RESTRICTED COMMERCIAL CHM/PEG/12/02

RESTRICTED COMMERCIAL
CHM/PEG/12/02
NOT FOR PUBLICATION
COMMISSION ON HUMAN MEDICINES
PARACETAMOL EXPERT GROUP
Title of paper:
BENEFIT RISK PROFILE OF ACETYLCYSTEINE IN THE MANAGEMENT
OF PARACETAMOL OVERDOSE
Type of paper:
For Advice
Product:
N-acetylcysteine 200
mg/mL injection
Assessors:
Marketing
Authorisation
Holders:
UCB Pharma
Teva UK Limited
Martindale Pharma
Previous
Assessments:
Active constituent:
N-acetylcysteine
Legal status:
ATC Class:
V03AB23: Antidotes
1
POM
BENEFIT RISK PROFILE OF ACETYLCYSTEINE IN THE MANAGEMENT OF
PARACETAMOL OVERDOSE
TABLE OF CONTENTS
1.0.
1.1.
1.2.
INTRODUCTION
Terms of reference for Ad hoc Paracetamol Group
Background
2.0.
2.1.
2.2.
2.3.
2.4.
2.5.
2.5.1.
2.6
2.6.1.
2.6.2.
2.6.3.
2.6.4.
2.6.5.
5
5
5
BENEFIT OF ACETYLCYSTEINE
Regulatory history of acetylcysteine
Current regulatory status of acetylcysteine
Current acetylcysteine posology
Mechanism of action
Efficacy of acetylcysteine
Efficacy of oral versus IV acetylcysteine
Patient Population – prediction of toxicity
Historical development of the nomogram
Risk of liver damage related to dose/paracetamol level.
Introduction of high risk line (100 line)
Prior published debate about the treatment nomogram in the UK
Further unpublished data on patients presenting with
heptatoxicity and with paracetamol levels <200mg/L at 4h.
2.7
Limitations in the use of the nomogram in identifying patient
populations for acetylcysteine treatment
2.7.1.
Risk factors
2.7.1.1.
Reduced food intake
2.7.1.2.
Rate of absorption of paracetamol
2.7.1.2.1. Opioid co-ingestion
2.7.1.3.
CYP 450 enzyme inducers
2.7.1.3.1. Alcohol
2.7.1.3.1.1. Induction of CYP 450 enzymes
2.7.1.3.1.2. Studies investigating the influence of alcohol consumption on
paracetamol toxicity
2.7.1.3.2. Other liver enzyme inducing drugs
2.7.1.4.
Pharmacogenomic factors
2.7.1.5.
Age
2.7.1.6.
Pregnancy
2.7.1.7.
Oral contraceptives
2.7.1.8.
Smoking
2.7.1.9.
Pre-existing liver damage/disease
2.7.1.10
Conclusions
2.7.2.
Assessment of an individuals risk of hepatotoxicity
2.7.2.1.
Demographics of at risk population
2.7.2.2.
Importance of an accurate time of ingestion
2.7.2.3.
Staggered overdose
2.8.
Other nomograms in use in Europe and internationally
2.9.
Other guidelines for the determining acetylcysteine treatment
2.10.
Other biomarkers of paracetamol toxicity
2.11.
Conclusions on the patient population indicated for acetylcysteine
treatment
7
7
7
7
8
19
11
12
12
15
17
18
21
3.0.
47
RISKS ASSOCIATED WITH THE USE OF ACETYLCYSTEINE
2
25
25
25
28
28
30
31
31
31
32
33
35
37
39
39
40
40
41
42
44
45
45
45
46
47
3.1.
3.1.1.
3.1.2.
3.1.3.
3.1.3.1.
3.1.3.2.
3.2.
3.2.1.
3.2.2.
3.2.3.
3.2.3.1.
3.2.3.2.
3.2.3.3.
3.2.3.4.
3.2.3.5.
3.2.3.6.
3.2.3.7.
3.2.4.
3.3.
3.3.1.
3.3.1.1.
3.3.2.
3.3.3.
4.0.
IN PARACETAMOL OVERDOSE
Posology
Pharmacokinetics of acetylcysteine.
Oral versus intravenous acetylcysteine
Other treatment options
Cysteamine
Methionine
Adverse Drug Reactions
Published literature
Profile of adverse drug reactions following oral administration
Spontaneous reporting
UK usage data
Spontaneous UK reports
Spontaneous Fatal UK reports
Spontaneous Non-UK data
Other data sources
Significant safety signals identified in the post marketing period
Marketing authorisation holder (MAH) pharmacovigilance cases
Conclusions
Administration errors associated with acetylcysteine
Published literature
Paediatric literature articles
National Patient Safety data
Conclusions
EVIDENCE OF INTERPRETATION OF CURRENT SmPC
GUIDANCE ON FROM CLINICAL USE OF ACETYLCYSTEINE
4.1.
4.2
4.3
4.4.
4.4.1.
4.5.
4.6.
Bristol data set
Experience of a district general hospital
Time taken between sampling and reporting a paracetamol level.
College of Emergency Medicine paracetamol audit
Conclusions
5.0
5.1.
5.2.
5.3.
5.4.
MAH REPORTS ON ACETYLCYSTEINE
UCB Pharma Ltd
Martindale Pharma
TEVA UK Ltd
MAH proposals to improve benefit risk of acetylcysteine
5.4.1.
5.4.2.
5.4.3.
5.4.4.
5.4.5.
5.4.6.
5.4.7.
5.4.8.
5.4.9.
Acetylcysteine posology
Identify patients at increased risk of a acetylcysteine ADR
Weight-based dosing tables
acetylcysteine Product Information
Pre-printed prescribing labels
Use of an integrated care pathway (ICP)
Use of electronic prescribing
Computerised acetylcysteine physician order entry by
template protocol
Simplify the acetylcysteine posology.
6.0.
MODELLING BENEFIT RISK OF ACETYLCYSTEINE
3
48
48
50
50
51
51
52
52
57
57
57
58
64
65
66
69
69
70
71
71
72
73
74
74
74
74
76
77
78
78
80
81
81
81
81
81
81
81
82
82
82
82
82
82
82
83
6.1.
6.1.1.
6.1.2.
6.1.3.
6.2.
Available data sources and discussion of assumptions and
limitations
The number of patients presenting with paracetamol overdose in
the UK
The number of people, presenting with a paracetamol overdose,
whose plasma paracetamol concentration falls between the “100”
and “200” at 4h treatment lines and an estimate of the proportion
of these who do not receive acetylcysteine
The number of people, presenting with a paracetamol overdose,
whose plasma paracetamol concentration falls above the “200”
treatment line or who have a staggered paracetamol intake.
83
83
85
87
88
6.4.
An estimate of the number of acetylcysteine associated deaths in
the UK
UK Yellow Card data
An estimate of the number of deaths occurring in patients not
treated with acetylcysteine who have plasma concentrations
between the “100” and “200” treatment lines
Quantitative analysis of benefit risk
7.0
COMMUNICATION STRATEGY
91
8.0.
8.1.
8.2.
8.3.
8.4.
CONCLUSIONS
Benefit/Selecting Patient Population
Risk with acetylcysteine
Medication errors
Balance of risks and benefits
91
91
92
93
93
9.0
CHM ADVICE
93
10.0.
REFERENCES
96
11.0.
APPENDICES
6.2.1.
6.3.
4
88
89
90
1.0.
INTRODUCTION
In November 2010, MHRA sought advice from the Commission of Human Medicines
(CHM) on a review of the use of the acetylcysteine for the treatment of paracetamol
overdose. On the basis of this review, CHM recommended that there were sufficient
major aspects to consider with regard to the treatment of paracetamol overdose to
warrant the formation of an expert working group.
1.1.
Terms of Reference for Ad hoc Paracetamol Group.
The Terms of Reference agreed by the group on its first meeting of the Ad Hoc
Group on 11 February 2011 were;
i.
To review the available preclinical and clinical evidence on the use of
acetylcysteine for the treatment of paracetamol overdose including a review of
worldwide experience.
ii.
To consider how effective are the current risk minimisation measures.
iii.
To consider how the treatment of paracetamol overdose can be optimised
including consideration of the use of the nomogram or not.
iv.
To consider how the use of acetylcysteine can be optimised including
consideration of posology and administration.
v.
To advise on options for regulatory action.
vi.
To advise on an information and communications strategy to cover the aspects
before, during and after a paracetamol overdose.
vi.
To outline possible future areas of research in the field
1.2.
Background
Paracetamol is a widely used analgesic and antipyretic agent. It first became
available in the UK in 1956 and was included in the British Pharmacopoeia in 1963.
Despite over 50 years of use however, its mechanism of action still remains a matter
of debate and an area of active research.1 The recommended adult oral dose is 500 1000 mg taken every four to six hours to a maximum of 4g daily (see Appendix I for
Summary of Product Characteristics). Current estimates are that paracetamol is
bought by half of the UK population with the average purchaser buying 4.8 packs per
year and 22 tablets per purchase. In addition paracetamol is the most widely used
and prescribed drug in the United Kingdom. In 2010, almost 39 million prescriptions
were dispensed for a product containing paracetamol either alone or in combination
with other medicine. a
a
Relates to NHS prescriptions dispensed in the community, i.e. by community pharmacists and
appliance contractors, dispensing doctors and prescriptions submitted by prescribing doctors for items
personally administered in England. Also included are prescriptions written in Wales, Scotland, Northern
Ireland and the Isle of Man but dispensed in England. The data do not cover drugs dispensed in
hospitals, including mental health trusts, or private prescriptions. In order to provide an estimate of UK
primary care data, the PPD data has been adjusted using a figure provided by the Office for National
Statistics which estimates that approximately 0.84 of the UK population lives in England.
5
The safety profile and toxicity of paracetamol is well established and the overall
hazard to health from this product is small if used strictly in accordance with the
product labelling. However, paracetamol has a relatively narrow therapeutic index
and can in most individuals become potentially toxic at a single dose of
.
Rare reports of toxicity at lower doses than this
have also been reported. As a result, paracetamol overdose is one of most common
causes of poisoning in the UK and worldwide. A number of risk minimisation
measures have been introduced in the UK over recent years aimed at reducing the
risk of liver damage following either deliberate or accidental overdose from
paracetamol. Despite this paracetamol remains the method of choice in a large
percentage of suicides. This seems particularly pertinent to young adolescents where
there is clear evidence that paracetamol is the drug of choice for self harm.2,3,4 Thus,
data from the Oxford Monitoring system reports that 50% of overdoses by under-16
years olds involved paracetamol.2 Similarly in a 3 centre study from March 2000August 2001, Hawton et al3 reported that paracetamol is used most frequently as a
method of self harm in the young, particularly the very young (<15 years of age and
15-24 years of age).
Fortunately there is a highly effective antidote to the toxic metabolite of paracetamol,
intravenous acetylcysteine (N-acetylcysteine or NAC), which is almost 100% effective
if administered within 8 h of the overdose.5,6,7,8 Current treatment guidelines are
based on the paracetamol treatment nomogram, published in the British National
Formulary (BNF), which is dependent on a plasma paracetamol concentration
assessed at least 4h after the overdose. The decision to treat is further modified by
the presence or absence of a number of risk factors such that patients considered to
be at “high risk” are treated at a lower plasma paracetamol concentration. Although
generally accurate, there have a number of case reports9 since the introduction of the
paracetamol treatment nomogram in the early 1970’s, in which patients have
presented with plasma paracetamol levels below the treatment threshold and did not
receive acetylcysteine and yet subsequently developed fulminant hepatic failure and
died.
In 2009 the MHRA was informed of the case of
a single overdose of 14 paracetamol tablets (7g) preceded by an acute alcohol
intake.
The four hour paracetamol level was found to be 103 mg/L,
fractionally above the ‘high’ risk treatment line on the nomogram.
The
patient was not however considered to fall into the ‘high’ risk treatment group with
regards to
weight, malnutrition, medications or alcohol intake and was
therefore, discharged with oral advice to return if
experienced any
symptoms. Unfortunately
later presented in fulminant liver failure
and died whilst waiting for a liver transplant. The consultant subsequently felt that a
history of poor eating
may have contributed to the
hepatotoxicity by depleting glutathione stores.
The key point of this case was that acetylcysteine was withheld based on the
understanding of what constitutes 'high’ risk. Given that such deaths are potentially
preventable, this case again raises questions with regard to the validity of the current
guidelines for the management of paracetamol overdose. At the inquest of the case
the coroner considered that the evidence gave rise to a concern that circumstances
existed which created a risk of other deaths in the future, and in his opinion, action
should be taken to prevent the occurrence or continuation of such circumstances.
6
The following report summarises the evidence presented to the Expert Working
Group specifically in terms of the balance of benefits and risks of acetylcysteine for
the treatment of paracetamol overdose and provides recommendations for improving
this balance. In addition, the report considers the range of administration errors
associated with the use of acetylcysteine and proposes a range of measures to
reduce the incidence of such errors.
2.0.
2.1.
BENEFIT OF ACETYLCYSTEINE
Regulatory history of acetylcysteine
acetylcysteine was first marketed in the UK in 1979 by Duncan Flockhart and
Company Limited under the brand name Parvolex. Duncan Flockhart was later
acquired by Wellcome UK Limited, which subsequently became part of
GlaxoSmithKline (GSK) Limited. In July 2005, following a series of mergers and
acquisitions, UCB Pharma became the Parvolex MA holder.
A key variation to the Parvolex MA took place in April 1996 when the current
treatment nomogram was added to section 4.4 of the acetylcysteine SmPC.
In addition to the brand leader Parvolex, two generic MA holders have entered the
UK market.
2.2.
Current regulatory status of acetylcysteine
There are currently three UK MA holders for acetylcysteine namely UCB
Pharma, which is the brand leader, and Teva and Martindale Pharma as
generic manufacturers. All three are national marketing authorisations.
Teva and Martindale are known to be marketing acetylcysteine in the UK.
However, since June 2011 UCB Pharma has been out of stock of
acetylcysteine and is therefore, at present, not marketing the Parvolex
product.
MA holder
Product
PL number
UCB Pharma
Parvolex
PL 00039/0410
Martindale
Pharma
N-acetylcysteine 200mg/mL
injection
PL 12064/0026
Teva
N-acetylcysteine 200mg/mL
injection
PL 00289/1543
Table 1: Marketing Authorisation Details for acetylcysteine.
2.3.
Current acetylcysteine posology
The licensed posology for acetylcysteine in adults is the administration by
intravenous infusion of a total IV dose of 300 mg/kg given over a period of 20¼ hours
in the following manner:
7
i.
An initial loading dose of 150 mg/kg infused in 200mL infusion fluid over
15 min,
50 mg/kg in 500mL infusion fluid over the subsequent four hours and
then,
100 mg/kg in 1L infusion fluid over last 16 hours (Table 2).
ii.
iii.
Dose
Acetylcysteine
Volume of 5%
sequence (mg/kg body weight) glucose for dilution
Duration of
infusion
1
150
200 mL
15 min
2
50
500 mL
4 hours
3
100
1000 mL
16 hours
If for any reason glucose is unsuitable, 0.9% sodium chloride solution may
be substituted.
Table 2:
acetylcysteine doses for intravenous infusion (adult and child >12 yrs)10
The following infusion fluids may be used: glucose 5%, 0.9% sodium chloride, 0.3%
potassium chloride with 5% glucose, or 0.3% potassium chloride with 0.9% sodium
chloride.
The UK licensed dose is also used in the United Kingdom, Australasia and Europe.
Children should be treated with the same doses and regimen as adults but the
quantity of IV fluid administered should be modified according to age and weight, as
fluid overload is a potential danger. The licence refers to the following guidance
provided by the National Poisons Information Service (NPIS) in the UK:
Children weighing 20kg or more:
150mg/kg intravenous infusion in 100mL infusion fluid over 15minutes; then 50mg/kg
in 250mL infusion fluid over 4 hours; then 100mg/kg in 500mL infusion fluid over 16
hours.
Children under 20kg:
Volumes for infusion of the above doses are the responsibility of the prescriber and
should be based on the daily maintenance requirements of the child by weight.
In the US, until recently acetylcysteine was only licensed for oral use in a much larger
total dose of 1330 mg/kg and over a period of 3 days (a loading dose of 140 mg/kg
followed by 17 doses of 70 mg/kg 4 hourly). However in 2004, acetylcysteine was
also licensed for intravenous use in the US with a posology almost identical to the
UK. Later amendments adjusted the initial loading dose such that it is given over a
period of 60minutes as opposed to 15minutes. These differences in posology will be
discussed in more detail later.
2.4.
Mechanism of action
It is a metabolite of paracetamol, N-acetyl-p-benzoquinoneimine (NAPQI) and not
paracetamol itself, which is hepatotoxic. The primary metabolic pathways for
paracetamol metabolism (Figure 1A) are glucuronidation and sulphation which
produce nontoxic metabolites. Although the sulphation pathway can be saturated at
relatively low doses of paracetamol (1g) the glucuronidation pathway is not readily
saturable.11 Thus, only approximately 5% of a therapeutic dose is metabolized by
hepatic CYP enzymes (in humans mostly CYP2E1 (85%) but CYP3A4 also
contributes (15%)), to NAPQI, which is then usually rapidly detoxified by glutathione
8
to form cysteine and mercapturic acid conjugates. However when the concentration
of NAPQI exceeds that of intracellular glutathione, NAPQI covalently binds to
hepatocytes leading to necrosis.12 Only 1-4% of a therapeutic dose is excreted
unchanged in the urine.
Clarification of this mechanism of paracetamol toxicity in the 1970’s opened the way
for the use of sulphydryl compounds as a treatment for severe paracetamol
poisoning. acetylcysteine was first proposed as an antidote for paracetamol toxicity in
197413 and studies from the same decade showed that the overall mortality rate
dropped from 3% (all poisonings) or 5% (all above the probable risk-line) to 0.7%
after its introduction.14 Its mechanism of action is thought to be dependent upon a
marked increase in circulating cysteine levels which is then used primarily in the
synthesis of glutathione thereby minimizing hepatic risk by detoxifying NAPQI (Figure
1(B)).15 Other mechanisms which might underlie its protective action in paracetamolinduced liver failure include an improvement in haemodynamics and oxygen use,
increased hepatic clearance and decreased cerebral oedema.12 Some of these
actions may be mediated by its antioxidant action which is also thought to be
particularly relevant in any protective effect in the later stages of paracetamol toxicity.
Figure 1: A, The Metabolism of Acetaminophen and, B, The Synthesis of
Glutathione 12
2.5.
