Paracetamol 10 mg/ ml solution for infusion – Summary of Product Characteristics (SmPC) for healthcare professionals

1 NAME OF THE MEDICINAL PRODUCT

Paracetamol 10 mg/ ml solution for infusion

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each 1 ml of solution contains 10 mg paracetamol.

Each bottle of 100 ml contains 1000 mg paracetamol.

For the full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Solution for infusion

The solution is clear, colourless and free of visible particles The pH is between 5.2 and 6.0

Osmolality is 250 to 330 mOsm/kg

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

Paracetamol is indicated for the short-term treatment of moderate pain, especially following surgery and for the short-term treatment of fever, when administration by intravenous route is clinically justified by an urgent need to treat pain or hyperthermia and/or when other routes of administration are not possible.

4.2 Posology and method of administration

Intravenous use.

This medicinal product is restricted to adults, adolescents and children weighing more than 33 kg.

Posology:

Dosing based on patient weight (please see the dosing table here below):

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

**Patients weighing less will require smaller volumes.

• The minimum interval between each administration must be at least 4 hours.

• No more than 4 doses to be given in 24 hours.

  Renal impairment

  In patients with renal insufficiency, the minimum interval between each administration must be modified according to the following scheme:

Hepatic impairment

In adult patients with chronic liver failure or compensated active liver disease, hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low hepatic glutathione reserves), dehydration, Gilbert’s disease or weighing less than 50 kg, the maximum daily dose must not exceed 3 g (see section 4.4).

Older patients

Dose adjustment is not required in the elderly. However, it should be taken into account that renal and/or hepatic insufficiency is more common in patients above 65 years of age (see section 5.2).

Method of administration:

Take care when prescribing and administering Paracetamol 10 mg/ml solution for infusion to avoid dosing errors due to confusion between milligram (mg) and millilitre (mL), which could result in accidental overdose and death. Take care to ensure the proper dose is communicated and dispensed. When writing prescriptions, include both the total dose in mg and the total dose in volume. Take care to ensure the dose is measured and administered accurately.

Before administration, the product should be visually inspected for any particulate matter and discolouration.

The paracetamol solution is administered as a 15-minute intravenous infusion.

For instruction on dilution of the medicinal product before administration, see section 6.6.

4.3 Contraindications

• Hypersensitivity to the active substance, propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients listed in section 6.1
• Severe hepatocellular insufficiency (Child-Pugh >9)

4.4 Special warnings and precautions for use

Warnings

RISK OF MEDICATION ERRORS

Take care to avoid dosing errors due to confusion between milligram (mg) and millilitre (mL), which could result in accidental overdose and death (see section 4.2).

It is recommended to use a suitable analgesic oral treatment as soon as this route of administration is possible.

In order to avoid the risk of overdose, check that no other medicinal products administered prescription or non-prescription contain paracetamol or propacetamol hydrochloride.

Doses higher than those recommended entail the risk of very serious liver damage. Clinical signs and symptoms of hepatic damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are not usually seen until two days, and up to a maximum of 4-6 days, after administration. Treatment with antidote should be given as soon as possible (see section 4.9).

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

Cases of high anion gap metabolic acidosis (HAGMA) due to pyroglutamic acidosis have been reported in patients with severe illness such as severe renal impairment and sepsis, or in patients with malnutrition or other sources of glutathione deficiency (e.g. chronic alcoholism) who were treated with paracetamol at therapeutic dose for a prolonged period or a combination of paracetamol and flucloxacillin. If HAGMA due to pyroglutamic acidosis is suspected, prompt discontinuation of paracetamol and close monitoring is recommended. The measurement of urinary 5-oxoproline may be useful to identify pyroglutamic acidosis as underlying cause of HAGMA in patients with multiple risk factors.

If flucloxacillin is continued after cessation of paracetamol, it is advisable to ensure that there are no signals of HAGMA, as there is a possibility of flucloxacillin maintaining the clinical picture of HAGMA (see section 4.5).

As for all solutions for infusion, close monitoring is needed notably at the end of the infusion to avoid air embolism (see section 6.6).

