4.1. Therapeutic indications

• Short-term treatment of moderate pain, especially following surgery,

• Short-term treatment of fever, when the 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 vial is restricted to adults, adolescents and children weighing more than 33 kg.

The 50 ml vial is adapted to term newborn infants, infants, toddlers and children weighing less than 33 kg.

Posology

Dosing based on patient weight - see the dosing table below.

Patient weight

Dose per administration

Volume per administration

Maximum volume 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

> 10 kg to ≤ 33 kg

15 mg/kg

1.5 ml/kg

49.5 ml

60 mg/kg not exceeding 2 g

> 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

*Pre-term newborn infants: No safety and efficacy data are available for pre-term newborn infants (see section 5.2).

** Patients weighing less will require smaller volumes.

*** 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.

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

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

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

Elderly

Dose adjustment is not required in elderly people (see section 5.2).

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 3 g (see section 4.4).

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.

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

Patients weighing < 10 kg:

• The glass vial should not be hung as an infusion due to the small volume of the medicinal product to be administered in this population.

• The volume to be administered should be withdrawn from the vial and could be administered undiluted or diluted (one volume into nine volumes diluent) in a 0.9% sodium chloride solution or 5% glucose solution and administered over 15 minutes. Use the diluted solution within the hour following its preparation (infusion time included). 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.

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.

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.

50ml vial only

Paracetamol can be diluted in a 0.9% sodium chloride solution or 5% glucose solution (one volume into nine volumes diluent). In this case, use the diluted solution within the hour following its preparation (infusion time included).

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 millilitre (ml), which could result in accidental overdose and death (see section 4.2).

Appropriate oral analgesia is recommended as soon as this route of administration can be used.

To avoid any risk of overdose, the absence of paracetamol or propacetamol from the composition of other concomitant medicinal products must be checked.

Doses higher than those recommended cause a risk of very severe liver damage. The symptoms and clinical signs of liver damage (including fulminant hepatitis, hepatic insufficiency, cholestatic hepatitis, cytolytic hepatitis) are generally observed after 2 days and normally reach their peak within 4 to 6 days. Treatment with an antidote should be administered 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.

As for all solutions for infusion presented in glass vials, a close monitoring is needed notably at the end of the infusion (see section 4.2).

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.

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

Excipients

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 paid to the concomitant intake of enzyme-inducing substances. These substances include, but are not limited to, barbiturates, isoniazid, carbamazepine, rifampicin and ethanol (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, especially in patients with high risk factors (see section 4.4).

4.6. Fertility, pregnancy and lactation

Pregnancy

Clinical experience of intravenous administration of paracetamol is limited. However, epidemiological data from the use of oral therapeutic doses of paracetamol indicate no undesirable effects on the pregnancy or on the health of the foetus / newborn infant.

Prospective data on pregnancies exposed to overdoses did not show an increase in malformation risk.

Reproductive studies with the intravenous form of paracetamol have not been performed in animals. However, studies with the oral route did not show any malformation of foetotoxic effects.

Nevertheless, paracetamol should only be used during pregnancy after a careful benefit-risk assessment. In this case, the recommended posology and duration must be strictly observed.

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

The frequency of adverse events listed below is defined using the following convention:

Common (≥1/100 to <1/10); Rare (≥ 1/10,000 to < 1/1,000); Very rare (< 1/10,000), Not known (cannot be estimated from the available data).

System Organ Class

Common

Rare

Very rare

Not known

Blood and lymphatic system disorders

Thrombocytopenia,

Leucopenia,

Neutropenia

Immune system disorders

Hypersensitivity reaction (1)

Anaphylactic shock (1)

Metabolism and nutrition disorders

High anion gap metabolic acidosis (HAGMA) (4)

Cardiac disorders

Tachycardia (2)

Vascular disorders

Hypotension

Flushing (2)

Hepatobiliary disorders

Increased levels of hepatic transaminases

Skin and subcutaneous tissue disorders

Rash (1), Urticaria (1), Serious skin reactions (3)

Pruritus (2),

Erythema (2)

General disorders and administration site conditions

Administration site reaction (pain and burning sensation)

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 and required discontinuation of treatment.

(4) Post marketing experience when paracetamol is used concomitantly with flucloxacillin; generally in the presence of risk factors (see section 4.4).

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 authorization 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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

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.