Efficacy of acetylcysteine
The efficacy of acetylcysteine in the management of paracetamol poisoning is well
established. acetylcysteine is considered to be virtually 100% effective in preventing
severe liver damage and death when given within 8-10 hours of ingesting
9
paracetamol16,7,8. However if the interval between ingestion of paracetamol and the
initiation of treatment with acetylcysteine is delayed beyond 8-10h, the efficacy
declines sharply.16,17,18,19,20,21,22 It is very important therefore that acetylcysteine is
initiated promptly in those patients for whom it is indicated. Treatment is still
recommended however for patients who present late (>12 hours) as even minor
benefit from treatment with acetylcysteine could ultimately tip the balance between
life and death. It may also be administered after 24 hours in patients at risk of severe
liver damage; however, guidance should be sought from a National Poisons Centre
(see summary of product characteristics for acetylcysteine, Appendix III).
For patients who have taken staggered overdoses over a period of hours or days, the
8-hour time window for the initiation of acetylcysteine does not apply.16 These
patients require careful assessment and those patients who have ingested more than
150 mg/kg in 24 hours (75 mg/kg for patients with risk factors) should be considered
for treatment with acetylcysteine.10
There have been sporadic reports where acetylcysteine therapy failed to protect
against liver toxicity despite treatment within 8h of the overdose.23,24,25,26 In a
retrospective observational case series Doyon and Klein-Schwartz23 examined the
records of patients hospitalised between 2004 and 2007 for acute paracetamol
overdose who were reported to a regional poison centre. The authors however had
no direct clinical involvement with the patients so the accuracy with regard to timing
of ingestion is impossible to completely confirm (see later discussion). Inclusion
criteria were paracetamol concentrations on or above the treatment line on the US
nomogram (see section 2.3), treatment with acetylcysteine <8h of ingestion and a
known outcome. Of the 77 patients who met the criteria, 7 received acetylcysteine for
longer than 21h due to persistent elevation of paracetamol levels, elevated liver
enzymes or both. Despite continuation of acetylcysteine therapy in 2 of these
patients, one died and the other required a liver transplant. Interestingly all but one of
these patients ingested combination products, 5 of whom ingested paracetamol
combined with diphenhydramine. In the patient who died, plasma paracetamol levels
continued to rise until 72h of therapy. Two further case reports also provide evidence
of delayed paracetamol absorption resulting in recurrent paracetamol peaks despite
IV acetylcysteine therapy.25,24 Other case reports present patients with non toxic
levels at 4h which increase to toxic levels at later time points.27,28 Such case reports
have implications not only for the decision on whether to continue acetylcysteine
therapy beyond 24h but also on the assessment of potential hepatotoxicity based on
a 4h paracetamol level. If absorption kinetics are substantially delayed by for
example the co-ingestion of anticholinergics, narcotic analgesics or other agents that
may inhibit gastric emptying, a 4h paracetamol level may not be an accurate
predictor of toxicity. A further example of this is provided in the observational case
report by Doyon and Klein-Schwartz in which one patient had a 4h paracetamol level
of 108mg/L which increased to 508mg/mL at 72h despite continuous IV
acetylcysteine therapy initiated at 4h post ingestion. However in this patient,
prolonging the acetylcysteine therapy beyond 20.25h did not prevent severe and fatal
liver damage. This would be in line with the data demonstrating that the efficacy of
acetylcysteine decreases with time post ingestion.
Lastly a recent publication29 provides some further limited evidence of the failure
acetylcysteine to completely abrogate liver damage arising from acute paracetamol
overdose. Although this single centre cohort study from Edinburgh focused on
adverse outcomes associated with staggered overdose with paracetamol, it also
reported outcomes in 395/450 single time point overdoses in which accurate timings
could be obtained. These overdoses included 78 overdoses in which <12h elapsed
between the last paracetamol ingestion and presentation to hospital services. Almost
10
90% of these overdoses received acetylcysteine in the referring hospital and yet all
patients subsequently suffered some acute liver injury which required admission to
the Scottish Liver Transplantation Unit in Edinburgh. Twenty two of these patients
developed encephalopathy, 16, were ventilated and 4 required transplantation. Nine
patients died. It must be emphasised that the time of <12h represents the time from
overdose to admission and not to acetylcysteine treatment and ALTs were quite
elevated at an early time point in this group at an average of 8697 IU/L. This would
suggest a longer time between ingestion of the overdose and presentation than
recorded. It is therefore possible therefore that acetylcysteine was administered
outside of the window of maximum efficacy which could explain the occurrence of
liver damage. Further data on single time point overdoses presenting to hospital at
12-24 and >24h after the overdose demonstrates a progressively worse outcome
with increasing numbers developing encephalophathy and a decreased survival
(76.4% at 12-24h and 64% at >24h).
Since 97.8% and 80.4% received
acetylcysteine at the referring hospital this data again illustrates that the efficacy of
acetylcysteine decreases with increasing time post overdose.
2.5.1. Efficacy of oral versus IV acetylcysteine
A review by Prescott16 in 2005, which included 8 different studies30,31,32,33,34,35,8,36
examined the efficacy of treatment with oral and IV acetylcysteine therapy in
paracetamol poisoning patients and concluded that oral and IV acetylcysteine were
equally effective. For both administration methods however there is a fall in efficacy
after 10h. For example, Smilkstein et al22 demonstrated that, in a series of 2540
patients with paracetamol levels >150mg/L treated with oral acetylcysteine,
hepatotoxicity developed in 6.1% of patients who received acetylcysteine within 10h
of the overdose and in 26.4% of patients who received acetylcysteine between 1024h. The incidence of hepatotoxicity appeared to increase slightly when plasma
paracetamol levels were higher. Similarly, Prescott et al19,18 reported that only 1/62
patients who received IV acetylcysteine within 10h had severe liver damage as
compared with 33/57 of patients who received only supportive therapy. The incidence
of liver damage increased progressively with delays in administration of
acetylcysteine treatment such that 18/27 (67%) of patients suffered severe liver
damage when IV acetylcysteine was administered between 10-24h after the
overdose. Although the incidence of hepatotoxicity appeared slightly higher in those
treated within 10h of ingestion with the oral versus IV dosing and slightly lower
thereafter, the lack of direct head to head trials make it impossible to draw firm
conclusions with regard to relative efficacy.
Buckley et al31 investigated the relative efficacy of intravenous versus oral
acetylcysteine in a meta-analysis of 981 patients. They concluded that the 30
patients who developed hepatotoxicity presented later, took large amounts of
paracetamol, had higher plasma concentrations and received acetylcysteine later
than those that did not. Patients had similar outcomes with both oral and IV
acetylcysteine irrespective of the level of paracetamol. A further more recent study
compared the IV protocol in over 2,000 patients from Canadian hospitals from 19802005 with 1,962 patients from US hospitals from 1976-1985.37 Entry criteria were
similar for both groups (potentially toxic paracetamol concentration defined as a level
on or above the 150mg/L at 4h line on the Rumack-Matthew nomogram and a
acetylcysteine treatment initiated between 4 and 24h after ingestion) except that
patients were also included in the oral acetylcysteine group if they had an estimated
ingestion of 7.5g (adult) or 140mg/kg (child). There were significant differences
between the groups in terms of age (mean age +/- 1yr), median extrapolated
paracetamol concentration (280.3±217.1mg/L (IV) vs 260.3±198.7mg/L (oral)) and
acute (25.2% (IV) vs 1.6% (oral)) and chronic (16.1% (IV) vs 4.1% (oral)) alcohol
ingestion. The data suggest that the relative risk of hepatotoxicity was lower in the
11
20h IV group when acetylcysteine was initiated within 12h of ingestion (RR 0.54, 95%
CI 0.38-0.75 following administration at 4h; RR 0.84, 95% CI, 0.71 -1.00 following
administration at 12h, 12mins). In contrast the relative risk was lower in the 72h oral
group when acetylcysteine was initiated later than 18h after ingestion (RR 1.19, 95%
CI 1.00-1.40 following administration at 18h, 27 mins; RR 1.61, 95% CI, 1.22 -2.12
following administration at 24h). There were no significant risk differences between
the groups when acetylcysteine was initiated 12-18h after ingestion. These results
suggest that the most appropriate acetylcysteine therapy could depend on the
interval between ingestion and initiation of therapy. Unfortunately the study is
significantly limited by comparing 2 separate data sets from different countries and
different study years and therefore this conclusion requires further validation.
In summary despite sporadic reports of liver damage following acetylcysteine
administration, there is no doubt that acetylcysteine treatment, whether oral or IV, is
a highly effective treatment for the prevention of paracetamol hepatotoxicity and its
introduction in the late 1970’s transformed the prognosis of patients with paracetamol
overdose. However because hepatotoxicity develops over a period of 1-2 days and is
not apparent within the first 8h after the overdose, the predominant difficulty lies in
predicting which patient requires treatment. The following discussion will carefully
outline the process by which the patient population for acetylcysteine treatment is
defined and the additional risk factors which influence this decision.
2.6.
Patient population – prediction of hepatotoxicity
A single oral dose of 150 mg/kg or more of paracetamol is thought to be the minimum
dose sufficient to cause liver damage. As such in adults, a conservative estimate of
the minimum single hepatotoxic dose is 7.5g but in most individuals the toxic dose
would be higher.11 However there is variability between patients and because
administration of the antidote acetylcysteine is not completely free of risk, some form
of cut-off was needed to determine in which patients the benefit risk of treatment with
acetylcysteine is favourable.
2.6.1. Historical development of the nomogram
acetylcysteine has been the treatment of choice for paracetamol poisoning for over 3
decades. The marketing authorisation for acetylcysteine incorporates a treatment
nomogram which plots a plasma paracetamol level against time after ingestion.
The first nomogram, which is reflected in the current UK Parvolex marketing
authorisation, was developed by Prescott and colleagues at Edinburgh. In a pivotal
publication in 1971, the authors describe the plasma half life of unchanged
paracetamol in 30 patients with paracetamol overdose who received supportive
treatment only. Plasma concentrations and paracetamol half lives were investigated
in these patients and correlated with liver damage.
A key finding in this study was that the mean half life (t½) of unchanged paracetamol
was more than twice as long in patients who developed hepatic necrosis (7.6±0.8h)
than in those without (2.9±0.3h) and three times longer than that observed after a
therapeutic dose (2.9±0.1h). With only a very few exceptions, t½ was >4h in those
that developed liver damage and <4h in those that did not (Figure 2).
Interesting the t½ was delayed very early, substantially before any toxicity would be
clinically apparent. The mechanism for this is unclear since only about 5% of a dose
is metabolised by hepatic enzymes and thus changes in this rate would only have a
minor effect on the overall rate of elimination. Sulphate metabolism is capacity limited
at higher paracetamol doses possibly due to depletion of activated sulphate or actual
12
saturation of the enzyme. Studies suggest that in adults sulphate metabolism may
become saturated at as little as 2g of paracetamol.38,39 However sulphate metabolism
only accounts for between 25-30% of overall metabolism and therefore would only be
likely to make a modest contribution to the t½. Hence in order to achieve
prolongation of the half life by up to 3 fold, a reduction in glucuronidation must occur.
Evidence for this was in fact provided by Prescott and colleagues in later studies.40,41
A mean reduction in the rate of conjugation of about 60% was observed in patients
with liver damage compared to those with no damage. Slattery and Levy39 also report
that over the dose range 1-32g, the fractions of the dose excreted as paracetamol
and cysteine and mercapturic conjugates increase more than threefold while the
fractions excreted as glucuronide and sulphate decrease by over 60%. Thus the
apparent limited capacity of the direct conjugation pathways causes a greater than
proportional increase in the formation of NAPQI with increasing dose.
Figure 2: Plasma concentrations of unchanged paracetamol in 30 patients
presenting with overdose.5
The authors concluded that although a single determination of plasma paracetamol 4
hours after ingestion was not always a reliable indicator of toxicity, plasma
paracetamol levels >300mg/L at 4h were always associated with severe hepatic
lesions while none were observed in patients with levels <120 mg/L at 4h. These
data and others42 were used to derive the first paracetamol nomogram in which the
plasma paracetamol concentration vs time curve extended from 200 mg/L at 4 h to
50 mg/L at 12 h (the ‘200-line’) (Figure 3). If the 200 line is superimposed on Figure
2, a single 4h paracetamol level would fail to capture 2 of the patients who
subsequently went on to develop hepatotoxicity underlying the authors comment with
regard to the reliability of a single early measurement at 4h. However a later
measurement would have identified them as at risk due to a slowed half life.
A number of different treatment nomograms are in use worldwide most of which were
introduced in the 1970’s. The data from the Prescott et al, 1971 study5 were
subsequently used in the US by Rumack and Matthew in 1975 to develop the
13
Rumack-Matthew nomogram in which the treatment line was extended to 24h.6
Following this in 1981, Rumack et al7 published a study in which the effectiveness of
oral acetylcysteine was investigated in 662 paracetamol overdose patients. Risk of
toxicity was defined using the Rumack-Matthew nomogram except that a “possible”
hepatotoxic zone was incorporated by the introduction of a line 25% below the
200mg/L treatment line (Figure 4). This was introduced at the request of the US
regulatory authority to provide an additional safety zone to allow for errors in timing of
ingestion and analytical errors. This nomogram was then used in a study of more
than 2540 patients investigating the efficacy of oral acetylcysteine in which there
were no deaths among patients who were treated within 15hours.8 This nomogram is
currently in use in the US.
Figure 3: Plasma-paracetamol concentration following overdose. Lower line is the
200mg/mL at 4h treatment line.43,42
14
Figure 4: Rumack-Matthew Nomogram: Plasma paracetamol concentration vs time
post-paracetamol ingestion6,7
2.6.2. Risk of liver damage related to dose/paracetamol level
In a review of the area in 1978 Prescott defined the percentage of patients who
developed liver damage in relation to 4h paracetamol levels.20 This data was used to
plot areas of greater and lesser liver damage on the paracetamol nomogram with one
line joining 300mg/L at 4h and 75 mg/L at 12h and another joining 100mg/L at 4h and
25mg/L at 12hours respectively (Figure 5). No liver damage was seen in patients with
levels below the “100” line but 23% of patients suffered severe liver damage (5/22,
ASR or ALT>1000U/L) between the “100” line and the “200” line (Table 3).
Table 3: Liver damage, renal failure and death in relation to admission plasma
paracetamol concentrations after overdose in 83 patients who received
supportive therapy only.20
Below 150mg/L approximately 7% of patients developed severe liver damage.
Unfortunately individual paracetamol levels for the 5 patients who developed liver
damage between the 100 and 200 lines were not stated although the mean
15
admission plasma paracetamol level at 5h was 142 mg/L. One 19 year old girl
however was discussed in more detail. She developed liver damage with a 3.5h level
of 145 mg/L after ingesting approximately 8g of paracetamol. Above the “200” line
the incidence of liver damage rose to 60% and above the 300 line, 93% of patients
suffered liver damage. Thus these data demonstrate that there is a relatively high
incidence of liver damage below the 200 treatment line (Table 2).
It is important to note however that none of the patients with paracetamol levels
below 200mg/L at 4h died while 6% and 11% of patients died with 4h levels greater
than 200 and 300mg/L lines respectively20.
Figure 5: Plasma paracetamol concentrations in relation to time after overdose
(plotted on a log scale).42
Similar results were found in a further set of 60 patients shown in Figure 6.44
16
(16)
% of patients with
severe liver damage
100
80
60
(15)
40
20
0
(23)
(16)
<150
150–250
250–300
>300
Plasma paracetamol concentration at 4h (mg/L)
Figure 6: Relationship between plasma paracetamol concentration after overdose
and the risk of severe liver damage (defined as plasma alanine
aminotransferase activity > 1000 u/L). The numbers of patients in each
group are given above the column. 11 Three patients died in the >300mg/L
group and 4 suffered renal failure. There were no deaths or renal failure
cases in the other groups.
2.6.3. Introduction of high risk line (100 line)
The relatively high incidence of liver damage below 200mg/L and the identification of
possible risk factors which may increase paracetamol toxicity45,46 led to the
introduction of a lower treatment line for high risk patients in the UK nomogram
starting at 100mg/L at 4 h and finishing at 15mg/L at 15h (Figure 7). The risk factors,
thought to influence the development of hepatotoxicity, are discussed in detail in
section 2.4.
[Note a therapeutic plasma paracetamol level is approximately 15 mg/L47. A level of
100mg/L therefore represents a level at least 6 fold greater than
therapeutic].
17
Figure 7: Paracetamol Nomogram (TOXBASE, UK)
2.6.4. Prior published debate about the treatment nomogram in the UK
In 1998, Bridger et al9 reported four cases of fatal hepatotoxicity all of whom
presented with a paracetamol concentration below the ‘200 line’. These cases did not
receive acetylcysteine initially which in three of the four cases was consistent with UK
guidance.
Case 1
A 16 year old girl presented to A&E four hours after ingesting 20 paracetamol tablets
(10g). She had no additional risk factors for enhanced hepatotoxicity. Her serum
paracetamol concentration was 156 mg/l and she was discharged after receiving 50g
of activated charcoal. Within the next 2 days, she was brought in to hospital for
treatment of acute hepatic failure and was started on acetylcysteine infusion at this
time. However she continued to deteriorate and died despite a liver transplant.
Case 2
A 24-year-old man who presented to A&E within four hours of ingesting 64
paracetamol tablets (32g). He had a history of alcohol misuse (approximately
100units per week). Four hours after the overdose he had a serum paracetamol
concentration of 178 mg/L. He was given 50g of activated charcoal and discharged.
He presented once again 48 hours after the overdose with signs of encephalopathy
and renal failure. He was started on acetylcysteine at this time and despite a partial
recovery of liver function ultimately died of septicaemia and persistent multifocal
seizures six days after the overdose.
Case 3
A 38 year-old-man who presented to A&E after ingesting 50 paracetamol tablets
(25g) and had no apparent risk factors for enhanced hepatotoxicity. Four hours after
the overdose his serum paracetamol concentration was 178 mg/L. He was admitted
to a psychiatric ward for observation but became increasingly confused over the next
2 days at which point investigations showed liver failure. He died 10 days after
overdose.
Case 4
18
A 34 year old woman who presented to A&E after ingesting 30 paracetamol tablets
(15g). She had no risk factors for enhanced hepatotoxicity. Six hours after the
overdose her serum paracetamol concentration was 122 mg/L. She ultimately died
15 days after overdose awaiting a liver transplant.
