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

> 10 kg to

≤ 33 kg

15 mg/kg

1.5 ml/kg

49.5 ml

60 mg/kg

not exceeding 2g

> 33 kg to

≤ 50 kg

15 mg/kg

1.5 ml/kg

75 ml

60 mg/kg

not exceeding 3g

> 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 milliliter (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The volume to be administered should be withdrawn from the container and diluted in a sodium chloride 9 mg/ml (0.9%) solution or glucose 50 mg/ml (5%) solution or a combination of both solutions up to one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 the 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 to slightly pinkish-orangish (perception may vary) and the container and its closure are undamaged. Colouration can intensify over time without adversely affecting the quality of the product.

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.

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.

As common practice in infusion therapy it is advisable to observe the patient for the occurrence of allergic reactions to the active ingredient or to the excipients (e.g. hydroxyethyl starch) (see also section 4.8).

This medicinal product contains 12.2 mg (0.53 mmol) sodium in 10 ml, 61mg (2.7 mmol) sodium in 50 ml and 122 mg (5.3 mmol) of sodium in 100ml. To be taken into account for patients on a controlled sodium diet The 10 ml ampoule contains less than 1 mmol sodium (23 mg), i.e. essentially sodium free.

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 par- acetamol treatment has been discontinued.

Pregnancy:

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

Prospective data on pregnancies exposed to overdoses did not show any increase in the risk of malformation.

No reproductive studies with the intravenous form of paracetamol have been performed in animals. However, studies with the oral route did not show any malformation or 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.

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:

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.

Independent of the presence and severity of possible hepatic impairment, symptoms of acute renal impairment may develop in case of an overdose.

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, in- creased 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 hospitalization

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.

Mechanism of action

The precise mechanism of the analgesic and antipyretic properties of paracetamol has still to be established; it may involve central and peripheral actions.

Pharmacodynamic effects

Paracetamol provides onset of pain relief within 5 to 10 minutes after the start of administration. The peak analgesic effect is obtained in 1 hour and the duration of this effect is usually 4 to 6 hours.

Paracetamol reduces fever within 30 minutes after the start of administration with a duration of the antipyretic effect of at least 6 hours.

Adults

Absorption:

Paracetamol pharmacokinetics is linear up to 2 g after single administration and after repeated administration during 24 hours.

The 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 (containing 500mg and 1 g paracetamol respectively). The maximal plasma concentration (Cmax) of paracetamol observed at the end of 15-minutes 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 1l/kg.

Paracetamol is not extensively bound to plasma proteins. Following infusion of 1 g paracetamol, significant concentrations of paracetamol (about 1.5 μg/ml) were observed in the cerebrospinal fluid at and after the 20th minute following infusion.

Biotransformation:

Paracetamol is metabolized mainly in the liver following two major hepatic pathways: glucuronic acid conjugation and sulphuric acid con- jugation. The latter route is rapidly saturable at doses that exceed the therapeutic doses. A small fraction (less than 4%) is metabolized by cy- tochrome P450 to a reactive intermediate (N-acetyl benzoquinone imine) which, under normal conditions of use, is rapidly detoxified by reduced glutathione and eliminated in the urine after conjugation with cysteine and mercapturic acid. However, during massive overdosing, 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.

Newborn infants, infants and children:

The pharmacokinetic parameters of paracetamol observed in infants and children are similar to those observed in adults, except for the plasma half-life that is slightly shorter (1.5 to 2 h) than in adults. In newborn infants, the plasma half-life is longer than in infants i.e. around 3.5 hours. Newborn infants, infants and children up to 10 years excrete significantly less glucuronide and more sulphate conjugates than adults.

Table - Age related pharmacokinetic values (standardised clearance, *CLstd/Foral×(l×h-1×70 kg-1)

* CLstd is the population estimate for CL

Special populations:

Renal insufficiency:

In cases of 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 slower in subjects with severe renal impairment than in healthy subjects. Therefore when giving paracetamol to patients with severe renal impairment (creatinine clearance ≤30ml/min),the minimum interval between each administration should be increased to 6 hours (see section4.2).

Elderly subjects:

The pharmacokinetics and the metabolism of paracetamol are not modified in elderly subjects. No dose adjustment is required in this population.

Non-clinical data reveal no special hazard for humans beyond the information included in other sections of the Directions for Use.

Studies on local tolerance of paracetamol in rats and rabbits showed good tolerability. Absence of delayed contact hypersensitivity has been tested in guinea pigs.

Mannitol

Hydroxyethyl starch

Sodium acetate trihydrate

 Sodium citrate dihydrate

Acetic acid glacial (for pH adjustment)

Water for injections

Bottles of low-density polyethylene; contents: 50 ml, 100 ml

Pack size: 10 × 50 ml, 10 × 100 ml

Not all pack sizes may be marketed