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Current Opinion

October 2005

IV paracetamol- where does it sit in hospital practice?

The limited data on IV paracetamol (Perfalgan™) available to date require that clinical
decisions on safety, efficacy and utility of Perfalgan™ are largely based on theoretical
considerations and extrapolations from data on oral paracetamol and the older intravenous
formulation, propacetamol. NSW TAG recommends that the place in therapy of intravenous
paracetamol is limited to management of mild to moderate pain in clinical situations where
oral or rectal paracetamol cannot be administered but paracetamol is considered preferable to
alternative injectable analgesic agents.

Background
Paracetamol is effective for mild to moderate pain, and an effective component in multimodal
analgesia in combination with morphine1, weak opioids and NSAIDs. 2 There is widespread
consensus on the benefit of multimodal, or balanced analgesia after surgery.3 It is also widely
used as an antipyretic agent.

Bioavailability of paracetamol
Paracetamol is available for administration by oral, rectal and most recently, by the
intravenous routes. The bioavailability of paracetamol varies depending on the route of
administration. Maximal plasma concentration following intravenous infusion of 1g of
intravenous paracetamol is about 30mg/L(200 micromol/L) occurring at 15mins (end of
infusion).4 Following oral administration, paracetamol is rapidly and almost completely
absorbed; with immediate release preparations, peak plasma concentrations are obtained
within one hour. In 27 fasted volunteers given 1g of rapidly absorbed paracetamol (Panadol
Rapid™) the mean maximal plasma concentration was 24mg/L (160 micromol/L) 5

In a study of 6 volunteers given paracetamol 1g intravenously and orally, comparisons of the


areas under the plasma concentration-times curves (AUC) indicated that oral bioavailability
was 0.89 ± 0.04. 6Bioavailability of suppositories is approximately 80% of that of the tablets,
with a slower rate of absorption and maximal plasma concentrations achieved about 2-3 hours
after administration. 7 There is considerable variation in the peak plasma concentrations
following rectal administration.

IV formulation
Because paracetamol is poorly soluble (1 in 70) and unstable in aqueous solution 8 it has been
administered parenterally as propacetamol, a water-soluble prodrug, which is readily cleaved
in the blood by esterases into paracetamol and diethylglycine 9 Two grams of propacetamol
yields one gram of paracetamol. Propacetamol was available in several European countries
for short-term management of acute postoperative pain, but was withdrawn from the market
when paracetamol IV was introduced.10 Propacetamol has never been licenced for use in
Australia.

Paracetamol IV (Perfalgan™) has been formulated as a 10 mg /mL aqueous solution (in ready
to use 50 mL and 100 mL vials for infusion over 15 minutes) by placing it in a relatively large
infusion containing several excipients including mannitol, sodium phosphate dibasic

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dihydrate, cysteine hydrochloride 25mg per 100mLs. The solution has been buffered to
neutral pH.

Bioequivalence
A bioequivalence study compared intravenous administration of propacetamol and
paracetamol in 24 healthy adult subjects 11 administered 3 separate 15 minute infusions of
paracetamol 0.5g, paracetamol 1g or propacetamol 2g, each separated by a one-week washout
period. The results indicated that 2g intravenous propacetamol was bioequivalent to 1g of
intravenous paracetamol (90% CI paracetamol 1g: propacetamol 2g ratios were 1.11-1.31 for
Cmax and 1.10-1.16 for AUCinf). These values are within acceptable bioequivalence intervals
in Australia.a It should be noted however that this study was of the effect of a single dose
only, and was conducted in healthy adults. There is no published bioequivalence data for
paracetamol IV in children or in a multiple dose setting. b

