4.1. Therapeutic indications

Paracetamol is indicated for:

● short-term treatment of moderate pain, especially following surgery,

● 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

The 100 ml bottle is restricted to adults, adolescents and children weighing more than 33 kg.

The 50 ml bottle is restricted to toddlers and children weighing more than 10 kg and up to 33 kg.

The 10 ml ampoule is restricted to term newborn infants, infants and toddlers weighing up to 10 kg.

Posology:

The dose to be administered and the bottle size to be used depend exclusively on the patient`s weight. The volume to be administered must not exceed the determined dose. If applicable the desired volume must be diluted in a suitable solution for infusion prior to administration (see section 6.6) or a syringe driver must be used.

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

10 ml ampoule

Patient weight

Dose per administration

Volume per administration

Maximum volume of Paracetamol (10 mg/ml) per administration based on upper weight limits of group (ml)***

Maximum daily dose**

≤ 10 kg*

7.5 mg/kg

0.75 ml/kg

7.5 ml

30 mg/kg

50 ml bottle

Patient weight

Dose per administration

Volume per administration

Maximum volume of Paracetamol (10 mg/ml) per administration based on upper weight limits of group (ml)***

Maximum daily dose**

> 10 kg to ≤ 33 kg

15 mg/kg

1.5 ml/kg

49.5 ml

60 mg/kg not exceeding 2 g

100 ml bottle

Patient weight

Dose (per administration)

Volume per administration

Maximum volume of Paracetamol (10 mg/ml) per administration based on upper weight limits of group (ml)***

Maximum daily dose**

> 33 kg to ≤ 50 kg

15 mg/kg

1.5 ml/kg

75 ml

60 mg/kg not exceeding 3 g

> 50 kg with additional risk factors for hepatotoxicity

1 g

100 ml

100 ml

3 g

> 50 kg and no additional risk factors for hepatotoxicity

1 g

100 ml

100 ml

4 g

* Preterm newborn infants:

No safety and efficacy data are available for premature newborn infants (see also section 5.2)

** 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.

The minimum interval between each administration in patients with severe renal insufficiency must be at least 6 hours.

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

Severe renal insufficiency:

It is recommended, when giving paracetamol to patients with severe renal impairment (creatinine clearance ≤ 30 ml/min), to reduce the dose and increase the minimum interval between each administration to 6 hours (See section 5.2).

Adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), dehydration:

The maximum daily dose must not exceed 3000 mg (see section 4.4).

Method of administration

Take care when prescribing and administering Paracetamol 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.

Intravenous use.

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

Patients weighing ≤10 kg:

● The volume to be administered should be withdrawn from the ampoule and diluted in a sodium chloride 9 mg/ml (0.9%) solution or glucose 50 mg/ml (5%) solution or a combination of both solutions up to one tenth (one volume Paracetamol into nine volumes diluent) and administered over 15 minutes. See also section 6.6

● A 5 or 10 ml syringe should be used to measure the dose as appropriate for the weight of the child and the desired volume. However, this should never exceed 7.5 ml per dose

● The user should be referred to the product information for dosing guidelines.

Paracetamol can be diluted in a 9 mg/ml (0.9%) sodium chloride solution or 50 mg/ml (5%) glucose solution or a combination of both solutions up to one tenth (one volume Paracetamol into nine volumes diluent). In this case, use the diluted solution within the hour following its preparation (infusion time included).

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

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

Before administration, the product should be visually inspected for any particulate matter and discolouration. Only to be used if solution is clear, colourless or slightly pinkish-orangish (perception may vary) and the container and its closure are undamaged.

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

4.3. Contraindications

● Hypersensitivity to paracetamol, propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients listed in section 6.1.

● Cases of severe hepatocellular insufficiency.

4.4. Special warnings and precautions for use

RISK OF MEDICATION ERRORS

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

Prolonged or frequent use is discouraged. It is recommended that a suitable analgesic oral treatment will be used as soon as this route of administration is possible.