This article published in 1998 raised questions about the validity of the normal
treatment nomogram for the prediction of paracetamol toxicity in patients ostensibly
without risk factors. Treatment was based on 200mg/L at 4h line (normal risk line)
and therefore although all patients were medically reviewed within six hours of
overdose, acetylcysteine was not given and three patients were discharged with no
follow up. Despite serum concentrations below the treatment line all 4 patients
developed fatal acute liver failure. Chronic alcohol abuse is a listed risk factor and
therefore case 3 should have received treatment based on the high risk line
(100mg/L at 4h). For the remaining cases the authors discussed several factors
which may account for the poor outcome including concealment of the real time of
overdose and number of tablets taken or an enhanced susceptibility to liver damage.
They pointed out that a 2 h error in the timing of the overdoses in cases 1 and 4 and
a 1 hour error in case 4 would be sufficient to return non toxic concentrations.
Alternatively they suggested that the rapid onset of acute liver failure might have
been the consequence of a repeated overdose or alternatively some of the patients
may have been more susceptible to the hepatotoxic effects.
This series of case reports9 generated considerable debate with regard to the
treatment guidelines. The hospital managing the first case commented that timing
was well established in this case in that the time at which the paracetamol was
purchased was known and that help was sought immediately after the overdose.
The authors commented that it was their view that the nomogram should allow for the
22% error seen in this case since “a treatment strategy should allow a margin of
safety that allows for some degree of inaccuracy in the history or an individual
patient’s susceptibility to paracetamol”. Following this case the hospital changed its
treatment protocol in 1994 such that every patient over 150mg/L at 4h was treated
which resulted in the treatment of an extra 60 patients/year of which only 33% (20
patients) were considered normal risk and would not therefore have been treated.
Interestingly a response from Aberdeen Royal Infirmary stated their policy was “to
admit all patients with overdose, checking paracetamol concentrations at four hours,
or on admission, and again four hours later, thus reducing the effect of timing errors.
We immediately start treatment with acetylcysteine in all patients who have ingested
more than 150mg/kg. We also check liver function and prothrombin time to identify
those with underlying liver abnormality or early hepatic damage. These patients can
then be treated earlier”.
In response to this debate, the Directors of UK National Poisons Information Service
(NPIS) published an article48 in the same year discussing the concerns raised by
Bridger et al.9 They emphasised the importance of the national guidelines that were
disseminated to the emergency departments in the UK in 1995. Before these, only 10
of 24 UK emergency departments surveyed had a formal written policy on managing
paracetamol poisoning. They also highlighted the importance of the ‘high risk
treatment’ line (the ‘100-line’) at half the concentration of the conventional treatment
line which covers patients taking long-term enzyme inducing drugs and patients with
other risk factors. They further reinforced the already existing crucial advice in the
guidelines that ‘if there is doubt about the timing or need of treatment, treat’. They did
not believe however that there was sufficient evidence to advocate reducing the
‘normal-risk’ treatment nomogram line for patients.
19
In 2007, Beer et al49 conducted a systematic retrospective survey to establish the
numbers of patients admitted to liver units of Newcastle (September 1996 – March
2003) and Edinburgh (January 1992 – June 2004) with paracetamol induced hepatic
dysfunction who had initial paracetamol concentrations below the relevant nomogram
level at their original presentation. Of the 124 patients who presented within 15h, 105
(81%) had paracetamol concentrations above the appropriate treatment line (either
the “100” or “200” line). The subsequent treatment or not of these patients is not
stated. The authors found only 14 patients who were admitted to a liver unit but who
had had initial paracetamol concentrations below the relevant treatment line within
15h of overdose and no evidence of liver damage at their original presentation. Of
these 14, only 6 patients had paracetamol levels between 100 and 200mg/L of which
one subsequently died. Of these 6 patients, 3 had co-ingested alcohol but had no
history of alcohol abuse, 1 had co-ingested codeine and paroxetine and 2 had no
known risk factors. Interestingly the remaining 9 cases presented with levels below
the 100mg/L line. Overall these 14 cases translated to an annual presentation of 0.15
episodes per million populations or about nine UK cases annually (using a UK
population of 60million). Considering only the cases between the two lines, the 6
cases would translate to an annual presentation of 0.06 episodes per million
populations or about 3-4 (3.8) UK cases annually.
The authors state that the estimates in their paper should be interpreted with
caution as not all patients with severe hepatotoxicity will be referred to a liver unit.
Furthermore, the authors state that the proportion of patients with paracetamol levels
between the 150 and 200 lines and treated with acetylcysteine increased from 25%
to 76% from 1994 and 2004.9 Similarly the proportion of patients with paracetamol
levels between the 100 and 150 lines and treated with acetylcysteine increased from
2% to 15% from 1994 and 2004.9 This increased treatment rate is likely to have
been influenced by the Bridger publication but in the current study would have
reduced the number of patients needing liver unit admission and thus resulted in an
underestimation of risk. The authors concluded that the use of the 150 line for
determining need for treatment would prevent only a few liver unit admissions but
would require treatment of very large numbers of patients. These marginal benefits
need to be offset against the inconvenience and costs of therapy and the risk of
adverse reactions associated with acetylcysteine. This is risk benefit will be
considered in more detail in later sections.
Beer et al49 also reported an analysis of data from 6 A&E departments in 1994 from
the northwest of England which estimated that 64%, 13% and 6.4% of patients
presented with paracetamol levels <100mg/L, between 100 and 150mg/L lines and
between 150 and 200 mg/L lines respectively. Equivalent figures for 352 patients
presenting to the Newcastle Clinical Toxicology Service estimated that 71%, 15%
and 6.4% of patients presented with paracetamol levels below the <100mg/L line,
between 100 and 150mg/L lines and between 150 and 200 mg/L lines respectively.
A recent paper published in November 201129 also provides information on cases of
hepatotoxicity admitted to the Scottish Liver Transplantation Unit following
paracetamol overdose between 01/11/1992 and 31-10-2008. Although the study
focuses on the clinical impact of staggered overdose and delayed presentation it also
contains data on 450 acute single point overdoses which resulted in hepatotoxicity
and thus admission to the Liver Unit. Although the vast majority of these cases were
treated with acetylcysteine the authors have provided additional details of 8 cases of
hepatotoxicity in which patients presented to hospital <12h following the overdose
but were not treated with acetylcysteine. All these patients subsequently presented
with severe liver injury. Details of the cases are provided in Table 4 below.
Unfortunately further details on the presence of any risk factors are not available.
20
Pt id
A
B
C
D
E
F
G
H
Sex
Age
No of
tabs
F
F
F
F
M
F
M
M
26
21
21
29
50
29
31
21
20
48
24
120
40
72
80
50
Delay to
present
(hr)
6
6.5
5
11
8
4
30
4
Para
level
First Alt
(IU/L)
First PT
(s)
Outcome
95
Missing
129
66
110
454
173
85
21
7834
328
Missing
2260
2190
Missing
4159
16
50
29
86
42
16
16
Missing
Survived
Survived
Survived
Survived
Survived
Died
Survived
Survived
Table 4: Demographics and clinical details on 8 patients who presented to hospital
<12h following a single point overdose but were not treated with NAC and
subsequently represented with severe liver injury. Unpublished data
supplied by Dr K Simpson, Royal Infirmary of Edinburgh.
According to the current nomogram Patient F should have been treated. Patients D
and E are also marginally above the normal risk lines and therefore should also have
received acetylcysteine treatment. Patients A, C and G fell between the normal and
high risk lines and therefore would only have received acetylcysteine if they were
considered to have risk factors, while patient H was very marginally below the high
risk line and would not have received treatment unless there was doubt about the
timing of the overdose. All patients presented before 2004. Patient A was included in
the data set presented in the paper by Beer et al49 and, although had co-ingested
alcohol and salicylate, had no further risk factors. Her maximum alanine
transaminase level was 11,000IU/L. Patients C and G were not included in the study
by Beer et al49 and therefore increase the numbers of patients presenting between
the lines with liver damage to 8 (annual presentation of 0.08 episodes per million
populations or about 5 UK cases annually).
2.6.5.
Further unpublished data on patients presenting with heptatoxicity and with
paracetamol levels <200mg/L at 4h.
Further data has also recently been provided by
21
22
23
24
2.7.
Limitations of the nomogram in identifying the patient population for
acetylcysteine treatment.
The previous cases illustrate some of the difficulties in interpreting a paracetamol level
in the context of an overdose especially in terms of the reliance on the patient to
provide an accurate clinical history. As such, despite the introduction of the high risk
line, there continues to be reports of hepatotoxicity occurring in patients who could
have been treated with acetylcysteine but were deemed not to be at risk. There are a
number of factors which influence the reliability of the treatment nomogram in
predicting hepatotoxicity. These factors, and additional possible risk factors not
recognised to date in the advice, were discussed at length by the Expert Working
Group and are reviewed in detail below.
2.7.1.
Risk factors
2.7.1.1.
Reduced food intake
Paracetamol metabolism and thus toxicity has been known for many years to be
influenced by diet and nutritional state. Consequently most animal models incorporate
fasting into the methodology to increase hepatotoxicity. Increased toxicity in the face of
calorific restriction is thought to arise in a number of ways. Firstly starvation/fasting is
known to alter plasma glutathione levels which are thought to reflect hepatic
glutathione levels.50 Thus patients with anorexic nervosa (BMI<17mg/kg2) have been
shown to exhibit lower circulating levels of free cysteine and free and total glutathione;
in 11 patients with anorexia versus 12 healthy controls both free and total glutathione
were reduced by approximately 30% and positively correlated with BMI. This reduction
in levels may place them at increased risk following a potentially hepatotoxic dose of
paracetamol. Other conditions thought to reduce glutathione levels include chronic
diseases such as cystic fibrosis, AIDS, Hepatitis C and other cachectic conditions. In
fact any condition which induces oxidative stress may reduce glutathione levels and as
such plasma glutathione levels have been demonstrated to be lower in patients with
cardiovascular disease51 and in surgical patients with abnormal liver histology and drug
ingestion (not paracetamol).52 To complicate the picture further there is also evidence
there may be temporal variations in hepatic GSH levels of an extent which might
influence toxicity.53
Unfortunately there are very limited data on the extent of glutathione reduction
required before paracetamol-induced toxicity becomes apparent. Studies in rats have
indicated that binding of paracetamol to hepatic proteins only occurred with doses of
paracetamol that resulted in a 70% or greater depletion of hepatic glutathione (Figure
8).54,55
25
Figure 8:
Hepatic glutathione and covalent binding to hepatic protein after increasing
doses of paracetamol. Glutathione concentration (filled circles) and
covalent binding (filled squares) of 3H-paracetamol were determined 120
minutes after administration. Points represent means±SEM of at least 3
mice.54
In contrast, in studies in mice Roberts et al56 reported a threshold of 25% and Antoine
et al57 recently demonstrated that serum ALTs began to rise in mice when hepatic GSH
content was reduced by 21% with significant rises of >2000IU/L when GSH was
depleted by 46% (Figure 9). It is this likely that significant interspecies differences exist
in terms of the critical glutathione threshold for toxicity.
Figure 9: Reduction in hepatic GSH content with increasing paracetamol dose (A) in
male mice with corresponding increases in serum ALT (B).57
To date alterations in paracetamol metabolism following fasting in humans have not
been conclusively demonstrated although there is some evidence that paracetamol
elimination time is substantially increased in protein malnourished children58,59,60 and
adults.52 In a retrospective analysis of 49 patients with paracetamol toxicity (aspartate
26
aminotransferase>1000U/mL) the prevalence of chronic alcohol use, recent alcohol
use and recent fasting were assessed.61 Recent fasting was defined as “…individuals
who had clear documented evidence of fasting or inability to eat prior to
acetaminophen ingestion” and was determined from medical record review. No
biochemical assessment was made. Twenty-one (43%) of the patients ingested
paracetamol for therapeutic purposes, 10 with moderate (4 – 10g/24h) and 11 with
excessive (>10g/24h) consumption. Intake was estimated on the basis of clinical
history as a paracetamol level does not predict toxicity following chronic ingestion. The
authors concluded that paracetamol toxicity was associated with fasting based on the
fact that 8 out of 10 patients in the moderate ingestion group and 5 of the 11 in the
excessive ingestion group satisfied the study definition of recent fasting.
Schenker et al62 examined the effects of a more defined calorific restriction on hepatic
metabolism following a single 2g dose of paracetamol. In a prospective study the
metabolism of 2g of paracetamol was assessed before and after a controlled food
restriction of 500 calories/day over 5 days and 1000 calories over 13 days. Both diets
were predominantly carbohydrate with 17 and 20% of calories from protein in the 500
and 1000 calorie diet respectively. Unfortunately the data are limited by the modest
dose of paracetamol used. Following a 500 calorie/day diet, 2g of paracetamol was not
sufficient to saturate even the sulphation pathway the contribution of which actually
increased from 24.07% of the dose to 26.95% of the dose after the 5 day diet period.
Since the sulphation pathway is the most easily saturable no changes in any other
metabolic pathway would be predicted. Similarly no effects on metabolism were seen
after the longer period of less severe food restriction.
A further two cases of paracetamol induced hepatoxicity were reported recently in the
British Medical Journal63 The cases were associated with therapeutic doses of
paracetamol but occurred in adult patients with low body weights. Both patients had
very low body mass indexes (12 and 17kg/m2) and yet received 4g of paracetamol/day
(equivalent to 133mg/kg and 91mg/kg respectively) which resulted in raised
paracetamol levels, 92 and 105mg/L at 4 and 3 days respectively, after the start of
administration. One patient died of multi-organ failure 12 days later despite
acetylcysteine treatment and the other recovered after full supportive care in the liver
intensive care unit. These cases, although cases of staggered overdoses, illustrate the
potential risk of increased hepatotoxicity in patients with low body weight. Both patients
had additional risk factors; one had a history of Crohn’s colitis and the second a history
of chronic alcoholism.
The data supporting an effect of fasting on heptatoxicity is more convincing in animal
models and as discussed earlier most experimental studies incorporate fasting to
increase hepatotoxicity. Price and Jollow64 reported in 1988 that a 24h fast in the rat
resulted in a reduction in glucuronidation following a hepatotoxic dose of paracetamol
(700mg/kg) due to a reduced rate of resynthesis of a key substrate. In line with these
results, a recent study suggests that 24h of fasting in the mouse increased
paracetamol induced liver necrosis at the expense of apoptosis, predominantly due to
a dramatic reduction in hepatic ATP (50%) and hepatic glycogen.65
In conclusion while these data raise sufficient concerns to list fasting as a risk factor
they are not prescriptive enough to provide clear guidelines to doctors as to what is or
is not a significant amount of food restriction to aid the diagnosis of potential toxicity.
The current SmPc for Parvolex states the following text referring prescribers to the high
risk treatment line (treatment line B on the nomogram present in the SmPC):
“Patients suffering from malnutrition, for example, patients with anorexia or AIDS, may
have depleted glutathione reserves. It has been recommended that paracetamol
overdose in such patients be treated as for chronic alcohol consumers or patients
taking anticonvulsant drugs (treatment line B- see graph).”
27
The BNF/TOXBASE advice has been updated
and now
states that acute or chronic starvation “for a few days” should be considered a risk
factor.
2.7.1.2. Rate of absorption of paracetamol
Fasting may also influence the assessment of toxicity by affecting the rate of
absorption of paracetamol. Divoll et al66 clearly demonstrated that administration of
650mg paracetamol with food significantly decreased peak plasma concentration,
prolonged the time to peak plasma concentration and reduced systemic availability
compared with the same dose of paracetamol given after an overnight fast (Figure 10).
In young subjects the mean peak plasma concentration after fasting (11.1 mg/L (6.214.6)) was substantially higher than that achieved after a standard breakfast (6.8 mg/L
(4.6-13.2)). Similarly the absorption half life was approximately twice as long after food
(14.0 min (fasting) vs 28.3 min (food)). The implications of these results is that a 4h
plasma paracetamol level appears to capture the peak level when the paracetamol is
administered after food but misses the peak levels when the paracetamol is
administered after a period of fasting (Figure 10, left hand panel) This may have
significant implications for the prediction of toxicity using a standard nomogram.
Figure 10: Plasma concentrations of paracetamol of an individual following oral
administration of a paracetamol elixir (left) or tablets (right hand panel) in
the fasted state or following a standard breakfast.66
2.7.1.2.1. Opioid Co-ingestion
Opioid co-ingestion may impair gastrointestinal absorption of paracetamol and
therefore in contrast to the situation with fasting may slow or reduce absorption.
Halcomb et al67 investigated the influence of the antihistamine diphenhydramine and
oxycodone on the absorption kinetics of a single 5 g dose of paracetamol on 3
separate days over a 3month period in 10 healthy adults. On study day one, subjects
ingested 10 x 500mg paracetamol. On the second study day they took 5g of
paracetamol in combination with 25mg of diphenhydramine and on the third day 5g of
paracetamol plus 5mg of oxycodone. Study days occurred in random order for each
subject with a minimum washout period of 7 days between study days. Each subject
28
served as his/her own control and underwent all three arms of the study. Blood levels
were assessed hourly for the first 8h and then at 24h for the assessment of
paracetamol levels. Figure 11 demonstrates that paracetamol levels were significantly
lower for paracetamol + oxycodone for hours 1-4 compared with both paracetamol
alone or paracetamol + diphenhydramine. No differences were observed between the
latter two blood measurements.
Figure 11: Hourly serum paracetamol levels 0 -8 hours after ingestion of dose. Data
represents mean ± SEM of 10 subjects. DPH= diphenhydramine’ OXY =
oxycodone; APAP= paracetamol.67
Thus co-ingestion of paracetamol with oxycodone resulted in a 27% lower area under
the curve but a 35% lower peak paracetamol concentration. Half life was also
prolonged by 42% in the oxycodone group. Hence there is a discrepancy between the
peak levels and area under the curve, with the former being reduced more than the
latter. The prolongation of t½ may also impact negatively on the ability of the
nomogram to predict toxicity. It is interesting to note, as for Figure 10, that a 4h
paracetamol level would miss the peak plasma level in subjects ingesting either
paracetamol alone or paracetamol in combination with diphenhydramine. There is no
information in the methods as to food intake in these subjects but the kinetics of the
data would suggest patients were not fasted prior to study drug administration. In
apparent contrast to this study, Waring and Benhalim68 report that serum
acetaminophen concentrations were not altered by opioid co-ingestion. In this
prospective observational study of 990 patients the primary outcome was serum
paracetamol levels and the equivalent 4h paracetamol level. No difference in the
relationship between stated dose and the equivalent 4h paracetamol level was
observed between patients who co-ingested opioids and those that did not. However
in Figure 11 above it can be seen that a single 4h measurement would also have
revealed no significant difference between the groups because the paracetamol only
groups had declined to the level seen in those that co-ingested opioids.