Pharmacokinetics
The pharmacokinetics of IV paracetamol have been recently studied in 7 children/adolescents
during major surgery 4 weeks after chemotherapy.12 The authors concluded that in these
young people (median age 13.7 years), neither major surgery (tumour resection) nor
chemotherapy had a major impact on the pharmacokinetic behaviour nor the between- subject
variability (BSV) of paracetamol after IV administration. Paracetamol, the glucuronide and
sulfate conjugates, as well as cysteine and mercapturic acid conjugates (both products of
oxidative pathways of paracetamol) were excreted in urine. Pharmacokinetics are best
described by a two-compartment model, with a t½ of 10-20 minutes and a mean terminal t½
of 2.5 hours. 6

The only other relevant kinetic data available are those obtained from studies of
propacetamol. In 12 healthy adult volunteers 1g propacetamol given intravenously resulted in
significantly higher plasma concentration of paracetamol than 500mg of oral paracetamol.
(Cmax 12.72 vs 5.49 mg/L (84.2 vs 36.3 micromoles/L) p<0.0001). However, after one hour
and up to 24 hours, plasma concentrations for both routes remained similar and linear.4 In a
study of 35 patients undergoing day surgery, 13 median plasma concentration after 2g IV
propacetamol peaked at 13.1 mg/L (87 micromoll/L) at 40mins.The median plasma
concentration after 1g oral paracetamol was 2.7 mg/L (18 micromol/L) at 40mins and 4.8
mg/L (32 micromol/L) at 80mins, however the authors were unable to identify the timing of
peak concentration after oral dosing, as the study included only the first 80 mins after
paracetamol intake.

Pharmacodynamics
a) Analgesia
Luthy et al have shown that the paracetamol plasma peak, and not the average plasma
concentration, influences the central analgesic effect of paracetamol. 14 Peak analgesic effect
of IV paracetamol occurs in one hour, with duration of approximately 4-6 hours. 4

a
Australia has adopted the European Union’s definition of bioequivalence. For a drug to be considered
bioequivalent it must comply with the following acceptance levels of the main pharmacokinetic
characteristics. See Reference 21.
Area Under the Concentration Curve (AUC) Ratio: The 90% confidence interval (CI) for this measure
of relative bioavailability should lie within an acceptance interval of 0.80 to 1.25
Maximum Plasma Concentration (Cmax) Ratio: The 90% CI for this measure of relative bioavailability
should lie within an acceptance interval of 0.80 to 1.25. The interval may be prospectively defined eg
0.75 to 1.33 and justified addressing in particular any safety or efficacy concerns for patients.
b
A number of studies have investigated propacetamol in the post-operative setting. All published
studies in adults used a dose of 2g of propacetamol (equivalent to 1g paracetamol).

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The analgesic effect of paracetamol has been assumed to relate directly to its blood
concentration, 15 but the concentration required for adequate analgesia is not well defined. To
address this, Anderson et al 16 monitored 120 children undergoing tonsillectomy (given oral or
rectal paracetamol) and determined that an effect-sitec concentration of 10mg/L is needed to
achieve a pain score of less than 4 out of 10.

Intravenous administration of propacetamol has been shown to be at least as effective as oral


administration of an equivalent dose of paracetamol, and the target concentration achieved
more rapidly and with less variability in plasma concentrations compared with enteral
formulations 13, 17 A comparison of the analgesic efficacy of propacetamol 2g IV and
paracetamol 1g orally in 323 patients with moderate pain following hallux valgus plasty,
showed a significantly greater and longer analgesic effect with the parenteral form (p<0.01).
18

Following third molar surgery, intravenous propacetamol 2g (followed 5 hours later by 1g)
was found to be as efficacious as intramuscular morphine10mg.8 Intravenous propacetamol
has been shown to reduce post operative opioid requirements in adult patients with mild to
moderate postoperative pain following orthopaedic 19 20 or gynaecological 21, 22 surgery.
However it did not decrease cumulative opioid consumption (PCA oxycodone), nor reduce
adverse effects within 3 days of surgery in a single study of 79 patients undergoing elective
coronary artery bypass. 23

