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SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Paracetamol 10 mg/ml solution for infusion

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

1 ml contains 10 mg paracetamol.

Each 50 ml vial or bag contains 500 mg paracetamol.

Each 100 ml vial or bag contains 1000 mg paracetamol.

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Solution for infusion

Clear and slightly yellowish solution.

The solution is iso-osmotic and its pH is between 5.0 and 7.0.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Paracetamol 10 mg/ml solution for infusion is indicated for:

•    the short-term treatment of moderate pain, especially following surgery,

•    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.

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

The 50 ml vial or bag is restricted to term newborn infants, infants, toddlers and children weighing up to 33 kg.

Posology:

Patient weight	Dose per administration	Volume per administration	Maximum volume of Paracetamol 10 mg/ml solution for infusion per administration based on upper weight limits of group (mL)1	Maximum Daily Dose2
10 kg3	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 and 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

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

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.

Patient weighing < 10 kg:

•    The glass vial or bag of Paracetamol 10 mg/ml solution for infusion should not be hung as an infusion due to the small volume of medicinal product to be administered in this population

•    The volume to be administered should be withdrawn from the vial or bag and diluted in 0.9% sodium chloride solution or 5% glucose solution up to one tenth (one volume Paracetamol 10 mg/ml solution for infusion into nine volumes diluent) and administered over 15 minutes

•    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 dilution of Paracetamol 10 mg/ml solution for infusion see section 6.6.

Contraindications

•    Hypersensitivity to the active substance, propacetamol hydrochloride (prodrug of paracetamol) or to any of the excipients ⁴

4.4 Special warnings and precautions for use

Warnings

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 do 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 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 <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.

Effects on laboratory tests

Paracetamol can affect tests for uric acid using phosphotungstic acid and blood sugar

tests using glucose-oxidase-peroxidase.

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.

•    The metabolism of paracetamol is impaired in patients taking enzyme-inducing medicinal products such as rifampicin, barbiturates, tricyclic antidepressants, and some antiepileptics (carbamazepine, phenytoin, phenobarbital, primidone).

•    Isolated reports describe unexpected hepatotoxicity in patients taking alcohol or enzyme-inducing 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.

4.6 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 or foetotoxic effects. Nevertheless, Paracetamol 10 mg/ml solution for infusion 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 10 mg/ml solution for infusion may be used in breast-feeding women.

4.7    Effects on ability to drive and use machines

Paracetamol 10 mg/ml solution for infusion has no 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:

>1/10

>1/100 to <1/10 >1/1,000 to <1/100 >1/10,000 to <1/1,000 <1/10,000

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:

System organ class	Rare	Very rare	Not known
Blood and lymphatic system disorders		Thrombocytopenia, leukopenia, neutropenia, agranulocytosis
Immune system disorders		Hypersensitivity (ranging from simple skin rash or urticaria to anaphylactic shock which requires immediate discontinuation of treatment), bronchospasm
Cardiac disorders			Tachycardia
Vascular disorders	Hypotension
Skin and subcutaneous tissue disorders			Erythema, flushing, pruritus
General disorders	Malaise

and administration site conditions
Investigations	Transaminases increased

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.

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. ⁵

5.1    Pharmacodynamic properties

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

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

Paracetamol 10 mg/ml solution for infusion 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 10 mg/ml solution for infusion 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 pg/ml and 30 pg/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 pg/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 halflife 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 hours) 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, *CL_std/F_oral (l.h^-1 70 kg^-1)

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

*CL_std is the population estimate for CL

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 <30 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.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Cysteine Mannitol (E421)

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

Vial or bag before opening 24 months

After_first opening

Chemical and physical in-use stability has been demonstrated for 24 hours at room temperature.

From a microbiological point of view, 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 and would normally not be longer than 24 hours, unless opening and storage have taken place in controlled and validated aseptic conditions.

If diluted in sodium chloride 9 mg/ml (0.9 %) solution or 50 mg/ml glucose (5 %) solution, the solution should also be used immediately.

However, if the diluted solution is not used immediately, do not store for more than 6 hours (infusion time included).

6.4    Special precautions for storage

Do not refrigerate or freeze.

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

6.5    Nature and contents of container

50 ml and 100 ml Type II glass vials closed with halobutyl stoppers and aluminium/plastic flip-off caps.

50 ml and 100 ml bags with the primary film, administration port (infusion port) and addition port (injection port) consisting of a polyolefin housing and an over pouch consisting of aluminium and containing an oxygen scavenger. The bags are closed with polyisoprene stoppers and polyethylene caps.

Pack sizes:

1 vial 10 vials 12 vials 20 vials 20 bags 50 bags 60 bags

6.6 Special precautions for disposal

Handling

As for all solutions for infusion presented in glass vials or bags, 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 10 mg/ml solution for infusion into nine volumes diluent).

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

7    MARKETING AUTHORISATION HOLDER

Fresenius Kabi Ltd Cestrian Court Eastgate Way,

Manor Park Runcorn,

Cheshire,

WA7 1NT United Kingdom

8    MARKETING AUTHORISATION NUMBER(S)

PL 08828/0226

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

10/12/2010

10    DATE OF REVISION OF THE TEXT

07/10/2013

1

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 (creatinine clearance < 30 ml/min) must be at least 6 hours.

-    The maximum daily dose must not exceed 3 g (see section 4.4) in adults with hepatocellular insufficiency, chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione), dehydration

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

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.

3

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

4

   Severe hepatocellular insufficiency (Child-Pugh >9)

5

   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.