29
Two retrospective studies from the same authors in Denmark have also attempted to
determine whether co-ingestion of opioids increase the risk of hepatotoxicity with
paracetamol.69,70,68 The two reports provide subtly different messages. An earlier study
reports a protective effect of concomitant overdosing with opioids in the development of
hepatic encephalopathy (OR, 0.26; 95% CI 0.07-0.96)70 while a study 1 year later using
a slightly extended data set reports that regular medication with opioid analgesics was
associated with an increased risk of hepatic dysfunction (OR, 5.39; 95% CI, 1.13-25.8).
Different mechanisms are likely to underlie these effects. The protective effect of
opioids when acutely co-ingested with paracetamol may result from a delayed or
reduced absorption of paracetamol (in Denmark all paracetamol cases are treated with
acetylcysteine irrespective of levels so co-ingestion with opioids will not influence the
decision to treat or not) while regular medication with opioids may increase risk of
hepatotoxicity by glutathione depletion 71,72. In addition patients taking regular
medication with opioid analgesics may have reduced appetite because of the
underlying condition.
There are additionally several case reports in the literature detailing delayed peak
paracetamol levels in patients co-ingesting codeine or antihistamines with
paracetamol.73,74,75,28 Furthermore in a retrospective observational case series Doyon
and Klein-Schwartz23 also reported the details of 6 patients who had persistent
elevation of paracetamol levels, elevated liver enzymes or both and who ingested
combination products. Five of these ingested paracetamol combined with
diphenhydramine.
These studies have implications for the assessment of potential hepatotoxicity based
on a 4h paracetamol level. If absorption kinetics are substantially delayed by for
example the co-ingestion of anticholinergics, narcotic analgesics or other agents that
may inhibit gastric emptying, a 4h paracetamol level may not be an accurate predictor
of toxicity.
2.7.1.3. CYP 450 enzyme inducers
In man, the CYP isoenzymes thought to be involved in the formation of NAPQI are
CYP2E1, CYP3A4, and CYP1A2.76 However there is debate as to the relative
contributions of these enzymes in the metabolism of paracetamol in man77,78,79 Some of
the discrepancies no doubt relate to interspecies differences and the use of a range of
experimental models80 as well as the substantial individual differences. Differences in
the affinity of the main CYP450 enzymes for paracetamol have also been reported with
CYP3A4 having a higher affinity than CYP2E1 but lower capacity. 78,81 Thus CYP3A4
activity may predominate following therapeutic doses of paracetamol while CYP2E1
may be quantitatively more important following overdose. As such Lee et al82
demonstrated in CYP2E1 null mice, no rise in ALT with paracetamol doses of up to
400mg/kg and only moderate rises with doses of 600mg/kg. The data in mice is
variable with regard to the involvement of CYP1A2.76,83 but would support an
involvement of CYP3A484. However this is not consistently supported by studies in
man.85,86,87 Hence an in vivo study in 16 healthy human volunteers, using disulfiram to
inhibit CYP2E1 and rifampicin to induce CYP3A4, demonstrated a major role for
CYP2E1 with little contribution from CYP3A4.85 Subjects were administered 500mg of
paracetamol following an overnight fast. Disulfiram decreased the recovery of all
oxidative metabolites substantially and more specifically the thiol metabolites, formed
by the conjugation of NAPQI with glutathione, were decreased by 69% and the
formation clearance of NAPQI was reduced by 74%. In contrast rifampicin caused
negligible changes in paracetamol kinetics suggesting that, even when induced, the
contribution of CYP3A4 to NAPPQI formation in vivo in man is small.
30
2.7.1.3.1. Alcohol
Alcohol has long been considered a risk factor for paracetamol induced hepatotoxicity
because it is thought to be metabolised by the same CYP enzymes as the toxic
metabolite of paracetamol. To support this view several case reports88,88 and
studies89,90,91 have been published which suggest increased toxicity following
paracetamol usage in chronic alcoholics. As a result product information states that
patients who routinely consume alcohol above recommended levels are believed to be
a risk of hepatoxicity. However the term “routinely” is not defined nor is for how long
alcohol must be consumed to increase the risk of toxicity.
2.7.1.3.1.1. Induction of CYP 450 enzymes
Chronic ethanol intake is thought to cause up to a four fold induction of CYP2E192,93,94
but the effect may be short lived and returns to normal after an abstinence of 5-10
days95,77,93 as CYP2E1 has a relatively short half life of 2.5 days.96 In humans,
concentrations of 22-45mM ethanol have been detected in serum 1h after consumption
of alcoholic drinks97,98 and in primary human hepatocytes ethanol concentrations as
low as 25mM were sufficient to induce CYP3A4/CYP2E1 protein within 48h. However
the concentration required varied between hepatocyte cultures from different donor
livers, as did the extent of induction by ethanol. In these cultures ethanol generally
increased CYP3A4 to a lesser extent (~3 fold) than rifampicin, a potent CYP3A4
inducer. There is little information however as to the time or amount of alcohol required
in vivo for the induction of CYP2E1, or indeed CYP3A4.
The picture with regard to alcohol consumption is further confused by the fact that
acute alcohol consumption will compete with paracetamol for metabolism via the
CYP2E1 pathway. As such ethanol, at doses as low as 2mM, has been demonstrated
to inhibit the formation of NAPQI but protection is lost after 6h.99 The effect of ethanol
will therefore depend on the timing of ingestion with regard to the paracetamol
overdose and thus presents a complicated picture for risk assessment. An additional
risk factor in such patients is that hepatic GSH levels are also reduced following regular
alcohol consumption.100,101
2.7.1.3.1.2. Studies investigating the influence of alcohol consumption on paracetamol
toxicity
A number of studies have attempted to define the complex relationship between
paracetamol hepatotoxicity and alcohol consumption in the clinical setting. In a
retrospective study of 553 patients admitted to a specialist liver unit between January
1987 and December 1993 there was no correlation between alcohol consumption and
the severity of hepatotoxicity (defined by mean INR and serum creatinine levels over
the first 7 days after the overdose).102
Seifert and Anderson101 in a prospective cohort study in a community based crisis
intervention centre similarly concluded that paracetamol induced hepatotoxicity was
uncommon in alcoholics despite elevated γ-glutamyl transferase and decreased
median plasma glutathione levels and evidence of increased paracetamol usage.
Schmidt et al91 examined the clinical course and outcome in 645 consecutive patients
admitted from 1994-2000 with single dose paracetamol overdose in Denmark. The
policy in Denmark is to treat all patients with suspected paracetamol overdose
regardless of severity so outcome in this study was assessed in terms of mortality rate
following acetylcysteine treatment.
Chronic alcohol abuse was defined as an excess of 14 units weekly for women
and 21 units for men (1 unit = 10g ethanol) but duration of use was not defined. Acute
alcohol was defined as ingestion of alcohol as part of the intoxication in excess of the
patient’s regular daily consumption. Consequently a single patient could fall into both
groups. In contrast to the previous 2 studies, chronic alcohol ingestion was identified as
31
an independent risk factor for mortality (Odds ratio [OR], 3.52; 95% CI, 1.78-6.97).
However, acute alcohol ingestion was an independent protective factor for mortality in
alcoholic patients (OR, 0.21; 95% CI, 003-1.67). Thus the effects of chronic alcohol
abuse were counteracted by concomitant acute alcohol ingestion. Patient age and
paracetamol dose were also independent risk factors. These risks were independent of
the time to acetylcysteine treatment which was the single most important risk factor up
to 72h.
Sivilotti et al89 also reported that in a series of 1,270 patients admitted with acute
paracetamol overdose, the risk of hepatotoxicity despite acetylcysteine treatment was
significantly higher in the absence of co-ingested alcohol and this risk was even higher
in alcoholics. That is the toxicity of paracetamol was reduced by 40% in the presence
of alcohol while abstinence in an alcoholic tripled the risk of toxicity after an overdose.
Given these competing factors, and thus the reliance on an accurate clinical history,
the determination of the effect of alcohol on the risk of hepatotoxicity will always be
difficult to determine. The presence of confusion in this area is supported by anecdotal
reports which suggest that doctors treat all patients who present with a history of coingestion as high risk when in fact they may not be. This may be because it is
considered the patient is not able to give a reliable clinical history. In contrast, the
apparent absence of an acute intoxication may lead a person who consumes alcohol
on a regular basis to be categorised as low risk.
2.7.1.3.2. Other liver enzyme inducing drugs
In a similar manner to alcohol, any drug which induces the CYP2E1 pathway will
predispose the patient to enhanced toxicity following a paracetamol overdose.
However the lack of clarity with regard to the involvement of CYP450 enzymes in the
metabolism of paracetamol means that the co-ingestion of a range of CYP3A4 as well
as CYP2E1 inducers may place a patient in the high risk category. Equally drugs which
act as substrates for or inhibit these pathways may reduce the toxicity of paracetamol.
There are a large number of commonly used drugs which interact with the CYP450
pathway, examples of which are provided in Table 6.103 However this list is by no
means comprehensive.
Consequently current guidelines recommend any patient on a range of enzyme
inducing drugs such as carbamazepine, phenobarbital, phenytoin, primidone,
rifampicin, rifabutin, efavirenz, nivirapine, St John’s Wort or other drugs that induce
liver enzymes should be treated in the high risk category. Theoretically other CYP450
inducers such as topiramate104 should be included. It is easy to imagine that in the
stress of an overdose situation, obtaining an accurate clinical history of a range of
possible co-ingesting medications will be difficult to achieve.
32
Table 6:
Clinically relevant CYP450-medicated interactions in the Intensive Care
Unit.103
2.7.1.4. Pharmacogenomic factors
A natural variation in the expression of CYP450 enzymes may also underlie the
apparent increased susceptibility to paracetamol in some individuals.105,106,107,81 For
example recent evidence107,108 demonstrates that there is substantial inter-individual
variability in the susceptibility to liver injury following chronic administration of
paracetamol. In a placebo controlled trial in 145 healthy adults Watkins et al107
demonstrated that approximately one third of adults who were administered the
maximum therapeutic dose of paracetamol (4g/day for 14 days) exhibited transient
asymptomatic elevations in serum alanine aminotransferase (ALT) greater than 3 fold
the upper limit of normal. A later double blind placebo controlled study108 in which
49/59 healthy subjects received 4g/day of paracetamol for 7 days demonstrated that
69% of these subjects had elevations in ALT 1.5 fold of their individual baseline (Figure
12). Values exceeding 2 fold baseline were observed in 37% while the most
susceptible subjects exhibited ALT elevations up to 6 fold higher than their baseline
levels (Figure 12). Interestingly 31% of individuals showed no elevations at all
emphasising the large inter-individual variability. These data would suggest that
individuals susceptible to transient low dose ALT elevations would have a substantially
decreased threshold for toxicity at higher doses. Predicting such individuals however is
currently not possible.
Critchley et al109 also demonstrated wide intersubject and ethnic differences which
influenced the metabolism of paracetamol. For example the production of mercapturic
and cysteine conjugates of paracetamol varied 60 fold among the ethnic groups
compared but only three fold in respect of glucuronide and sulphate conjugation
(Figure 13). The few individuals in the Caucasian group with very extensive metabolic
activation will be particularly vulnerable to the hepatoxic effects of paracetamol.
33
Figure 12: Maximum serum ALT fold change measured in human volunteers taking daily oral
doses of acetaminophen. The peak ALT fold change over baseline reached over
the course of treatment by each subject in the cohort is shown. Subjects were
considered responders (N = 34) if peak serum ALT reached greater than 1.5-fold
(line) higher than the subject’s baseline value.108
Figure 13: Frequency distribution (in 2% increments) of percentage of total excreted
as the combined mercapturic acid and cysteine conjugates of paracetamol
in Caucasians, Ghanaians, Kenyans.109
34
Furthermore the substantial influence such variability can have on toxicity is provided
by the fact that a 500mg/kg dose of paracetamol failed to induce necrosis in the rat
(low CYP2E1 activity) compared with a 76% incidence in the mouse. Other studies
have demonstrated that a Rsa I restriction fragment length polymorphism (RFLP) in the
5'-flanking region of the CYP2E1 gene (termed c2) showed greater transcriptional
activity, higher protein levels and increased activity compared with the wild-type allele
(c1). The frequency of these alleles were determined in 95 Caucasian patients with
alcohol liver disease (ALD) compared with 205 control subjects (comprising 58
alcoholics with no liver disease, 47 patients with non-alcoholic liver disease and 100
healthy volunteers). The results demonstrated that in controls, the frequency (0.024) of
the c2 allele was similar to that previously reported in other Caucasian populations.
The c2 allele frequency in patients with ALD (0.1), however, was significantly higher
than in control subjects (p = 0.0003; odds ratio (OR) 4.5, 95% CI 1.9-10.9). The
authors concluded that Caucasians carrying the Rsa 1 c2 allele of the CYP2E1 gene
may be at higher risk of developing ALD if they abuse alcohol. In a similar manner the
hepatic expression of CYP3A4 has also been shown to vary by more than 10 fold
between different individuals and activity to vary by as much as 20 fold.110 Kostrubsky
et al111 also reported that the amount of immunoreactive CYP3A4 varied between 3
different livers. Such variability alone, currently impossible to predict in a hospital
setting, is probably sufficient to explain the enhanced toxicity seen in some patients
following a paracetamol overdose.
2.7.1.5. Age
There is little evidence to suggest that paracetamol induced metabolism per se is
altered in the elderly unless renal function or liver function is significantly
impaired.112,113,114 In very elderly patients however (80-90 years) there is some
35
evidence of an increased systemic exposure to paracetamol, which can be at least in
part explained by reduced kidney and/or liver function.115,116 Food intake may also be
reduced in such patients, which may affect glutathione levels and absorption.
Increased age per se is not however currently considered a risk factor for toxicity.
Several studies suggest however that children, particularly young children, are more
resistant to paracetamol toxicity and the threshold for toxicity resulting from a single
acute ingestion should be closer to 200mg/kg.117,118 In support of this were the results
of Mohler et al119 who carried out a prospective observational study of calls to a
regional poison centre over a 25 month period. A total of 1039 patients were included
(519 girls and 520 boys, median age 2.3 years (all <6years) with acute maximum
exposure to paracetamol of 20 - 200mg/kg. Of these, 236 had exposures of 100200mg/kg and 68 of 150-200mg/kg. Seventy-two hours after the initial contact, 1019
patients were well without signs or symptoms of hepatotoxicity. Twenty patients were
either lost to follow up or had incomplete data. Since this was an observational study
no information on serum paracetamol level or liver enzymes was provided.
Furthermore the maximum possible ingestions were estimated as was the weight of the
children. Lastly clinical evaluation of the condition of the children was performed by the
parents and it is impossible to determine whether any mild liver dysfunction was
present.
Anderson et al118 simulated paracetamol concentrations for 1000 children (1-5 years)
with pharmacokinetic parameters and their expected variability. The distribution of
concentrations arising from a 300mg/kg single dose at different age groups (1 year,
weight 8-12kg; 5 years, weight 16-22kg; adults, weight 55-85 kg) was predicted. The
predictions were then validated by comparison with 4h serum paracetamol
concentrations (>1.5mg/L) from 121 children with accidental ingestion of paracetamol
liquid (>50mg/kg). In this publication, the authors state that because clearance of drugs
is a nonlinear function of weight that decreases with increasing weight118, larger doses
are required in younger children to achieve similar concentrations than older children or
adults. Therefore serum concentrations predicted on the basis of an allometric power
model predicted lower serum paracetamol concentrations than the per kilogram dose.
As such peak concentrations of 200mg/L would require a dose of 300mg/kg in a 1 year
old (8-12kg), 280 mg/kg in 5 year olds (16-22kg) and 230 mg/kg in an adult (55-85 kg).
Simulated time-concentration profiles (95% CI) for children and adults after 300mg/kg
paracetamol with the allometric model are shown in Figure 15. Importantly to note
however in terms of clinical management is that metabolism is substantially faster in
young children (<5years).
36
Figure 15:
Confidence intervals (CI, 5% to 95%) of simulated concentration-time profiles for
children and adults given 300mg/kg paracetamol (Solid line = 1 year; dashed line =
5 years; dotted line = adults). Rumack-Matthew action line is same as 95% CI
concentration-time profile for 1-year-old child.
A later publication from the same authors120 suggests that due to a lower total body
clearance at birth of 64% and a volume of distribution 174% of that of older children,
lower doses of paracetamol would be required in children under one to achieve a
serum concentration of 10mg/L. The authors120 suggest that a serum concentration of
10mg/L in approximately 50% of children could be achieved with a dose of
45mg/kg/day at birth, 60mg/kg/day at 1months, 72mg/kg/day at 6 months, and
90mg/kg/day up to 9months. However the dose can be reduced to 75mg/kg/day in an 8
year old child due to the nonlinearity between clearance and weight.
Irrespective of the above, it is interesting to note from Figure 15 that despite this careful
modelling, predicted serum paracetamol concentrations arising from a 300mg/kg dose
still span a large range from 32-280mg/L (95% CI) 4 hours after ingestion. Thus even
after allowing for age related differences in clearance, substantial variability in
concentrations resulting from a single dose still seem to exist. Anderson et al118
conclude by recommending that a serum concentration measurement is taken only in
children (<5 years) who have ingested >250mg/kg of paracetamol and that this
measurement could be taken at 2h. A concentration of 225mg/L would then indicate
possible toxicity. Bond121 also suggest that a single acute dose of 200mg/kg is
relatively safe in healthy children and should be used as a referral threshold for
preschool children following acute unintentional ingestion of paracetamol. However
neither of these authors considered children older than 5 years and how these
recommendations relate to this age group is unclear. Furthermore the impact of coexisting risk factors, such as acute starvation, on this threshold was not considered.
2.7.1.6. Pregnancy
Pregnancy is not currently considered to influence the risk of paracetamol-induced
hepatotoxicity. However due to the fact that plasma volume increases by 40-50% there
was discussion among the expert working group as to the reliability of a plasma
paracetamol level in the prediction of toxicity. Rayburn et al122 compared paracetamol
37
pharmacokinetics in 6 healthy women who ingested a standard 1000mg dose after an
overnight fast at 36 weeks gestation and 6 weeks post partum. As a result of the
increased volume of distribution, the area under the curve was reduced significantly
(Figure 16).
The
maximum
plasma
concentration occurred at 0.8h
(kinetics in line with fasted
patient shown in Figure 10) in
both groups and was not
significantly different during
pregnancy (20.8±6.9μg/ml) and
the
non
pregnant
state
(23.7±6.0μg/ml).
Plasma
concentrations between 4-8h
were consistently lower in
pregnancy and it is likely that
differences would be larger with
the larger doses seen in an
overdose
situation. It is possible
Figure 16:
Mean
plasma
paracetamol
therefore
that
this
could
concentrations after a single
potentially
impact
on
the
1000mg oral dose in 6 healthy
prediction
of
risk.