Murat et al have reported the tolerability and analgesic efficacy of IV paracetamol in 183
children aged 1-2 years after inguinal hernia surgery. 24 The patients were randomized in
double-blind fashion to receive either IV paracetamol 15mg/ kg (n=95) or propacetamol
30mg/ kg (n=88) as a single infusion for post operative pain as soon as pain intensity was
greater than 30 on a 100 mm visual analogue scale. Efficacy was evaluated at various
intervals up to 6 hours after the start of the 15 min infusion. No significant difference was
obtained between treatment groups for pain relief, pain intensity difference from baseline, and
objective pain scale intensity difference. However injection site pain was significantly
reduced in the IV paracetamol group (14.7% vs 33.0% of propacetamol treated children,
p=0.005).

b) Anti-pyretic effects
Concentrations of paracetamol between 10 and 20 mg/L (66.2 - 132.4 micromol/L) are known
to produce an antipyretic effect. 25 The appropriateness of paracetamol use in fever remains
controversial. 26 Infants and children tolerate low grade fever (≤ 38.5℃per axilla) well and
there may be no therapeutic advantage to giving paracetamol in this situation. NSW Health’s
document Acute management of infants and children with fever states that ‘reducing fever
may help a child feel better’, but ‘since a fever is the body’s natural response to infection, it is
not always necessary to reduce a fever’.27

There are no published data on IV paracetamol in reduction of fever. An unpublished study of


41 children aged 3-12 years with acute fever of infectious origin given 30mg/kg propacetamol
or placebo showed that the mean body temperature reduction from baseline to 6 hours was
significantly greater in the treatment group (p=0.0002).4 The Perfalgan™ product information
states that fever is reduced within 30 minutes with the antipyretic effect lasting at least 6
hours. 4

Safety

c
Based on two compartment model where first compartment was used to predict concentrations in the
central compartment (volume of distribution) and the second compartment was used to predict
concentrations at the site of action (effect site).

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Paracetamol is known to have a reasonable therapeutic index but hepatic toxicity, though
extremely rare, can occur if therapeutic doses are exceeded. There are reports of liver failure
in children caused by chronic ingestion of paracetamol, with several patients apparently
receiving doses in the therapeutic range. 28 29

Hepatotoxicity is mediated by a reactive metabolic product (N-acetyl- p-benzoquinone-imine)


30
and is a function of the total dose absorbed. Hepatotoxicity develops when the rate of
production of the reactive metabolite markedly exceeds the rate of supply of reduced
glutathione. Some 5-8% of a therapeutic dose of paracetamol is normally converted to the
toxic metabolite. There are no reports to date of hepatotoxicity from intravenous
administrations of paracetamol (Perfalgan™) but there is no reason to suppose its toxicology
differs from enteral preparations. A conservative estimate of a dose with the potential for
hepatotoxicity in an adult is greater than 150 mg/kg body weight. Recent data support a
minimum risk dose for children 1-5years of age of 225 mg/kg. 31

If IV paracetamol is administered in the hospital setting, massive inadvertent overdose is most


unlikely, however it would be advisable to prospectively set up local procedures to manage
such an event. The value and place of the Rumack-Mathews nomogram in managing
inadvertent paracetamol overdose via the intravenous route has not been established.

According to the approved product information, like other paracetamol formulations,


paracetamol IV is contraindicated in cases of severe hepatocellular insufficiency and hepatic
failure, and should be used with caution in patients with a creatinine clearance < 30mls/min,
chronic alcoholism, chronic malnutrition (low reserves of hepatic glutathione) and
dehydration. 4 A recent review of the tolerability of paracetamol 32 emphasized that although
hepatotoxicity due to paracetamol overdosage is well recognized, standard recommended
doses do not appear to have adverse effects in patients with liver disease. No problems were
encountered with the use of paracetamol to manage the “flu-like” symptoms associated with
interferon treatment of patients with hepatitis C. 33 In addition, there are no convincing data
of increased hepatotoxicity in patients with cirrhosis, possibly because the enzymes forming
the toxic metabolite are compromised in cirrhosis. 33 Hence, paracetamol is not
contraindicated in patients with liver disease, provided that recommended doses are not
exceeded. 34