Paracetamol should be used with particular caution under the following circumstances:

• Abnormal Liver Function and Hepatocellular insufficiency (Child-Pugh

  ≤9)

• Hepatobiliary disorders
• Meulengracht Gilbert Syndrome (familial non-haemolytic jaundice)
• Severe renal insufficiency (creatinine clearance 10-30 ml/min), see sections 4.2 and 5.2
• Chronic alcohol abuse
• Chronic malnutrition (low reserves of hepatic glutathione)
• Total parenteral nutrition (TPN) use
• Use of enzyme inducers
• Use of hepatotoxic agents

• In patients suffering from a genetically caused G-6-PD deficiency

  (favism) the occurrence of a haemolytic anaemia is possible due to the reduced allocation of glutathione following the administration of paracetamol.

• Dehydration

Effects on laboratory tests

Paracetamol can affect tests for uric acid using phosphotungstic acid and blood sugar tests using glucose-oxidase-peroxidase.

Excipients with known effect

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, that is to say essentially “sodium free”.

4.5 Interaction with other medicinal products and other forms of interaction

• Probenecid causes an almost 2-fold reduction in clearance of paracetamol by inhibiting its conjugation with glucuronic acid. A reduction in the paracetamol dose should be considered if it is to be used concomitantly with probenecid.
• Salicylamide may prolong the elimination half-life of paracetamol.
• Caution is advised when medicinal products with enzyme-inducing properties are administered concomitantly. Such substances include, but are not limited to, rifampicin and barbiturates. Other medicinal products that interact with, or are substrates of, hepatic cytochrome enzymes – for example tricyclic antidepressants, isoniazid and certain antiepileptics (including carbamazepine, phenytoin, phenobarbital and primidone) – should also be co-administered with caution.
• Isolated reports describe unexpected hepatotoxicity in patients taking alcohol or enzymeinducing medicinal products (see section 4.9).
• Concurrent administration of paracetamol and chloramphenicol may prolong the action of chloramphenicol.

• Concurrent administration of paracetamol and AZT (zidovudine)

  enhances the tendency to neutropenia.

• Concurrent administration of paracetamol and oral contraceptives may reduce the elimination half-life of paracetamol.
• Concomitant use of paracetamol (4 g per day for at least 4 days) with oral anticoagulants may lead to slight variations of INR values. In this case, increased monitoring of INR values should be conducted during the period of concomitant use as well as for 1 week after paracetamol treatment has been discontinued.

• Caution should be taken when paracetamol is used concomitantly with flucloxacillin as

  concurrent intake has been associated with high anion gap metabolic acidosis due to pyroglutamic acidosis, especially in patients with risk factors (see section 4.4.).

4.6 Fertility, pregnancy and lactation

Pregnancy:

Clinical experience of intravenous administration of paracetamol is limited. However, a large amount of data from the use of oral therapeutic doses of paracetamol in pregnant women indicate neither malformative, nor feto/neonatal toxicity.

Epidemiological studies on neurodevelopment in children exposed to paracetamol in utero show inconclusive results. If clinically needed, paracetamol can be used during pregnancy however it should be used at the lowest effective dose for the shortest possible time and at the lowest possible frequency.

Breast-feeding:

After oral administration, paracetamol is excreted into breast milk in small quantities. No undesirable effects on nursing infants have been reported. Consequently, Paracetamol may be used in breastfeeding women.

Fertility:

Reproductive toxicity has not been fully evaluated (see section 5.3).

4.7 Effects on ability to drive and use machines

Paracetamol has no or negligible influence on the ability to drive and use machines.

4.8 Undesirable effects

The evaluation of undesirable effects is based on the following definition of frequency:

Very common ≥1/10

Common ≥1/100 to <1/10

Uncommon ≥1/1 000 to <1/100

Rare ≥1/10 000 to <1/1 000

Very rare <1/10 000

Not known Frequency cannot be estimated from the available

data

As with all paracetamol containing medicinal products, undesirable effects are rare or very rare. They are described in the following table:

* Very rare cases of hypersensitivity reactions in the form of anaphylactic shock, urticaria, skin rash have been reported and require discontinuation of treatment.