No
significant
women during and after pregnancy.
differences were observed in the
percentage
of
the
dose
metabolised via the different metabolic pathways although there appeared to be a
tendency for an increase in cysteine adduct formation (Table 7). However the small N
numbers and thus large variability substantially reduce the power of the study to pick
up significant differences.
Parameter
Pregnant
Non Pregnant
P
t½ (hr)
3.7±0.4
3.1±0.4
NS
20.8±6.9
23.7±6.0
NS
Cmax (μg/mL)
Tmax (hr)
0.8±0.4
0.8±0.4
NS
48.15±12.6
66.4±11.9
<0.05
AUC (μg/hr/mL)
CL/F (L/hr)
21.9±5.37
15.4±2.5
<0.05
CL/R (L/hr)
0.61±0.64
0.35±0.34
NS
Urinary Excretion (%)
Paracetamol
2.5±2.1
2.5±2.3
NS
Glucuronide
40.2±21.5
40.6±20.7
NS
Sulphate
17.8±14.8
24.7±18.1
NS
Cysteine adduct
6.5±1.9
3.8±1.7
NS
Mercapturic acid
2.5±1.1
2.1±1.5
NS
Cmax = Maximum plasma concentration; Tmax= time to max concentration; AUC = area
under the plasma concentration curve; CL/F= oral clearance; Cl/R = renal clearance.
Table 7:
Pharmacokinetic parameters of paracetamol disposition in pregnant and
non pregnant women (+1 SD).122
In pregnant rats following an IV paracetamol dose of 300mg/kg, total plasma clearance
was significantly lower and the biological half life longer but Cmax was the same. In line
with the results in table 7, the percentage of the dose excreted as sulphate was
significantly decreased in pregnant rats with no change in the glucuronide component.
Unfortunately the study did not examine the formation of the key toxic cysteine and
mercapturic acid adducts possibly because expression of CYP2E1 is low in the rat. In
38
addition, examining the influence of factors on paracetamol metabolism in animal
models is flawed due to the substantial inter-species differences in the relative
dependence on the different pathways (Table 8). Thus the rat is heavily dependent on
sulphate metabolism with little reliance on glucuronidation, the opposite to man.
Despite the paucity of data, given the fact that paracetamol is known to cross the
placenta123 and there is evidence foetal liver cells can produce the toxic metabolites124,
the group considered that such patients should be treated according to the high risk
line of the nomogram.
Conjugates
Species
Glucuronide
Sulphate
Cysteine
Mercapturate
Man
Mouse
Rat
Hamster
Guinea-pig
Rabbit
Cat
Dog
Pony
Baboon
50-60
50-60
10-20
40-50
80-90
77
1-15
75
60
-
25-35
10-20
40-80
20-30
4-7
16
60-90
15
35
-
2-5
15-25
1-5
0-2
1
<1
5-10
3-4
2-4
1-3
2-6
10-15
1
6
1-2
0
<1
Table 8:
<1
Species difference in the metabolism of paracetamol as shown by the
average percentage urinary excretion of conjugates.11
2.7.1.7. Oral Contraceptives
A number of studies have investigated the effects of oral contraceptives, predominantly
low dose oestrogen tablets (<50μg oestrogen) on paracetamol metabolism and
elimination.125,126,127 Miners et al125 investigated the effects of combination pills
including Microgynon, which is still widely used. Ethinyl estradiol is known to be
extensively metabolised, primarily by intestinal sulphation and hepatic oxidation,
glucuronidation and sulphation.128 CYP3A4 metabolism is the major route of
metabolism and as such inhibitors of this pathway can give rise to increased plasma
concentrations and risk of vascular disease. CYP2E1 is thought to play a negligible
role. Consistent among all these publications was that the oral contraceptive pill
increased significantly the glucuronidation component of paracetamol metabolism,
while having no effect on sulphation, with a subsequent lower elimination half life.
Fractional clearance of the cysteine adduct also increased significantly (15±2mL/min vs
32±5mL/min) but clearance of paracetamol mercapturic acid did not change
significantly (15±2mL/min vs 20±4mL/min).127 Miners et al125 reported that the increase
in the clearance of oxidative metabolites overall was 36% versus control females which
may be sufficient to increase the risk of paracetamol toxicity in females particularly if
combined with other risk factors.
2.7.1.8. Smoking
Tobacco use can potently induce the CYP1A2 pathway which may play a minor role in
the metabolism of paracetamol. Given the theoretical potential to enhance the
hepatotoxicity of paracetamol Schmidt and Dalhoff129 retrospectively examined the
medical records of 602 patients admitted for single dose paracetamol overdose for
whom current tobacco use was recorded. As for other studies from this group, outcome
was the effect of current tobacco use on the morbidity and mortality from paracetamol
hepatotoxicity despite IV acetylcysteine treatment. The level of tobacco use (but not
the length of use) was recorded in 386/424 smokers of which 137 were quantified as
39
light smokers (< 20 cigarettes/day), 127 as moderate smokers (20 cigarettes/day) and
122 as heavy smokers (>20 cigarettes/day). Current tobacco use (70%) in patients was
considerable higher than that of the local population (31%) and was an independent
risk factor for the development of hepatic encephalopathy (Odds ratio (OR), 2.68; 95%
CI, 1.28-15.62) and mortality (OR 3.64; 95% CI, 1.23-10.75. No significant differences
were seen between the different smoking levels. Current tobacco use was also
independently associated with high peak values for alanine transaminase and the
international normalised ratio (INR). Known or potential risk factors included in the
multivariate analysis were, age, sex, time to acetylcysteine treatment, paracetamol
dose, acute alcohol ingestion, chronic alcohol ingestion, and acetylsalicylic acid,
benzodiazepine or opioid co-ingestion. Potential confounders such as diet, social
deprivation or recreational or other drug use however could not be considered. The
authors acknowledge this limitation but also comment that whatever the underlying
causes for the increased risk of hepatotoxicity with tobacco use, the data suggest that
smokers should be considered as high risk patients. Current UK guidelines do not
include smoking as a risk factor.
2.7.1.9. Pre-existing liver damage/disease
There is some limited evidence that paracetamol-induced hepatotoxicity may be more
severe in patients with pre-existing liver disease.130,131 Nguyen et al130 carried out a
retrospective analysis of the Nationwide Inpatient Sample (NIS) (1998-2005) which
incorporates a 20% sample of US hospitals to identify patients with paracetamol
overdose. They assessed the development of acute liver failure, in hospital mortality,
severe liver failure and resource utilisation. In the 42,781 admissions for paracetamol
overdose, the risk of acute liver failure was increased with hepatitis C (OR 1.80; 95%
CI, 1.30-2.48), non-alcoholic liver disease (OR, 7.43; 95% CI, 3.30-16.7), alcoholic liver
disease (OR, 6.46; 95% CI 4.53-9.21) and malnutrition (OR 3.48; 95% CI 1.88-6.70).
Crude mortality was higher with hepatitis C than in those without (2.1% vs 0.9%;
P=0.01). However this study was severely limited by the lack of clinical information
accompanying the NIS data making the assessment of other clinical predictors of
hepatotoxicity impossible. For example paracetamol levels and dose, time to
acetylcysteine administration and the use of concomitant drugs could not be assessed.
The absence of this information means that the significance or otherwise of these
results are impossible to determine. Myers et al131 also carried out a population based
study in which they examined the outcomes of paracetamol overdose using
administrative data in a large Canadian health region. They concluded that underlying
liver disease (OR 3.50; 95% CI 1.57-7.77), alcohol abuse (OR, 2.21; 95% CI, 1.303.76), unintentional overdoses (odds ratio [OR], 5.18; 95% confidence interval [CI],
3.00-8.95), and receipt of acetylcysteine treatment (OR, 6.75; 95% CI, 2.78-16.39)
were independently associated with hepatotoxicity. Again this study was limited by the
retrospective nature of the study and the lack of information on paracetamol dose or
plasma levels. However unintentional overdose (OR, 5.18; 95% CI, 3.00-8.95), alcohol
abuse (OR, 3.50; 95% CI, 1.30-3.76), underlying liver disease (OR, 3.50; 95% CI, 1.577.77), and acetylcysteine treatment (OR 6.75; 95% CI 2.78-16.39) were all
independently associated with hepatotoxicity. Cirrhosis alone was also a significant
predictor of hepatotoxicity (OR 2.75; 95% CI, 0.66-11.53).
2.7.1.10. Conclusions
The work of Prescott and colleagues in 19715 highlighted that there is substantial
variability in the metabolism of paracetamol between individuals. This variability is likely
to arise due to the modulatory effect of the risk factors outlined above, some of which,
but not all are listed in the product information.
Reduced food intake is a recognised risk factor in the product information and there is
clear evidence from animal studies that starvation increases hepatotoxicity. The
mechanism of this effect is believed to be via a reduction in glutathione levels.
40
However there is no clear information in man as to the extent of reduction in food
intake required to reduce glutathione levels sufficiently to influence toxicity. There is
likely to be considerable inter-individual variability. Similarly the influence of different
diets or factors affecting food intake e.g. chronic diseases or absorption e.g.
medications on hepatotoxicity is unclear. Furthermore critically an accurate
assessment of risk will depend on an accurate clinical history. Thus while the data
raise sufficient concerns to list fasting as a risk factor, they are not prescriptive enough
to provide clear guidelines to prescribers.
Modulation of CYP 450 expression is also recognised as a risk factor for hepatotoxicity.
Predominant among enzyme inducers is alcohol and as such chronic alcohol abuse is
a listed risk factor. However the extent or duration of alcohol consumption required to
induce CYP2E1 and thus influence hepatotoxicity is unknown and thus the term
chronic is impossible to define. The influence of alcohol is further complicated by the
fact that acute alcohol consumption may reduce toxicity. The effect of ethanol will
therefore depend on the timing of ingestion with regard to the paracetamol overdose
and thus presents a complicated picture for risk assessment.
The consumption of a range of other CYP450 enzyme inducing medications is also
listed as a risk factor for toxicity since the involvement of other CYP enzymes in the
metabolism of paracetamol in overdose is unclear. Again extent and duration of use
required to influence toxicity and the relationship to dose is unknown. Irrespective of
this, an accurate assessment of risk is dependent upon a comprehensive list which will
require constant updating and revision of product information as new enzymes
inducers are identified.
Perhaps most important of all is the influence of pharmacogenetic factors on the
metabolism of paracetamol. Recent pivotal publications have illustrated that there is a
large variability in the susceptibility of individuals to paracetamol, even at therapeutic
doses. This review highlights therefore that such individuals are likely to have a
substantially decreased threshold for toxicity at higher doses which may be sufficient
alone to explain the enhanced toxicity seen in some patients following a paracetamol
overdose. Predicting such individuals is currently impossible in the clinical setting and
the risk cannot therefore be managed via product information and represents an
important area where further research is required.
The review also considers a range of other possible risk factors for which the evidence
is weaker or more equivocal although in some cases is supported by retrospective
studies (age, pregnancy, oral contraceptives, smoking and pre-existing liver disease)
Particularly concerning among these is the influence of pre-existing liver disease and
smoking on the risk of hepatotoxicity. The apparent risk associated with these factors
may arise from other confounders but nevertheless the data suggest that they should
be considered independent predictors of toxicity. Neither of these is currently
highlighted in product information.
Considering all these variables, along with the difficulty of obtaining a reliable history
from overdose patients, it is concluded that the assessment of risk factors for
hepatotoxicity is generally poorly evidenced, lacks precision and is difficult to apply.
2.7.2. Assessment of an individual’s risk of hepatotoxicity
Clearly the accuracy of the nomogram in predicting toxicity is completely dependent
upon an accurate clinical history not only in terms of obtaining a reliable report of the
time of ingestion but also in the assessment of risk factors discussed above which
determine the treatment line used for the prediction of toxicity. Without an accurate
history, an assessment of risk is not possible. There are a number of factors which are
likely to influence the reliability of a clinical history which are discussed in detail below.
41
2.7.2.1. Demographics of at risk population
Paracetamol is still the predominant form of self poisoning especially in adolescents.
Generally there is a paucity of data on UK national demographics of self poisoning,
especially the relationship to ethnicity, social status and urban versus rural location.
The estimates of numbers of self poisonings are variable. Hospital attendances for self
harm in England and Wales range between 170,000132 and 190,000 3 of which
approximately 40% are for paracetamol/paracetamol compound poisoning. This
translates to approximately 68,000-70,000 presentations for paracetamol overdoses in
England and Wales annually. For the whole of the UK, estimates would be in the range
of 82,000 to 90,000 paracetamol poisonings annually (see section 6.1).
A recent study provided detailed demographic data on 1598 episodes of self poisoning
presenting to a large UK regional teaching hospital over a 12 month period.133
Paracetamol was the most commonly used drug in overdose in these episodes being
involved in 42.5% of all overdoses. Co-codamol was involved in a further 5.1% of
overdoses. The age distribution by gender is provided in Figure 17 and demonstrates
that the distribution of patients between age groups differed by gender. The female to
male ratio was highest in the younger age groups especially the 16-20 year group.
Furthermore in 57.6% of cases there was a documentation of a previous psychiatric
history including depression although there was no significant gender difference for risk
of psychiatric history (57.4% of men vs 57.7 % of women). The likelihood of having a
psychiatric history was much lower in the 16–20 year age group than in the remaining
patients (40.2% vs 62.2%; P < 0.0001). However adolescents (12-19 years) are also
known to display psychological or social characteristics associated with repeated self
harm.134 Of 49 adolescents with paracetamol overdose of suicidal intent, 18 had a
known psychiatric disorder and a further 10 were newly diagnosed with depression.
Figure 17: The age distribution by gender for all episodes of self poisoning. Pink
female; blue male.133
Most patients who have taken an overdose tend to present outside working hours
compared with other causes of presentation to the Emergency Department with the
majority (70.7%) presenting to hospital within 4 h of taking the overdose where timing
was known (Figure 18). Only 9.9% presented 12h or more after the overdose. Thus in
42
the vast majority of cases, patients who take an overdose appear to regret the decision
quickly underlying the impulsive nature of these events. Fortunately this profile means
that the majority of patients present for treatment within the window of efficacy of
acetylcysteine. In a study in 110 adolescents 51 patients had no suicidal intent and
although the overdose was a deliberate act, usually triggered by a row with a boy/girl
friend or parent, was immediately regretted by the patient.134 This highly impulsive
nature of paracetamol overdose is in line with a recent interview study in the UK which
reports that over 50% of 60 patients interviewed following a paracetamol overdose
thought for 60 minutes or less before taking the overdose.135 Twenty-five percent
overall thought for 15 minutes or less. This latter study also identified the main reasons
for taking an overdose as wanting to die, to get relief from a terrible state of mind or
escape an unbearable situation. Almost 50% of patients identified the underlying
problem as relationship problems with a partner. In addition to these issues, a further
characteristic of overdoses is that a large number of cases involve a co-ingestion with
alcohol.
Figure 18: The distribution of time from reported ingestion to presentation by plotting
the number of patients presenting with overdose in each hour block. Note
paracetamol was involved in 47.6% of these cases.
Re-admissions for deliberate self harm are common. A systematic review of studies
across Europe found median proportions of repetition 1 year later were 16% non-fatal,
with a slow rise to up to 20-25% over the following few years.136 Median proportions for
fatal repetitions were ~2% after 1 year, although a disparity was found between UK
and non UK studies with the former having a substantially lower repetition rate. The
authors could find no explanation for this disparity. After more than 9 years, around 7%
of patients had died of suicide (median estimate across all studies considered).
In summary therefore paracetamol overdose patients are likely to be young,
predominantly female, to have ingested paracetamol under stressful, impulsive
circumstances, often with alcohol or other substances of abuse, and to have a
psychiatric history. All these factors increase the likelihood of an unreliable clinical
history not only in terms of the accuracy of the time of ingestion but also in terms of the
history of food intake and other co-medications. There is some evidence to suggest
however that patient history with regard to the reported dose of ingested paracetamol
was relatively accurate which may relate to the fact that the majority of patients present
shortly after the overdose.137
43
2.7.2.2. Importance of an accurate assessment of time of ingestion
The nomogram is a plot of plasma concentration against time since the overdose and
therefore obviously an accurate record of the time of ingestion and thus the time of the
plasma paracetamol concentration is absolutely critical in order to reliably predict
toxicity. This is particularly pertinent during the first 6h following an overdose when
plasma concentrations are falling rapidly. Figure 19 shows the current UK paracetamol
nomogram with the known cases of overdose who were not treated with acetylcysteine
despite presenting to hospital within 12h of the overdose and who died or suffered liver
damage. This is unlikely to be the sum total of the cases but represents those of which
the MHRA is currently aware
Figure 19: UK paracetamol nomogram showing cases of paracetamol overdose since
1992 (in which level and time of ingestion is known) where a patient
presented to hospital within 12h of the overdose but was not treated with
acetylcysteine within 12h and subsequently suffered either fatal
hepatotoxicity (filled black squares) or acute liver damage (blue circles).
It is clear that an error of between approximately 30-60 minutes would be sufficient in
many of these cases to move the patient either above the high risk line or above the
normal risk line and might have altered the diagnosis of possible toxicity. This is
44
therefore a fundamental weakness of the nomogram, that the decision to treat or not
should be so dependent upon an accurate record of ingestion from a patient in a state
of crisis who may have consumed large amounts of alcohol. However the only way a
dependence on time could be avoided, in the absence of a treat all policy, would be to
introduce the assessment of paracetamol half life as a method by which to assess
toxicity. Such a proposal would require a second paracetamol plasma test at a known
time after the first.
2.7.2.3. Staggered overdose
Staggered or unintentional overdose is known to be associated with poor
outcome.131,138,139,29 Accidental overdoses have different demographics to intentional
overdose with patients tending to be older, and predominantly male.138 In addition time
from first ingestion to presentation is of the range of hours to days. Paracetamol levels
are generally in the therapeutic range (10-15mg/L). Clearly the nomogram is not useful
for the prediction of toxicity in these cases and guidelines state that all patients
suspected of having a staggered overdose should be treated with acetylcysteine
irrespective of the plasma paracetamol level and despite the fact that the window of
primary efficacy has passed. Although the nomogram is not a useful tool in these
cases, an accurate clinical history is still critical to determine the extent of the overdose
and the time period over which it occurred since this may influence subsequent
treatment decisions.
There is very little guidance in the literature as to the definition of the term “staggered”.