Potential hepatotoxicity from chronic enteral dosing in children (‘therapeutic misadventure’)


has been recognised as of concern. 28 35 A risk profile for such toxicity has been identified and
includes ‘sustained administration of high doses (> 90 mg/kg/day) to a sick child (ie one with
repeated vomiting/ diarrhea and poor oral food intake) who is 2 years or younger, for a
duration or more than one day). 36 The risk of hepatotoxicity and recommendations for
appropriate dosing may therefore differ depending on the clinical context and specific
indications for which paracetamol is being used, particularly in children. Therefore all
paracetamol prescriptions should be preceded by a careful risk assessment and therapy
adjusted accordingly.

The safety and efficacy of IV paracetamol in premature neonates has not been established,
and there are limited data in neonates and infants less than 6 months. 30 According to the
product information 4 the most frequent adverse effect in children is injection site pain or
reaction (14.7% of 95 children in the clinical trial set).

Dosage
In adults the recommended dose is 1g up to four times daily, with a minimum interval
between each administration of at least 4 hours (6 hours in patients with renal and/or hepatic
impairment).

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For children weighing up to 33kg, the recommended dose is 15mg/kg per administration (ie
1.5ml per kg) up to four times daily, with a minimum interval between each administration of
6 hours. The Australian approved product information states that the maximum daily dose
must not exceed 60mg/kg. Current recommended maximum daily dose for oral formulations
for children is 90mg/kg. 37 Care should be taken not to exceed recommended daily doses.

A dosage reduction by half in neonates less than 10days (ie 7.5mg/kg of paracetamol per
administration) without exceeding 4 doses per day, is recommended in the product
information. However very little data exist for this age group.

Cost comparison
No cost effectiveness data could be found for IV paracetamol.
As at August 2005, the acquisition cost to hospitals for the various preparations of
paracetamol are as follows:

Tablet: 500mg $0.013 (ie 1.3cents)


Liquid: 240mg/5ml $1.15
Suppository 500mg $0.62
250mg $0.52
IV: 1g vial $3.30
500mg vial $2.15

Place in Therapy
Published evidence has demonstrated the efficacy and safety of propacetamol vs placebo in
the perioperative setting. Propacetamol has been shown to reduce postoperative opiate
requirements in adult patients undergoing dental, orthopaedic and gynaecological surgery but
not cardiac surgery. One published study of a single dose of IV paracetamol in children 24 has
shown that it is a safe and effective analgesic following inguinal hernia repair.

Analgesic efficacy of paracetamol is related to peak plasma concentrations. 14 Since certain


oral formulations of paracetamol may achieve peak plasma concentrations close to those
achieved with IV paracetamol 5, the IV formulation can only be justified in circumstances
where the oral formulation cannot be given.

A case can be made for use of IV paracetamol as an adjunct to opioid analgesia, based on
extrapolations from trials using propacetamol. However, the evidence is equivocal. Further
research would be useful to elucidate the position of IV paracetamol in this indication.

There is also a lack of published data on safety and efficacy of IV paracetamol for treatment
of fever. Perfalgan™ has approval for treatment of fever but the Product Information contains
supporting data only for the pro-drug propacetamol in this indication. Given that
bioequivalence has not been demonstrated between intravenous propacetamol and
paracetamol in paediatric patients, it is premature to assume efficacy or safety with IV
paracetamol (especially with multiple dosing as is likely in the management of febrile illness).

It should be emphasised that there have been very small numbers of patients (adults or
children) studied to date and there are no data about safety in multiple dosing schedules of the
IV presentation.

Recommendations
The TGA approved indication for IV paracetamol (Perfalgan™) is relief of mild to moderate
pain and the reduction of fever where an intravenous route of administration is considered
clinically necessary. There is no therapeutic advantage in using the intravenous form and
enteral formulations should be used wherever possible.

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If paracetamol is required for management of fever, then oral or rectal routes are preferable.

