

As with the use of all paracetamol-containing medicinal products, adverse reactions occur rarely
(≥ 1/10,000 to 1/1,000) or very rarely (< 1/10,000), see Table 3.

Table 3

Systems or organs	Rare (≥ 1/10000 to < 1/1000)	Very rare (< 1/10000)	Unknown (cannot be estimated from available data)
Blood and lymphatic system disorders		Thrombocytopenia, leukopenia, neutropenia
Immune system disorders		Hypersensitivity reaction (1, 3)
Cardiac disorders			Tachycardia (2)
Vascular disorders	Hypotension		Flushing (2)
Hepatobiliary disorders	Increased levels of liver transaminases
Skin and subcutaneous tissue disorders		Serious skin reactions (3)	Pruritus (2), erythema (2)
General disorders and administration site reactions	Weakness

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

(2) Isolated cases.

(3) Very rare cases of serious skin reactions have been reported.

During clinical trials, adverse reactions at the injection site (pain and burning sensation) were frequently reported.

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

Shelf life.

Unopened

2 years

After first opening

Infusion must be started immediately after connecting the vial to the infusion system.

After dilution

Chemical and physical in-use stability of the solution (including administration time) has been maintained for 48 hours at 23 °C.

To avoid microbiological contamination, the medicinal product should be used immediately. If not used immediately, the responsibility for storage duration and conditions prior to use lies with the user.

Storage conditions.

Store at a temperature not exceeding 25 °C.

Keep out of reach of children.

Store in the original packaging to protect from light.

Incompatibilities.

Paracetamol B. Braun 10 mg/mL must not be mixed with other medicinal products except those specified in the section "Dosage and administration".

Prescription status.

Prescription only.

Packaging.

10 ml in ampoules; 20 ampoules in a cardboard box.

50 ml or 100 ml in vials; 10 vials in a cardboard box.

Manufacturer.

B. Braun Medical S.A./B. Braun Medical SA.

Manufacturer's address and location of operations.

Carretera de Terrassa 121, 08191 Rubí (Barcelona), Spain / Carretera de Terrassa 121, 08191 Rubi (Barcelona), Spain.