The BNF defined the term as several hours while a recent update to TOXBASE defines
staggered as ingestion over a period of more than 1h. In contrast Craig et al29 define
staggered overdose as the ingestion of two or more supratherapeutic doses over a
time interval of greater than 8h resulting in a cumulative dose of >4g per day. Acute
overdose in this study was defined as an overdose of >4g of paracetamol taken at a
single defined timepoint. A clearer definition of the term staggered overdose is required
which should be consistent across the different sources of advice.
2.8.
Other nomograms in use in Europe and internationally
As discussed in earlier sections a modification of the UK nomogram is used in the US
(the Rumack-Mathew nomogram) (Figure 4). In contrast to the UK nomogram, the US
nomogram has a single line starting at a 4h plasma level of 150mg/L (approximately
10x the therapeutic level) but no consideration is given to the presence of risk factors.
Thus on one side the US approach is more conservative than that in the UK in that any
patient with a level above 150mg/L is treated but on the other side is less conservative
in that a patient considered to have risk factors would be treated at a lower level of
100mg/L in the UK.
In the EU both the UK and Rumack-Mathew nomograms are in use. In total 14
countries use a nomogram for the prediction of paracetamol toxicity based on a timed
plasma paracetamol level. Of these 4 countries (including the UK) use the UK
nomogram with 2 treatment lines and 9 countries use the Rumack-Matthew nomogram.
However 7 of the 9 countries stated that the Rumack-Matthew nomogram had been
modified by setting an additional high risk line at either 100 or 75mg/L.
2.9.
Other guidelines for determining acetylcysteine treatment
In 1996 Denmark adopted a policy of treating all suspected cases of paracetamol
overdose with intravenous acetylcysteine for 36 hours. Prior to 1996 there were no
national guidelines, with practice varying between treatment centres. The aim in 1996
was to unify the treatment of paracetamol overdose in Denmark following a series of
cases where acetylcysteine was withheld because of inaccuracies in assessing the
45
time of overdose and the patients subsequently died. Currently if a subsequent blood
test reveals the absence of paracetamol, acetylcysteine treatment is stopped.
Three other countries within the EU do not use a nomogram to predict paracetamol
toxicity (where a toxic dose was considered to be between 75 and 150mg/kg). Three
countries assess the risk of hepatotoxicity based on paracetamol dose ingested or treat
all patients with a paracetamol level greater than therapeutic.
2.10.
Other biomarkers of paracetamol toxicity
Despite a substantial amount of research work, no other clinical indicator in addition to
a blood plasma level has emerged to improve the prediction of paracetamol-induced
hepatotoxicity.140 New markers of risk present in the early phase of toxicity are clearly
needed to supplement the information provided by the plasma paracetamol level. Of
the current predictors of risk, it seems that prothrombin time (PT) is a more accurate
measure of liver damage that liver enzymes such as ALT. However this may not be a
useful marker of liver injury in the presence of acetylcysteine since in vitro experiments
on human blood demonstrated that increased serum acetylcysteine concentrations
were associated with clinically significant increases in PT (Figure 20)141 Although the
rises were significantly less than those expected during liver failure, caution should be
exercised when interpreting subtle changes in PT.
Figure 20: Prothrombin time as it relates to serum acetylcysteine concentration.
Human plasma was incubated for 1 hour at 37ºC with 4 different
concentrations of acetylcysteine to simulate the concentrations achieved
during a typical infusion: 0 mg/L, 1000mg/L, 500mg/L and 100mg/L.141 At
1000mg/L (first infusion), two PT values exceeded 22sec and half exceeded
17sec.
Aminotransferases are not generally increased until at least 10h after the overdose142
but have been suggested as a useful later predictor of toxicity especially when
combined with the paracetamol plasma concentration.143 Creatinine may also predict
46
poor outcome in paracetamol overdose.144,145 Biomarkers reflecting the balance of
hepatocyte apoptosis versus necrosis (and subsequent inflammation) also have
potential 57 but these need to be validated by larger prospective studies in man. In
particular there is a lack of biomarkers characteristic of a staggered overdose which
would allow this condition to be better predicted.
Paracetamol half life may also be a useful additional marker of paracetamol toxicity.
The data in Figure 2 clearly demonstrates that half life is prolonged very early following
a hepatotoxic dose and is a predictor of toxicity. The mechanism for this early
prolongation of half life is unclear since the integrity of the hepatocytes is not
compromised for several days after the overdose. It is possible that formation of large
amounts of NAPQI within a short period of time in some way compromises the
glucuronidation pathway such that conjugation is slowed. Whatever the mechanism it is
clear that half life is slowed in patients at risk which opens the possibility that a second
plasma paracetamol level, taken a known time after the first would allow the calculation
of the plasma half life and improve the accuracy of diagnosis of toxicity in those in
which doubt existed.
In conclusion although research is continuing in this area89, further work is required to
identify novel potential early markers of impending toxicity which could be used either
to complement the existing nomogram or replace it.
2.11.
Conclusions on the patient population indicated for acetylcysteine
treatment
From the preceding discussion it seems clear that while the nomogram in the UK
SmPCs for acetylcysteine is a very valuable tool in the prediction of paracetamol
toxicity its dependence on a very accurate knowledge of the time of ingestion and the
assessment of the presence of risk factors is a fundamental limitation with potentially
fatal implications. As such errors in timing of 45mins, leading to a decision not to treat
with acetylcysteine, could potentially result in fatal consequences (Figure 19).
The characteristics of the patient population together with the long list of potential risk
factors, the high degree of uncertainty which surrounds their definition, the unreliability
with which these are likely reported by patients and the fact that there are clearly other
variables which increase the susceptibility to toxicity means that it is impossible to be
certain that a patient does not fall into the high risk category. Difficulty with determining
risk may explain why TOXBASE states that NPIS Units identify almost half of their
patients as high risk (Appendix V). Given that acetylcysteine is almost 100% effective if
given within 8h of the overdose, the accuracy of diagnosis of potential toxicity in all
patients should also approach this level of certainty. If risk cannot be accurately
assigned, the decision to treat should not be dependent upon it.
3.
RISKS ASSOCIATED WITH
PARACETAMOL OVERDOSE
THE
USE
OF
ACETYLCYSTEINE
IN
There is no doubt that acetylcysteine is a highly effective antidote to paracetamolinduced hepatotoxicity and is virtually 100% effective if administered, via whatever
route, within 8h of the overdose. Balanced against this the risk of severe liver damage
is 23% in patients with paracetamol levels between the 100 and 200 lines. Below
150mg/L approximately 7% of patients developed severe liver damage.11 Above the
200 line the incidence of liver damage rose to 60% and above the 300 line, 93% of
patients suffered liver damage. The benefit of acetylcysteine therefore in patients
considered to be at risk of toxicity is undisputed. However no medicine is without an
element of risk and the following sections attempt to define at which point the riskbenefit ratio for acetylcysteine becomes negative.
47
3.1.
Posology
The dose of acetylcysteine currently licensed was originally empirically derived with no
formal dose–response studies performed. This was true for both the IV and oral
doses.146 While it is possible that alternative posologies may provide equivalent
efficacy with a reduced rate of adverse reactions, ethical implications make research in
this area very difficult. However there continues to be calls for the acetylcysteine
protocol to be shortened36,146,147,148 or the dose simplified.147 It is interesting to note that
an IV formulation for acetylcysteine was licensed in the US in 2004 and is marketed by
Cumberland Pharmaceuticals under the brand name Acetadote. The most recently
published FDA package insert is attached at Appendix VI, and at Appendix III is the
current approved UK Summary of Product Characteristics (SmPC) for Parvolex for
comparison.
There are similarities between the UK and USA labels in that the acetylcysteine
strength is 200 mg/mL (20%) and the posology is based on three doses. However
there are several key differences between the UK and US labels:
• The initial loading dose is administered over 60 minutes in the USA compared to 15
minutes in the UK.
• The acetylcysteine is presented in a 30mL vial in the US compared to
predominantly a 10mL vial in the UK.
• The posology approved in the US uses a weight-based table.
• The US label uses the Rumack-Matthews nomogram.
• The US label includes the recommendation ‘…If time of ingestion is unknown or
patient is considered unreliable, consider empiric initiation of acetylcysteine…’
Acetadote was initially licensed in the US with an infusion time of 15mins as in the UK.
In 2006 the infusion time of the initial loading dose was extended to 60mins
3.1.1. Pharmacokinetics of acetylcysteine
As discussed earlier according to the current UK regimen over half the total dose of
acetylcysteine is administered within the first 15mins with the remainder being
administered over the subsequent 20h. Acetylcysteine can be present in a free form or
bound to proteins in the reduced or oxidised state. Thus in a 70kg person 10.5g of
acetylcysteine would be infused in the first 15mins. In a study of 17 patients severely
poisoned with paracetamol (>200mg/L at 4h line), Prescott et al149 reported that the
mean maximum plasma concentration of total acetylcysteine 15min after the initial
loading dose was 554mg/L. Concentrations then rapidly fell and after 12h a mean
steady state level of approximately 35mg/L was maintained. At the end of therapy,
acetylcysteine disappeared with a half life of 5.7h (Figure 21). However the range of
Cmax achieved with the initial dose was large (304-875mg/L) as was the range of steady
state plasma concentrations at the end of the infusion (11-90mg/L). The clearance of
acetylcysteine was not reduced and its plasma concentrations were not increased in
patients with severe liver damage (5 patients in whom time to acetylcysteine therapy
was >8h) nor was the plasma paracetamol half life related to any of the
pharmacokinetic variables for acetylcysteine apart from a weak but significant
correlation with area under the curve (r=0.53; p<0.05). The mean plasma concentration
of acetylcysteine was actually lower in the 5 patients with severe liver damage, but the
differences between the groups were not significant at any time. Importantly outcome
did not differ between patients with low and high Cmax.
In 2005 Kerr et al33undertook a randomised multicentre prospective trial of patients
presenting with paracetamol overdose and who were treated with acetylcysteine
(patients had to have no previous history of hypersensitivity to acetylcysteine). Patients
48
were randomly assigned to receive the initial dose of acetylcysteine over either a 15
minute or 60 minute period. Baseline signs and symptoms of adverse events were
serially evaluated before and during the administration of acetylcysteine and outcome
was assessed via liver and coagulation tests at baseline and at 12h intervals.
Importantly no patient who received acetylcysteine in either group <8h after ingestion,
and for whom alanine aminotransferase levels were measured, developed an ALT level
>150IU/L. This suggests that in these patients an initial infusion period of 60 mins had
equivalent efficacy to one of 15 mins. Of the patients who received acetylcysteine >8h
after ingestion, the incidence of maximum ALT rises (>1000IU/L) was 8.1% in the 15
minute group and 13.2% for the 60minute group. However this study has been
criticised due to small group sizes and a failure to measure plasma paracetamol levels
in the group. Therefore it is not known whether the severity of paracetamol poisoning
was similar between the groups or what the delay was to acetylcysteine treatment.
Furthermore the method of randomisation chosen resulted in unblocked random
allocation such that there was unequal numbers in each group.
Figure 21: Plasma concentrations of total acetylcysteine following infusion of 150mg/kg
in 15min, 50mg/kg in 4h and 100mg/kg in 16h in 18 patients with
paracetamol overdose.149
Pharmacokinetics differ substantially following oral administration. Systemic
bioavailability after an oral dose is estimated at only 10% as acetylcysteine undergoes
quick and extensive metabolism in the stomach wall and liver. In fact bioavailability of
the reduced form may be even lower as it is oxidised by the gut wall.150 After an oral
dose of acetylcysteine of 200 to 400mg (between 24.5 and 49 fold less than that
administered for the treatment of paracetamol overdose in a 70kg person), a peak
plasma concentration of 0.35 to 4 mg/L is achieved within 1 to 2 hours. The volume of
distribution ranges from 0.33 to 0.47 L/kg and protein binding is significant, reaching
approximately 50%, 4 hours after the dose. Renal clearance has been reported as
0.190 to 0.211 L/h/kg and approximately 70% of the total body clearance is non renal.
Following oral administration, reduced acetylcysteine has a terminal half-life of 6.25h.
However the relevant concentration in terms of paracetamol hepatotoxicity following
49
oral administration is the concentration in the liver, which is likely to be significantly
higher than that seen in the plasma. Unfortunately there are no studies investigating
hepatic concentrations relative to systemic concentrations after either oral or IV
acetylcysteine therapy.
Due to its rapid metabolism, repeated dosing with acetylcysteine does not cause
significant accumulation of acetylcysteine or plasma cysteine but plasma glutathione
significantly increases.150
These studies therefore suggest that dose of acetylcysteine may not be critical
provided presumably that a certain threshold concentration is achieved. Unfortunately
however there are several uncertainties. The studies do not identify what this critical
threshold would be or how quickly it should be attained nor is it known for how long
exposure to acetylcysteine is required. Studies do appear however to consistently
identify 8h post ingestion as a critical time point for the onset of liver damage but the
study by Kerr et al33 provides re-assurance that despite this, an initial 60 minute
infusion period initiated within 8h would have equivalent efficacy to one of 15 minutes.
Such a conclusion would be in line with clinical experience as currently the initial high
infusion is stopped and slowed if a patient experiences adverse effects to
acetylcysteine. In addition we are not aware of any reports from the US of reduced
efficacy since the posology was changed to include an initial 60 minute infusion time.
3.1.2. Oral versus intravenous acetylcysteine
Whilst acetylcysteine has transformed the management of paracetamol poisoning,
debate continues over the most effective dose, route of administration and duration of
therapy. Acetylcysteine can be administered either IV or orally. One possible
advantage of the oral route is that the whole dose of acetylcysteine passes through the
liver, producing very high local concentrations precisely at the primary site of action in
the liver.16 However the benefits associated with IV administration of acetylcysteine
include a shorter stay in the hospital with reduced costs, less inconvenience for
patients and hospital staff, and the avoidance of problems associated with the
absorption of oral acetylcysteine as a result of vomiting or previous administration of
charcoal. It is maybe for these reasons that the US introduced an IV formulation of
acetylcysteine in 2004. Oral acetylcysteine therapy is also extremely unpleasant. In line
with this Prescott et al18 attempted to directly compare the oral versus IV therapy. Fifty
two consecutive patients with paracetamol levels >200mg/L were entered into the trial.
Of these 33 had to be excluded from oral therapy because of vomiting, coma or
poisoning with a combination of propoxyphene hydrochloride and paracetamol. Eight of
the remaining 19 patients started the oral therapy but 4 of these had to be transferred
to IV therapy because of persistent vomiting. Thus only 2 patients could complete the
oral therapy. However as discussed in section 2.2.1., there is little convincing evidence
for any differential efficacy between the two routes of administration.
3.1.3. Other treatment options
Prior to the introduction of acetylcysteine, other glutathione precursors such as
cysteine, cysteamine42 and the cysteine precursor, methionine43,18 had been utilised for
the prevention of paracetamol induced hepatotoxicity. Methionine is currently licensed
in the UK by Pharma Nord for the oral treatment of paracetamol overdose if IV
acetylcysteine is not available or the patient cannot tolerate acetylcysteine (see
Appendix VII for SmPC). There are no licensed IV methionine products. The
recommended dose for the oral product is an initial dose of 2.5g of methionine followed
by a further 2.5g every 4h up to a total dose of 10g. As for all treatment options for
paracetamol induced hepatotoxicity this dosage regimen was empirically based on its
action as a glutathione precursor. No dose finding studies have been identified and the
license application by Pharma Nord was a bibliographical application.
50
3.1.3.1. Cysteamine
Prescott and colleagues examined the ability of cysteamine to prevent paracetamol
induced hepatotoxicity in 27 patients.18 An initial dose of 2g of cysteamine was given IV
over 10min followed by 3 x 400mg doses. The total dose was 3.2g given over a period
of 20h. When given within 10h, cysteamine protected against severe liver damage,
renal failure and death. The ALT activity remained normal in 41% of patients given
cysteamine compared with 76% of patients given acetylcysteine. However as for
acetylcysteine if therapy was delayed beyond 10h, the incidence of liver damage rose
progressively.
3.1.3.2. Methionine
Oral L-methionine in a dose of 2.5g (~36mg/kg in 70kg adult) every 4h to a total 10g
was effective at preventing severe liver damage in 27 of 30 patients with plasma
paracetamol levels above the 200mg/L treatment line. In 96 patients given oral
methionine within 10h of ingestion, all survived although 7 suffered severe liver
damage (aspartate transaminase>1000IU/L) and 1 patient went into acute renal
damage.151,152 Six of the 7 patients with high AST had plasma paracetamol levels
>300mg/L at 4h. As for all therapies if the administration of methionine was delayed
beyond 10h of ingestion, the incidence of liver damage increased; 17/36 patients
suffered severe liver damage, 2 acute renal failure and 2 patients died. These statistics
are similar to those for patients receiving support therapy only. Similar results were
obtained with intravenous methionine given in a total dose of 20g over 20h.43 Of 15
patients given methionine within 10h of overdose, none died or suffered renal failure
and in 12, liver damage was absent or trivial. However 3 patients who received
methionine at 8.8, 9.5 and 9.7h after ingestion suffered severe liver damage. The
reasons for the treatment failure of these 3 patients are unclear. Brok et al14 in a
Cochrane meta-analysis reported that hepatotoxicity developed in 31 of 197 patients
(16%) treated with methionine (either oral or IV) plus supportive therapy within 24h of
an overdose compared with 52 of 90 (58%) of patients given supportive therapy only.
For comparison 80/637 patients (13%) given IV acetylcysteine plus supportive therapy
developed hepatotoxicity. If therapy was initiated within 10-24h of an overdose, no
patient died and hepatotoxicity was 9% (13/143) and 6% (58/949) with methionine and
acetylcysteine respectively. Brok et al14 actually concluded that the superiority of
acetylcysteine over methionine remained unproven.
Oral methionine may cause nausea, vomiting, drowsiness, and irritability. Vomiting is a
particularly common side effect in the treatment of paracetamol overdose. Daily doses
of 6 – 20 g can cause neurological changes, and can precipitate encephalopathy in
patients with hepatic cirrhosis, especially if portal hypertension is present. [Concern
with regard to for this ADR led to a decision in several studies to withhold methionine if
patients presented >10h after the overdose.] Large doses of methionine cause nausea,
vomiting, drowsiness, and irritability. With overdose, general supportive measures
should be taken; activated charcoal may be used. However in the most recent PSUR
for methionine no ADRS related to the use in overdose were reported. No reports of
anaphylactoid type reactions have been identified.
Few adverse effects have been reported with the use of oral methionine other than
nausea and vomiting highlighted above. There are only 4 suspected ADR reports on
the Yellow Card System, only 1 of which appears to be associated with a single
constituent product taken orally for 3 days. The reaction was of macular rash and
pruritus. None of the ADRs were associated with the use of methionine for the
treatment of paracetamol overdose.