Clinicians may find the following checklist helpful in deciding whether IV paracetamol is
appropriate for a particular patient:-

o patient is over 6 months of age and weighs more than 5kg


o enteral routes of therapy unavailable
o mild to moderate (but not severe) pain
o anticipated short duration of therapy

Risk Management Strategies


With the advent of a liquid product for infusion, there is the potential for other (oral) liquid
paracetamol formulations to inadvertently be injected into a drip set.

As with other medications given perioperatively, it will be important to have systems in place
within individual institutions to avoid inadvertent overdose. Systems should ensure that
perioperative doses of IV paracetamol are clearly recorded on the medication chart and
included in the cumulative daily dose calculation. Since the recommended maximum doses
are different in some paediatric age groups, attention will need to be given to dosing if IV and
enteral administration occur on the same day.

Individual hospital policy documents should clearly identify safe prescribing and
administration systems for IV paracetamol. The following are suggested:

• Vials should be stored in pharmacy and operating suite only.


• 100ml vials should NOT be supplied to paediatric wards.
• Prescription should be restricted to pain teams, anaesthetists and intensivists.
• Prescription should always state an appropriate maximum daily dose.
• In children, vials should never be connected to IV infusion sets; the dose should be
drawn up in a syringe, added to an infusion burette and labelled appropriately.
• All orders should be reviewed at least daily and enteral paracetamol substituted for
the intravenous formulation as soon as practicable.
• Prescriptions should include the trade name of the drug (in addition to the generic
name) to minimize confusion with enteral paracetamol.
• Wherever confusion may arise, consideration should be given to labeling oral
paracetamol liquids ‘FOR ORAL USE ONLY’
• Purpose manufactured oral syringes should be used to measure doses of oral
paracetamol liquids

Acknowledgments: NSW TAG would like to thank the following people who contributed to or reviewed this
document: Ms Sharon Davis (NSW TAG); Professor Garry Graham (Department of Clinical Pharmacology, St
Vincents Hospital, Sydney); Dr Andis Graudins (Emergency Physician and Director, Clinical and Experimental
Toxicology Unit, Prince of Wales Hospital, Sydney); Dr Madlen Gazarian (Paediatric Clinical Pharmacologist,
Sydney Children’s Hospital, Randwick); Dr Ed Loughman (Senior Specialist, Anaesthetics Department, Prince of
Wales Hospital, Sydney); Dr Ross MacPherson (Senior Lecturer, Department of Anaesthesia and Pain
Management, Royal North Shore Hospital); Professor Paul Seale (Professor of Clinical Pharmacology, Discipline
of Pharmacology, University of Sydney)

This work is copyright of the NSW Therapeutic Advisory Group Inc and NSW Health Department. Apart from any use as
permitted under the Copyright Act 1968, no part of this information may be reproduced by any process without written
permission. Whilst the information contained in this document has been presented with all due care, and the information is
considered to be true and correct at the date of publication, changes in circumstances after publication may impact on the
accuracy of the information. This document represents expert consensus opinion and should not be relied on as professional
advice other than in this context. The information provided should not be regarded as a substitute for detailed expert advice in
individual cases. NSW Therapeutic Advisory Group Inc will accept no responsibility for any loss, claim or damage suffered or
caused by any person acting or refraining from action as a result of any material in this document.

NSW Therapeutic Advisory Group 6


NSW Therapeutic Advisory Group (NSW TAG) is an association of clinical pharmacologists, directors of
pharmacy and other clinicians from the teaching hospitals in New South Wales, funded by NSW Department
of Health. NSW TAG aims to investigate and establish therapeutic initiatives that foster high quality, cost-
effective drug usage in the public hospitals of NSW and the wider community.
For further information contact: NSW TAG, PO Box 766, Darlinghurst NSW 2010
Phone (02) 8382 2852 Fax (02) 83823529 Email: nswtag@stvincents.com.au
Website: www.nswtag.org.au

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