** High anion gap metabolic acidosis: Cases of high anion gap metabolic acidosis due to pyroglutamic acidosis have been observed in patients with risk factors using paracetamol (see section 4.4). Pyroglutamic acidosis may occur as a consequence of low glutathione levels in these patients.

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

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any

suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

At particular risk for hepatic damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are elderly patients, young children, patients with hepatic disorders, chronic alcoholism, chronic malnutrition and patients concurrently receiving medicinal products that lead to enzyme induction. In such cases, overdose may be fatal.

Symptoms of overdose

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

Overdose with 7.5 g or more of paracetamol in a single administration in adults or 140 mg/kg of body weight in a single administration in paediatric patients, leads to hepatic cell necrosis, which can cause complete and irreversible necrosis and subsequently hepatocellular insufficiency, metabolic acidosis and encephalopathy. This, in turn, can lead to coma, sometimes with fatal outcome. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin in combination with decreased prothrombin levels are observed, which may occur 12 to 48 hours after administration. Clinical symptoms of hepatic damage are usually evident after two days and reach a maximum after 4 to 6 days.

Acute renal failure with acute tubular necrosis may also develop. Cardiac arrhythmias and pancreatitis have also been reported.

Treatment of overdose

• Immediate hospitalisation
• Before initiating treatment, and as soon as possible following the overdose, a blood sample for determination of plasma paracetamol levels should be taken.

• The treatment includes administration of the antidote, N-acetylcysteine

  (NAC) either by the intravenous or the oral route, if possible during the first 10 hours. N-acetylcysteine can also offer some degree of protection even after 10 hours, but in this case prolonged treatment will be required.

• Symptomatic treatment
• Liver function tests must be carried out at the beginning of treatment and repeated every 24 hours. Usually, hepatic transaminases return to normal in one to two weeks with full recovery of normal liver function. In very severe cases, however, liver transplantation may be necessary.
• Haemodialysis can reduce the plasma paracetamol concentration, but the effects are limited.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Other analgesics and antipyretics, anilides, ATC code: N02BE01

Mechanism of action

The precise analgesic and antipyretic mode of action of paracetamol has not been established. A central and peripheral effect is likely.

Pharmacodynamic effects

Paracetamol provides onset of pain relief within 5 to 10 minutes following administration. The peak analgesic effect is obtained within 1 hour and analgesia usually persists 4 to 6 hours.

Paracetamol reduces fever within 30 minutes following administration. The antipyretic effect persists for at least 6 hours.

5.2 Pharmacokinetic properties

Adults

Absorption

Following single and repeated administration during 24 hours paracetamol pharmacokinetics is linear up to 2 g.

Bioavailability of paracetamol following infusion of 500 mg and 1 g of paracetamol is similar to that observed following infusion of 1 g and 2 g propacetamol (corresponding to 500 mg and 1 g paracetamol), respectively. The maximal plasma concentration (C_max) of paracetamol observed at the end of a 15-minute intravenous infusion of 500 mg and 1 g of paracetamol is about 15 μg/ml and 30 μg/ml, respectively.

Distribution

The volume of distribution of paracetamol is approximately 1 l/kg. Paracetamol is not extensively bound to plasma proteins (about 10 %). Twenty minutes following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 µg/ml) were observed in the cerebrospinal fluid.

Biotransformation

Paracetamol is mainly metabolised in the liver following two major hepatic pathways: conjugation with glucuronic acid and sulphuric acid. At doses that exceed the therapeutic dose, the latter route is rapidly saturated. A small fraction (less than 4 %) is metabolised by cytochrome P450 to a reactive intermediate

(N-acetyl benzoquinone imine) which, with normal dosing, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugation with cysteine and mercapturic acid. However, in the event of massive overdose, the quantity of this toxic metabolite is increased.