51
On the basis of these studies, it was decided over 30 years ago that neither methionine
nor cysteamine provided better efficacy against paracetamol induced hepatotoxicity
than acetylcysteine and no new data has emerged to challenge that view. IV
acetylcysteine was considered to avoid the potential treatment failures associated with
oral therapy due to common nausea and vomiting. Having said that clearly oral
methionine can provide effective protection against paracetamol induced hepatotoxicity
when delivered as four 2.5g doses. However no studies are available demonstrating
the efficacy of a single oral dose of methionine against paracetamol-induced
hepatotoxicity.
3.2
Adverse Drug Reactions
A number of adverse effects are listed in the SmPC for Parvolex. The following text is
currently included in the SmPC:
“Anaphylactoid' or 'hypersensitivity-like' reactions have been reported. They include
nausea/vomiting, injection-site reactions, flushing, itching, rashes/urticaria,
angioedema, bronchospasm/respiratory distress, hypotension, and rarely, tachycardia
or hypertension. These have usually occurred between 15 and 60 minutes after the
start of infusion. In many cases, symptoms have been relieved by stopping the
infusion. Occasionally, an antihistamine drug may be necessary. Corticosteroids may
occasionally be required. Once an anaphylactoid reaction is under control, the infusion
can normally be restarted at the lowest infusion rate (100mg/kg in 1 litre over 16
hours). In rare instances, the following side-effects have occurred: coughing, chest
tightness or pain, puffy eyes, sweating, malaise, raised temperature, vasodilation,
blurred vision, bradycardia, facial or eye pain, syncope, acidosis, thrombocytopenia,
respiratory or cardiac arrest, stridor, anxiety, extravasation, arthropathy, arthralgia,
deterioration of liver function, generalised seizure, cyanosis, lowered blood urea,
prothrombin time abnormal. Rare instances of fatality have also occurred.
Hypokalaemia and ECG changes have been noted in patients with paracetamol
poisoning irrespective of the treatment given. Monitoring of plasma potassium
concentration is, therefore, recommended.”
The evidence underpinning this text is discussed below.
3.2.1
Published literature
Over the past 30 years, a variety of suspected adverse drug reactions (ADRs) have
been reported with acetylcysteine ranging in severity from nausea to severe life
anaphylactoid reactions reflected in the current SmPC for acetylcysteine. The more
severe reactions have features similar to anaphylaxis, but these are in fact nonimmunological and hence classified as ‘anaphylactoid’. The characteristic symptoms of
anaphylactoid reactions include flushing, pruritus, rash, angioedema, bronchospasm
and hypotension are potentially life threatening. These anaphylactoid reactions are not
IgE-mediated and do not require previous exposure to acetylcysteine. Thus, treatment
can often be safely re-introduced without complication following a reaction.153
The overall incidence of adverse effects has been variably recorded up to 23% in
retrospective studies154,155,156, } and 50% in prospective studies.33,157,158,159,160,161 37,162
However only one fatality with the licensed posology was reported in a case report in
2002163 which was a case of a brittle asthmatic and which is included in the later
discussion of spontaneous reports. In 1984 Mant et al164 published a report describing
2 deaths following approximately 10 fold overdoses of acetylcysteine although in
neither case could the death be definitively associated with acetylcysteine.
The wide range of incidence of ADRs predominantly reflects different selection criteria
of ‘anaphylactoid’ between different studies and the inclusion or not of ADRs such as
52
nausea, headache and flushing. These latter ADRs are relatively mild reactions which
are controllable. However, a recent review by Sandilands and Bateman153 reported that
the incidence of more severe systemic anaphylactoid reactions is reassuringly lower
than that quoted for ADRs overall. Kerr et al33 reported that the incidence of moderate
reactions and severe reactions as 21% and 1% respectively with Waring et al159
reporting an incidence of anaphylactoid reactions of 14.9% out of an overall 40.9%.
The majority of reactions in this study (24.9%) were gastrointestinal (abdominal pain,
nausea or vomiting) reactions. Whyte et al21 reported that of 399 patients who were
treated with IV acetylcysteine, only 22.8% had an adverse reaction of which only 7
(1.8% of total) were anaphylactoid (no deaths occurred). This was a retrospective
analysis of all paracetamol overdoses on the Hunter Area Toxicology Service
Database in New South Wales Australia where data were collected prospectively
according to a published protocol and included patient characteristics, exposures to
paracetamol and other potential toxins, treatment and outcomes. A retrospective study
from Denmark examining 529 consecutive patients with paracetamol poisoning
similarly reported that 8.5% of patients (95% CI 6.4, 11%) developed side effects to
acetylcysteine, in 3.4% of which the effects were systemic (non dermal,
bronchospasm, angioedema and nausea).90 The vast majority of reactions were
cutaneous reactions such as rash, pruritus and flushing. Side effects were managed in
the majority of cases by the use of antihistamines (42 patients) and corticosteroids (34
patients); 1 patient required adrenaline and one inhaled β2-agonists. A recent
prospective study from Newcastle in 128 patients who received acetylcysteine from
December 2005-2006, reported 25 (18%) had anaphylactoid reactions.162 Thus the
incidence of severe anaphylactoid reactions is difficult to estimate because of the
failure of studies to separate such reactions from milder anaphylactoid reactions such
as itch, flushing oedema and rash. Where severe was specified the incidence is stated
at 1%.33
Despite the anaphylactoid origin, histamine appears to be an important mediator of
these reactions.165 Consequently, intradermal weal and flare responses to
acetylcysteine can be suppressed with prior administration of a H1-antagonist.157
Furthermore, the severity of these adverse effects has been shown to correlate with
histamine release.165 As such despite similar plasma concentrations at baseline, peak
histamine levels were greater in patients experiencing moderate and severe adverse
reactions compared with those experiencing minimal reactions (Figure 22). In contrast
plasma acetylcysteine concentrations were similar among all the groups (Figure 23)
suggesting that the incidence of anaphylactoid reactions is unrelated to peak
acetylcysteine plasma concentration although temporally the peak in reactions occurs
shortly after the peak concentration. Clearly however the study could not investigate
whether lowering the acetylcysteine concentration in those patients experiencing a
reaction would have reduced the overall incidence. Furthermore, patients receiving
inadvertent overdoses of acetylcysteine appear to have an increased rate of
anaphylactoid reactions which tended to be more severe and fatal reactions are more
common in this group.155,164,164 In support of a dose response relationship, Coulson and
Thompson166 have recently demonstrated that acetylcysteine increased histamine
secretion from human mast cell line 1 (HMC-1) and human peripheral blood
mononucleocytes (PBMCs) at concentrations from 20-50mg/mL and 2.5–100 mg/mL
respectively. A clear dose response relationship was seen. The variability in peak
acetylcysteine levels seen during the first infusion period (maximum level of ~900mg/L
or 0.9mg/mL; Figure 21), means levels may begin to approach concentrations required
to activate PBMCs especially in sensitive or atopic individuals.
Many investigators have therefore suggested that the incidence and severity of
reactions could be reduced simply by slowing or discontinuing the initial rate of
infusion.158,8,156 Indeed slowing of the infusion rate in patients with ADRs appears
effective at managing and reducing the incidence of further ADRs. In a prospective
53
case controlled study by Lynch and Robertson158, 71% of reactions occurred during the
first bag (15minutes) and all within the first hour. As discussed previously, Kerr et al33
examined the rate of ADRs in patients who received the initial dose of acetylcysteine
either over 15minutes or over 60minutes. No difference in drug related adverse events
were observed. Drug related adverse events occurred in 49 (45%) of patients in the
15minute group and 27 (61%) of patients in the 60minute group. Thirty (28%) and 15
(21%) of these were classed as moderate in the 15 and 60min groups respectively.
One patient in each group experienced a serious anaphylactoid reaction. No significant
differences were observed between the groups but the study was limited by small
group sizes (109 and 71 in the 15 and 60minute groups respectively) uneven
randomisation, incomplete characterisation of the patients’ allergy history and the
failure to record paracetamol levels. Thus additional trials are required to confirm
whether slowing the infusion rate reduces the overall incidence of ADRs although the
results of this study contributed to the decision by the FDA to change the initial infusion
time of their IV acetylcysteine product from 15 to 60minutes.153
Figure 22: Median plasma histamine concentrations (ng/mL) at baseline, and 15min,
30min, 1h and 2h after commencing iv acetylcysteine infusion according to
the severity of the adverse reactions: minimal (diamonds), moderate
(squares) and severe (triangles).165
54
Figure 23: Median plasma acetylcysteine concentration (mg/L) after IV infusion
according to the severity of the adverse reactions: minimal (diamonds),
moderate (squares) and severe (triangles).165
A joint clinical trial (NCT01050270)167 between Edinburgh and Newcastle Universities
is currently underway to investigate the efficacy and safety of a modified acetylcysteine
regiment in the treatment of paracetamol overdose. The modified protocol consists of
100mg/kg over 2 h followed by 200mg/kg over 10hours. This study will also investigate
the efficacy of prophylactic anti-emetic therapy at reducing the incidence of vomiting
and retching within 2h of initiating acetylcysteine treatment and of nausea and vomiting
within 12h of initiation of acetylcysteine treatment.
A further study (NCT01209455)168 in Edinburgh is investigating further the mechanism
of acetylcysteine -mediated adverse effects in the human forearm with a specific focus
on the role of histamine and any possible protective effect of the level of paracetamol.
The ability of H1 or H2 antagonists to reduce vasodilatation will also be examined.
Given the role of histamine, atopy and particularly asthma have been suggested to be
risk factors for anaphylactoid ADRs.90,163 Schmidt and Dalhoff90 reported that
asthmatics were 2.9 times (95% CI, 2.1-4.7) more likely to develop side effects but the
effects were of equal severity in asthmatics and non asthmatics. There may also be
greater association with those with a family history of drug allergy (odds ratio (95% CI):
2.89 (1.39-5.99) and female gender.165 Nevertheless, such ADRs are not a reason for
withholding acetylcysteine treatment as the adverse effects are usually mild and can be
easily treated. Prophylactically pre-treating high risk patients with a H1-antagonist or
even an inhaled beta-agonist in asthmatics may be considered as a potential risk
minimisation measure, but again given the mild nature of the majority of the adverse
reactions, acetylcysteine treatment should not be delayed on this basis.90 A research
project is underway to investigate this.
It appears that paracetamol itself may play a role in protecting against acetylcysteine induced anaphylactoid reactions. As such an increased rate of anaphylactoid reactions
has been reported among patients who received acetylcysteine and had low
paracetamol concentrations.90,159,165,169 Lynch and Robertson158 reported that 42% of
patients who developed anaphylactoid reactions to acetylcysteine had paracetamol
levels below the high risk treatment line, while 87% of the cases of anaphylactoid
reactions reported to the Australian Adverse Drug Reaction Advisory Committee
(ADRAC) had similarly low paracetamol concentrations.32 Conversely, patients with
high serum paracetamol concentrations have been associated with a reduced
frequency of anaphylactoid reactions, suggesting a protective effect.90,159 In line with
this, Zyoud et al170 have recently shown that late time to acetylcysteine infusion was
55
reported as a risk factor for cutaneous anaphylactoid ADRs. No significant association
was observed for gastrointestinal reactions, central nervous system reactions,
respiratory reactions or cardiovascular reactions and these authors suggest that the
protection of high paracetamol levels related mainly to cutaneous reactions.171 In the
study by Schmidt and Dalhoff90 mean paracetamol levels were below the current UK
threshold of treatment in both the patients experiencing (10.57mg/L) vs those that did
not (77.01mg/L). Similarly Pakravan et al165 reported that the incidence of severe ADRs
was associated with paracetamol levels below the current UK high risk treatment line of
100 (median concentration 46mg/L (0-101mg/L). Reactions were classified as severe if
acetylcysteine was stopped due to severe flushing, respiratory distress, moderate to
severe chest pain, >50% reduction in peak expiratory flow (where available) or
hypotension (systolic blood pressure >90mmHg or diastolic blood pressure <50mmHg).
Moderate reactions were associated with moderate paracetamol levels (108 mg/L (54178mg/L) and minimal reactions in those with high levels (119mg/L (77-174mg/L).
Waring et al159 also reported an inverse association of anaphylactoid reactions with
paracetamol level (Figure 24). No such association was observed for gastrointestinal
reactions. Anaphylactoid reactions were classed as minor (e.g. flushing) moderate (e.g.
uticaria) or severe (e.g. angioedema or respiratory symptoms) but the association was
not further defined on this basis. In support of these studies Coulson and Thompson166
demonstrated that concentrations of paracetamol as low as 2.5mg/L significantly
reduced acetylcysteine -induced histamine secretion in HMC-1 cells and PBMCs.
Figure 24: Proportion of patients with (A) anaphylactoid and (B) gastrointestinal
reactions to acetylcysteine with respect to equivalent 4h paracetamol level.
Data is shown as 95% CI. P=0.004 for anaphylactoid reactions, p=0.052 for
gastrointestinal reactions by Cochran-Armitage tests. 159
Thus, although further work is required, the apparent association between plasma
paracetamol concentration and the incidence of ADRs makes the appropriate use of
this antidote only in patients who fulfil treatment criteria an important issue.
56
There is uncertainty as to the role of the excipients (EDTA and sodium hydroxide) in
the adverse reactions to the IV acetylcysteine. At present, there are no marketed
formulations in the UK lacking these agents but such formulations are in
development.153
However Cumberland Pharmaceuticals who market the IV
acetylcysteine formulation in the US have recently (first quarter of 2011) introduced a
new formulation which does not contain ethylene diamine tetra acetic acid or any other
stabilising or chelating agents and is free of preservatives.
There have also been a number of fatalities reported with acetylcysteine 163,164 some of
which are associated with acetylcysteine overdoses due to medication errors164 (see
section 3.3). The medication errors are commonly associated with the administration of
acetylcysteine as the protocol requires the accurate preparation and delivery of
different concentrations of acetylcysteine on a per kg body weight basis.172 Other rarer
ADRs reported with acetylcysteine are ECG abnormalities173, status epilepticus174 and
a serum sickness-like illness175.
In conclusion adverse effects associated with acetylcysteine are usually mild and thus
simply discontinuation of therapy for a short period is usually sufficient to resolve the
symptoms. If required, antihistamines, corticosteroids, inhaled beta-agonists and in
severe cases intramuscular adrenaline can all be successfully used to bring about
symptomatic improvement and allow continuation of therapy.90 Reports in the literature
of fatalities relate mostly to reports of fatalities associated with medication errors. Thus
the potential occurrence of an adverse event should not preclude a patient from
receiving acetylcysteine, particularly in the context of significant paracetamol ingestion.
There is however evidence that the rate of occurrence of ADRs, especially the more
severe ADRs, is negatively associated with paracetamol level and thus more common
in those with levels below the 100 mg/L treatment line. The risk of paracetamol induced
toxicity is low in these patients with no hepatotoxicity observed followed an acute
overdose at levels <100mg/L20 and therefore the decision to treat these patients with
acetylcysteine should be considered carefully.
3.2.2. Profile of adverse drug reactions following oral administration
Although the pattern of adverse reactions differs between oral and IV dosing, the
reported frequency of ADRs overall is equivalent.153 However oral administration of
acetylcysteine is more commonly associated with milder adverse reactions such as
nausea and vomiting. Adverse effects such as rashes, erythema, angioedema and
anaphylaxis seem to be rare with this route. Nonetheless due to the increased
incidence of vomiting, the risk of therapeutic failure is reported to be higher with oral
acetylcysteine. Thus, the overall benefits of IV acetylcysteine make it a preferred route
of administration in the UK.16
3.2.3. Spontaneous reporting
3.2.3.1. UK usage data
The sales of acetylcysteine have remained constant over the last 5 years at
approximately 600,000 ampoules per year. However there is a significant trend
towards the use of generic formulations rather than Parvolex. This data is supplied in
the number of ampoules sold and it should be noted that there is evidence that there is
significant off label use. To treat a 70kg adult patient 105ml of acetylcysteine would be
needed which equates to 10.5 10ml ampoules and therefore 600,000 ampoules would
equate to over 57,000 treatment courses for a 70kg adult. However data presented in
section 6 estimates that currently between 18,860 and 39,540 patients are treated with
acetylcysteine annually.
57
700000
Total NAC
Number of ampoules
600000
500000
Generic
400000
300000
200000
Parvolex
100000
0
07/2005 - 06/2006 07/2006 -06/2007 07/2007 - 06/2008 07/2008 - 06/2009 07/2009 - 06/2010
Time period
Figure 25: Usage of acetylcysteine over a 5 year period (07/2005 – 06/2010; IMS
MIDAS).
30
350
All NAC reports
Cumulative (all)
300
Number of reports
25
250
20
200
15
150
10
100
5
Cumulative total number of reports
3.2.3.2. Spontaneous UK ADR reports
As of 03rd January 2012, the MHRA had received 294 spontaneous reports of
suspected Adverse Drug Reactions (ADRs) for intravenous acetylcysteine. These
reports included a total of 615 suspected reactions. Of these reports 58 reports
(19.7%) were serious and 6 were fatal (2.0%). Figure 26 shows the number of reports
received for intravenous acetylcysteine each year since the date of the first report in
1979.
50
0
5
6
19
87
19
88
19
89
19
90
19
91
19
92
19
93
19
94
19
95
19
96
19
97
19
98
19
99
20
00
20
01
20
02
20
03
20
04
20
05
20
06
20
07
20
08
20
09
20
10
19
8
19
8
3
2
1
4
19
8
19
8
19
8
19
8
9
19
7
19
8
0
0
Reporting Year
Figure 26: Number of IV acetylcysteine reports each year from 1979-2011.
These data show a relatively consistent number of reports over this time averaging
between 10-15 per year, with a period of an increased number of reports per year
between 1993 - 1995 where the number of reports per year was 20-25. This data
should be viewed in the context of the estimated acetylcysteine usage for the treatment
of paracetamol which is between 18,860 and 39,540 patients treated with
acetylcysteine annually.
58
A total of 65 reports were received between 1993 and 1995, 46 reports (65%) were
direct reports from healthcare professionals, and 19 (35%) were industry reports.
During 1994 a total of 13 reports (10 direct and 3 industry reports) were received from
a single hospital, representing a significant contribution to the number of reports
received in this year (25 in total). The majority of the reported reactions in these cases
are from the Skin SOC, and are listed in the product information. There are three
reports of anaphylaxis, both reported as recovered. Other reported reactions are listed
reactions, consistent with allergic or hypersensitivity responses. Where reported, all the
reaction outcomes are recovered or recovering, with no fatal cases. The majority of the
patients are young adults.