In order to avoid the risk of overdose, check that other medicines administered do not contain either paracetamol or propacetamol. The dose may require adjustment (see section 4.2).

Doses higher than those recommended entail the risk of very serious liver damage. Clinical signs and symptoms of liver damage (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis) are usually first seen after two days of drug administration with a peak seen, usually after 4 – 6 days. Treatment with antidote should be given as soon as possible (See section 4.9).

Paracetamol should be used with caution in cases of:

● hepatocellular insufficiency

● severe renal insufficiency (creatinine clearance ≤ 30 ml/min) (see sections 4.2 and 5.2)

● chronic alcoholism

● chronic malnutrition (low reserves of hepatic glutathione)

● dehydration

● 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.

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.

This medicinal product contains less than 1 mmol sodium (23 mg) per container , i.e. essentially 'sodium- free'.

4.5. Interaction with other medicinal products and other forms of interaction

● Probenecid causes an almost two-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 should be taken with the concomitant intake of enzyme-inducing substances (see section 4.9).

● Concomitant use of paracetamol (4 000 mg 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 risks factors (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy:

A large amount of data on 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.

Lactation:

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 breast-feeding women.

4.7. Effects on ability to drive and use machines

Not relevant.

4.8. Undesirable effects

As with all paracetamol products, adverse drug reactions are rare (≥ 1/10 000 to <1/1 000) or very rare (<1/10 000). They are described below:

System Organ Class

Rare (≥1/10 000 to <1/1 000)

Very rare (<1/10 000)

Not known (cannot be estimated from the available data)

Blood and lymphatic system disorders

—

Thrombocytopenia, Leucopenia, Neutropenia

—

Immune system disorders

—

Hypersensitivity reaction (1, 3)

—

Metabolism and nutrition disorders

High anion gap metabolic acidosis

Cardiac disorders

—

—

Tachycardia (2)

Vascular disorders

Hypotension

—

Flushing (2)

Hepatobiliary disorders

Increased levels of hepatic trans­aminases

—

—

Skin and subcutaneous tissue disorders

—

serious skin reactions (3)

Pruritus (2), Erythema (2)

General disorders and administration site conditions

Malaise

—

—

(1) Very rare cases of hypersensitivity reactions ranging from simple skin rash or urticaria to anaphylactic shock have been reported and require discontinuation of treatment.

(2) Isolated cases

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

Description of selected adverse reactions

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.

Frequent adverse reactions at injection site have been reported during clinical trials (pain and burning sensation).

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 at: www.mhra.gov.uk/yellowcard.

4.9. Overdose

Symptoms

There is a risk of liver injury (including fulminant hepatitis, hepatic failure, cholestatic hepatitis, cytolytic hepatitis), particularly in elderly subjects, in young children, in patients with liver disease, in cases of chronic alcoholism, in patients with chronic malnutrition and in patients receiving enzyme inducers. Overdosing may be fatal in these cases.

Symptoms generally appear within the first 24 hours and comprise: nausea, vomiting, anorexia, pallor and abdominal pain. Immediate emergency measures are necessary in case of paracetamol overdose, even when no symptoms are present.

Overdose, 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 children, causes hepatic cytolysis likely to induce complete and irreversible necrosis, resulting in hepatocellular insufficiency, metabolic acidosis and encephalopathy which may lead to coma and death. Simultaneously, increased levels of hepatic transaminases (AST, ALT), lactate dehydrogenase and bilirubin are observed together with decreased prothrombin levels that may appear 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.

Treatment

Immediate hospitalisation.

Before beginning treatment, take a blood sample for plasma paracetamol assay, as soon as possible after the overdose.

The treatment includes administration of the antidote, N-acetylcysteine (NAC) by the intravenous or oral route, if possible before the 10th hour. NAC can, however, give some degree of protection even after 10 hours, but in these cases prolonged treatment is given.

Symptomatic treatment.

Hepatic tests must be carried out at the beginning of treatment and repeated every 24 hours. In most cases hepatic transaminases restitution to normal in one to two weeks with full return of normal liver function. In very severe cases, however, liver transplantation may be necessary.