Elimination

The metabolites of paracetamol are mainly excreted in the urine. 90 % of the dose administered is excreted within 24 hours, mainly as glucuronide (60-80 %) and sulphate (20-30 %) conjugates. Less than 5 % is eliminated unchanged. Plasma half-life is 2.7 hours and total body clearance is 18 l/h.

Special population

Renal insufficiency

In severe renal impairment (creatinine clearance 10-30 ml/min), the elimination of paracetamol is slightly delayed, the elimination half-life ranging from 2 to 5.3 hours. For the glucuronide and sulphate conjugates, the elimination rate is 3 times lower in subjects with severe renal impairment than in healthy subjects. Therefore, when giving paracetamol to patients with severe renal impairment (creatinine clearance 10-50 ml/min), the minimum interval between each administration should be increased to 6 hours (see section 4.2).

Elderly

The pharmacokinetics and metabolism of paracetamol are not altered in elderly. No dose adjustment is required in this patient population.

5.3 Preclinical safety data

Preclinical data reveal no special hazard for humans beyond the information included in other sections of the SmPC. Studies on local tolerance of paracetamol solution for infusion in rats and rabbits showed good tolerability. Absence of delayed contact hypersensitivity has been tested in guinea pigs.

Conventional studies using the currently accepted standards for the evaluation of toxicity to reproduction and development are not available.

Paracetamol was found to be noncarcinogenic in male rats as well as in male and female mice. Equivocal evidence of carcinogenic activity was noted for female rats based on an increased incidence of mononuclear cell leukemia.

A comparative review of the literature on paracetamol genotoxicity and carcinogenicity showed that genotoxic effects of paracetamol appear only at dosages above the recommended range resulting in severe toxic effects including pronounced liver and bone marrow toxicity. The threshold level for genotoxicity is not reached at therapeutic dosages of paracetamol.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Mannitol (E421)

Sodium citrate dihydrate

Monothioglycerol

Acetic acid (for pH adjustment)

Sodium hydroxide (for pH adjustment)

Water for Injections

6.2 Incompatibilities

This medicinal product must not be mixed with other medicinal products except those mentioned in section 6.6.

6.3 Shelf life

Bottle before opening

2 years

After first opening

Chemical and physical in-use stability has been demonstrated for 24 hours at 25°C.

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

After dilution:

Shelf life after dilution with sodium chloride 9 mg/ml (0.9%) solution or 50 mg/ml glucose (5%) solution or mixture of both: Chemical and physical in-use stability has been demonstrated for 48 hours up to 30 °C.

From a microbiological point of view, unless the method of opening precludes the risk of microbial contamination, the product should be used immediately. If not used immediately, in-use storage times and conditions prior to use are the responsibility of the user.

6.4 Special precautions for storage

Keep the bottles in the outer carton in order to protect from light.

For storage conditions of the diluted medicinal product, see section 6.3.

6.5 Nature and contents of container

LDPE bottles are closed with a cap containing an administration and an addition port, which are two separate, clearly identifiable ports for infusion and injection. A rubber disk allows insertion of the needle.

Pack sizes:

10 x 100 ml

40 x 100 ml

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

For single use only. Any unused solution should be discarded.

Handling

As for all solutions for infusion presented in bottles, it should be remembered that close monitoring is needed notably at the end of the infusion, regardless of infusion route. This monitoring at the end of the infusion applies particularly for central route infusions, in order to avoid air embolism.

Compatibility

Paracetamol 10 mg/ml solution for infusion can be diluted in sodium chloride 9 mg/ml (0.9 %) solution or 50 mg/ml glucose (5 %) solution up to one tenth (one volume Paracetamol 1000 mg/100 ml solution for infusion into nine volumes diluent) or a mixture of both.

The diluted solution should be visually inspected and should not be used in the presence of opalescence, visible particulate matter or precipitate.

Disposal

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7 MARKETING AUTHORISATION HOLDER

Fresenius Kabi Limited

Cestrian Court

Eastgate Way,

Manor Park

Runcorn, Cheshire,

WA7 1NT, United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL 08828/0393

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

04/08/2026

10 DATE OF REVISION OF THE TEXT

04/08/2026