Of the 294 reports received, 247 (84.0%) were industry reports, and 47 (16.0%) were
direct reports.
Figure 27 shows the direct intravenous acetylcysteine reports broken down by reporter
source *. The two biggest sources of spontaneous IV acetylcysteine reports are
physicians (104 reports, 42.1%) and Other HCPs (105 reports, 42.5%). A single report
was received directly from a patient (the reported reaction in this case was
anaphylaxis).
Patient
0.4%
GP
2.4%
Pharmacist
9.7%
Other Health
Professional
42.5%
Physician
42.1%
Nurse
2.8%
Figure 27: Direct intravenous acetylcysteine reports broken down by reporter source
Figure 28 shows a breakdown of the IV acetylcysteine reports by patient sex and age
group. This shows that the majority of reported cases (197 reports, 67%) are in female
patients, and that there are more reports concerning patients in a younger age group
for both males and females. The higher number of reports in young females may
simply reflect the higher number of overdoses cases in patient population although
Pakravan et al165 also reported a higher rate of moderate to serious ADRs to
acetylcysteine in females from a population of which 42% were male. Therefore the
below data may reflect a true association.
*
Reporter qualifications have been grouped as follows: Pharmacist (community, hospital and unspecified), Physician
(hospital doctor and physician), Other Healthcare Professional (optometrist, dentist, coroner, other healthcare professional),
Nurse (hospital nurse and nurse), Patient (patient, carer and parent), GP (GP only)
59
50
45
Female
Male
Number of reports
40
35
30
25
20
15
10
5
0
<18
18-24
25-34
35-44
45-54
55-64
65-74
75-84
>84
Unknown
Age Group
Figure 28: Direct IV acetylcysteine reports categorised by patient sex and age.
Figure 29 shows the proportion of reports received by System Organ Class (SOC) and
the corresponding Empirical Bayes Geometric Mean (EBGM) values. * The SOC with
the largest proportion of reactions is the ‘Skin and subcutaneous tissue disorders‘
SOC, which contains 26.34% of all reported reactions associated with the use of
acetylcysteine. A greater proportion of reactions are from this SOC for acetylcysteine
compared to all other drugs. Within this SOC 234 reactions were reported. Of these,
198 (84.6%) were reported in connection with IV acetylcysteine.
The most commonly reported reactions in the ‘Skin and subcutaneous tissue disorders‘
SOC were: urticaria, rash, pruritus, and rash erythematous. These reactions are listed
in the product information for IV acetylcysteine. Table 9 below provides a summary of
these reactions.
Reaction
Urticaria
Rash
Pruritus
Rash erythematous
Table 9:
Skin SOC
Number of IV acetylcysteine
reports
44
36
29
22
Most commonly reported reactions in the Skin and Subcutaneous tissue
disorder system order class.
Two SOCs have a raised EBGM above the threshold value of 2.5; the Immune system
disorders SOC and the Respiratory disorders SOC.
*
The EBGM is the measure of disproportionality currently used by the MHRA to detect signals from
spontaneous reports. Disproportionality analyses identify drug-event combinations that are being reported
unusually frequently compared to the background of other reports in the same database. The EBGM is
calculated using the Bayesian Multi-Item Gamma Poisson Shrinker (MGPS) algorithm. Percentage of
reports and EBGM values were calculated using data for the substance acetylcysteine, and are inclusive
of cases that were not IV acetylcysteine
60
Within the Immune SOC 104 reactions were reported. Of these, 91.3% (95 reactions)
were reported in association with intravenous use of acetylcysteine. Anaphylactoid and
hypersensitivity reactions are listed in the product information for intravenous
acetylcysteine. Table 10 below provides a summary of these reactions.
Immune system disorders SOC
Number of IV
Reaction
acetylcysteine reports
Anaphylactic reaction
58
Anaphylactoid reaction
16
Hypersensitivity reaction
16
Anaphylactic shock
5
Total
95
Table 10: Most commonly reported reactions in the Skin and Subcutaneous tissue
disorder system order class.
The distribution of these reports throughout the time period 1979 – 2011, follows the
reporting distribution for all IV acetylcysteine reports. The distribution of reports by
patient sex and age also follows the same pattern as for all IV acetylcysteine reports,
with 58 reports (61%) in female patients, and the majority of the report concerning
young adults.
61
12.0
30%
NAC
25%
% All other drugs
10.0
Log EBGM
8.0
20%
6.0
15%
4.0
10%
2.0
5%
0.0
-2.0
Sk
Im in
m
u
R n
es
p
G
as
tr
Va
sc
G
en
rl
N
er
v
C
ar
d
Ey
e
In
R v
en
a
In l
j&
Ps P
yc
h
M
us
c
In
fe
c
Bl
oo
M d
et
ab
C
on
g
Ea
H r
ep
a
So t
cC
En i
d
N o
eo
pl
Pr
e
R g
ep
ro
Su
rg
0%
System Organ Class (SOC)
Figure 29: Suspected ADR Reports for acetylcysteine by System Organ Class (SOC)
62
EBGM
% of Total Reactions Reported
EBGM
There were 84 reactions from other SOCs in these reports, with 7.3% (7 reports) also
reporting bronchospasm as a reaction. Other reported reactions include dyspnoea
(5), rash (5), tachycardia (4), cyanosis (3), vomiting (3) and wheeze (3), which
together make up 27% of the non-immune reactions from these reports. These
reactions are listed in the product information for IV acetylcysteine.
24 reports (25%) were considered serious by the reporter. The outcome was
reported as ‘recovered’ in 73 cases (77%).
Within the Respiratory SOC 113 reactions were reported. Of these, 78% (88
reactions) were reported in association with intravenous use of acetylcysteine. In this
SOC the most commonly reported reactions were dyspnoea, bronchospasm and
wheezing. These reactions are listed in the product information for IV acetylcysteine.
Table 11 below provides a summary of these reactions.
Respiratory SOC
Number of IV acetylcysteine
reports
29
22
14
Reaction
Dyspnoea
Bronchospasm
Wheezing
Table 11:
Most commonly reported reactions in the Skin and Subcutaneous tissue
disorder system order class.
The outcome was reported as recovered in 229 (75.6 %) of cases, recovering in 24
(7.9 %) of cases, not recovered in 14 (4.6 %) cases, fatal in 6 (2.0 %) cases and
unknown in 31 (9.9 %) cases (Figure 28). [Note since a case may have more than
one reaction, with different reported outcomes, the total number of reports cannot be
calculated by adding the numbers of reported outcomes]
9.9
2.0
4.6
Not recovered/not
resolved
Recovered/resolved
7.9
Recovering/resolving
Unknown
Fatal
75.6
Figure 30: Outcome of Spontaneous UK acetylcysteine ADR reports
[Note since a case may have more than one reaction, with different reported outcomes, the
total number of reports cannot be calculated by adding the numbers of reported outcomes.]
63
3.2.3.3. Spontaneous Fatal UK reports:
There are five UK cases of anaphylactoid reactions in connection with intravenous
acetylcysteine which had a fatal outcome. Four had a confirmed fatality due to an
anaphylactoid reaction when intravenous acetylcysteine was administered as a
treatment for paracetamol overdose (Table 12). For the remaining case, the cause of
death
.
The first case in the table was a 4 year old child who suffered an anaphylactoid
reaction following an overdose of acetylcysteine. The article in the Notes and News
section of the 1984 Lancet176 states that “The child was given an intravenous bolus of
2.17g followed by an infusion of 0.36g/h (this is twice the recommended infusion
dose).” Based on the first dose and the recommended posology, the weight of the
child was 14.46kg and therefore the infusion rate for the second bag should have
been 0.18g/h. The article goes on the state that “Twenty minutes later the patient
suddenly became cyanosed and hypotensive with severe tachycardia but no
bronchospasm. Serum electrolytes and liver function were normal. Despite a
temporary improvement after resuscitative measures the child did not recover from
the circulatory collapse. Necropsy revealed circulatory congestion and small bilateral
subdural haematomas.” It is unclear therefore whether the child suffered the reaction
20 mins after starting the second bag or 20 mins after finishing the second bag.
However it appears the child tolerated the initial large infusion. Obviously it is
impossible to know whether this reaction was caused by the administration error
which resulted in the second infusion being delivered at double the recommended
dose.
A sixth UK case was a fatal outcome with IV acetylcysteine; the fatal reaction in this
case was ‘aortic aneurysm’. The case details indicate that the IV acetylcysteine was
not used to treat a paracetamol overdose, and that the patient did not experience an
anaphylactoid response.
Three of these cases are direct reports from healthcare professionals. Two are
industry reports, including one derived from a literature article.
In cases 5, and 6 in Table 12 below, the reactions occurred during the high infusion
rate period of acetylcysteine administration.
Yellow Card regional monitoring centres were requested to provide details of fatal
reports for IV acetylcysteine received during the last 10 years. Two responses were
received, indicating that they were not aware any fatal reports of hypersensitivity or
anaphylactoid reactions received within this time.
64
Table 12:
Fatal ‘anaphylactoid’ ADR reports with intravenous acetylcysteine
3.2.3.6. Spontaneous non-UK data
Other sources of ADR data for IV acetylcysteine are non-UK cases received by the
MHRA from the industry, reports from the US Food and Drugs Administration (FDA)
Adverse Event Reporting System (AERS) database, EudraVigilance, and WHO data
from the Uppsala Monitoring Centre (UMC).
Table 13 below shows the number of spontaneous non-UK ADR reports received by
the MHRA for acetylcysteine from outside the UK (excluding the United States, see
Table 14). These data use the same inclusion criteria as the UK spontaneous data in
section 2 (all reports where acetylcysteine was given by IV route, and reports where
the route was not specified, and the case could not be excluded as a possible IV
acetylcysteine report on the basis of the product name or reported indication).
Country of origin
Number of cases
Australia
Belgium
Canada
Denmark
France
Germany
Ireland
New Zealand
Russian Federation
Spain
Switzerland
2
1
1
15
1
12
1
1
1
4
1
Total: 40
Table 13: Worldwide spontaneous acetylcysteine ADR data
In these cases the SOC with the largest proportion of reported reactions was the
‘Skin and subcutaneous tissue disorders‘ SOC, which contains 26% of the reactions.
Of the 15 cases originating from Denmark, 7 are reports of hypersensitivity, with 2
reports of anaphylactic reaction and one report of anaphylactic shock. Of these ten
reports, eight reported an outcome of recovered, while two were reported as not
recovered. Since 1996 all suspected cases of paracetamol overdose in Denmark are
treated with intravenous acetylcysteine for 36 hours. None of the cases reported from
Denmark had a fatal outcome.
65
Of the non-UK cases in table 13, four cases had fatal outcomes; the reactions in
these cases were Toxic epidermal necrolysis (2 cases), Stevens-Johnson Syndrome
(1 case), and pulmonary embolism (1 case). Indications for acetylcysteine and
reaction onset times with respect to acetylcysteine are not provided in these cases,
but the case details do not suggest that these are patients who are likely to have
been treated with IV acetylcysteine for paracetamol overdose.
66
67
68
3.2.3.6.
Significant safety signals identified in the post marketing period.
Addition of:
•
A sodium content warning to Section 4.4 (01/02/2010),
•
Information of haemostatic parameters and caution advised when used in
children <40kg because of risk of fluid overload warning to Section 4.4;
•
Prothrombin time abnormal as an additional side effect to Section 4.8
(18/03/2010)
•
Details of a literature case reporting a death from overdose in a child
(22/02/2006) to section 4.9.177 [Note these details were included into the
SmPC of a different acetylcysteine product whose licence was subsequently
transferred to
. Consequently the details of this case are not
included in Section 4.9 of the
.
3.2.3.7. Marketing Authorisation Holder (MAH) pharmacovigilance cases
There are currently three companies who hold Marketing Authorisations (MAs) for
intravenous acetylcysteine. UCB Pharma (UCB) holds the licence for the brand
leader Parvolex which it acquired in July 2005. Teva UK Ltd and Martindale Pharma
both market a generic product.
All companies with MAs for acetylcysteine for the treatment of paracetamol overdose
were asked to supply updated pharmacovigilance data subsequent to the latest
periodic safety update report (PSUR) for acetylcysteine. This data was assessed and
compared against the MHRA Yellow Card database all 3 companies Martindale
Pharma, Teva and UCB Pharma.
69
3.2.4. Conclusions
From the preceding discussion and analysis of the literature it is clear that the
incidence of adverse events to acetylcysteine infusion are variably reported up to
50% but in the vast majority of cases are minor, easily treatable and would not be
considered a reason to withhold acetylcysteine. In over 30 years of treatment with
acetylcysteine with an estimated exposure of over 600,000 patients, there are only 5
confirmed fatalities associated with acetylcysteine on the UK Yellow Card database,
.
Most adverse reactions occur predominantly within the first 15 minutes of infusion
and can be easily managed by stopping the infusion, and re-starting it at a slower
rate. The incidence of more severe reactions has been estimated at 1% but again
can usually be managed by treatment with an antihistamine, corticosteroids and/or
adrenaline. The SmPC states that antihistamines and corticosteroids may
occasionally be required to manage reactions.
There is evidence however that patients with a history of asthma, atopy or familial
allergy may be at increased risk of anaphylactoid reactions. Thus there may be
justification for suggesting that patients with this clinical history are prophylactically
treated with an antihistamine before acetylcysteine is administered. In fact TOXBASE
was updated in June 2011 to advise that H1 & H2 antagonists should be used
prophylactically in patients receiving IV acetylcysteine who have a history of previous
severe reactions to acetylcysteine. It should be noted that the current approved
SmPC for acetylcysteine makes no reference to prophylaxis.
The suggestion that the incidence of adverse drug reactions, particularly severe
adverse drug reactions, may be higher when the plasma paracetamol concentration
is lower has implications for the risk-benefit profile of acetylcysteine and the point at
which it becomes negative. Both Waring et al159 and Pakravan et al165 report an
inverse relationship between the incidence of adverse reactions, especially severe
ones, and plasma paracetamol level (Figure 24A) which appears particularly marked
at levels <100mg/L. The risk of hepatotoxicity at paracetamol levels below 100mg/L
is very low and hence the risk of adverse reactions to acetylcysteine may be greater
than the risk of hepatotoxicity from paracetamol in the majority of people. As always
the validity of this association is dependent on an accurate time to ingestion but in
the absence of a treat all policy this is unavoidable.
70
3.3.
Administration Errors Associated with acetylcysteine
In addition to the inherent risks due to adverse reactions to acetylcysteine, the risks
associated with errors in its administration also need to be carefully considered.
3.3.1. Published literature
The IV protocol for the administration of acetylcysteine is complicated, consisting of a
loading dose (150mg/kg (max 16.5g) over 15mins) followed by 2 maintenance doses,
each with a different infusion rate (50mg/kg (max 5.5g) over 4h and 100mg/kg (max
11g) over 16h). Thus the total treatment period is 20.25hours and requires the
calculation of doses on a mg/kg basis. A number of publications of recent
years178,179,172 have highlighted the opportunity for serious dosing errors with
potentially fatal consequences.
Ferner et al172 examined prospectively the concentrations of acetylcysteine in each of
the infusion bags for 66 anonymous patients. The concentration in each bag was
measured and on the basis of patient weight the percentage of the anticipated dose
that had been administered was calculated. In 68 of 184 individual bags (37%) the
experimentally determined dose was within 10% of the anticipated dose, in 61% of
the bags within 20% of the dose and in 17 bags was more than 50% from the
anticipated dose. The median difference between pre- and post-infusion samples
was 0% but the interquartile range was -5.2% to +14.6% and 9% showed disparity of
greater than 50%. Hayes et al178 retrospectively examined the charts of 221
paracetamol overdose cases over a 13 month period and concluded that medication
errors occurred in 33% (74) patients. The frequency and type of errors were 1.4%
incorrect dose, 5% incorrect infusion rate, 18.6% >1h interruption in therapy and
13.1% unnecessary medication (paracetamol levels below the treatment line). In a
series of 128 patients treated with IV acetylcysteine in Newcastle, 1.4% (5) of the 352
infusions has dose calculations errors of >10% although only 2 were considered
clinically significant.162 These were >3 fold excess doses involving the second
infusion, both in patients who developed anaphylactoid reactions. Selvan et al179
similarly reported that the incidence of dosing errors was up to 24%, 6% of the time
when the dose was calculated by doctors and 24% of the time when calculated by
nurses. Prescribing errors in both groups included 1000 fold under or overdoses.
However importantly no errors were made by either group when a weight based chart
was introduced to calculate doses or volumes (Table 17).
As discussed earlier there have also been some fatalities associated with overdose
of acetylcysteine although direct causality in these cases cannot be established.
Mant et al164 report two fatalities associated with an up to 10 fold overdose of the
loading dose of acetylcysteine. In the first case a 32 year old woman was admitted
approximately 12 hours after the overdose with a paracetamol level of 145mg/L. This
level would be associated with severe paracetamol toxicity. An infusion of 10 times
the correct loading dose was initiated and then stopped after she had been given
between 2.5 and 6 times the correct dose as she developed flushing and
hypotension. She was resuscitated but subsequently developed disseminated
intravascular coagulation, bled extensively and was hypotensive for about 12 hours.
She died 10 days after admission, after being anuric throughout this time. Post
mortem examination showed hepatorenal failure to have been the principal cause of
death. The other fatality was a patient who was found unconscious at home and on
admission to hospital was diagnosed with an overdose of prochlorperazine and
paracetamol (level of 230mg/L – unknown time of ingestion). She was given 10 times
the loading dose over the first one and a quarter hours. Eight hours after admission
she suffered a cardiac arrest and died. It is not stated whether there was a reaction
to the overdose. The authors state that it is unclear the extent to which acetylcysteine
71
was implicated in these deaths. Disseminated intravascular coagulation, hepatorenal
failure and renal failure in the absence of significant hepatic damage are all
recognised complications of severe paracetamol overdose. In addition both patients
were admitted with high paracetamol levels at an uncertain time after ingestion.
Table 17: Weight-based N-acetylcysteine (acetylcysteine) dosing chart for adults.
*The calculated Parvolex (200 mg/ml acetylcysteine) volumes are
compatible with the dosing calculator provided by TOXBASE
(http://www.spib.axl.co.uk) which aids calculation of acetylcysteine dose in
milliliters from the patient’s weight. All volumes are rounded to the nearest
milliliter for ease of measurement.179
3.3.1.1. Paediatric literature articles
IV acetylcysteine has also been reported to result in hyponatraemia (and
subsequently seizures) in children180 predominantly when the volume of IV fluid was
not adjusted to account for the weight of the child.181 A further medication error which
resulted in the administration of double the dose during the second infusion was
associated with the first fatal UK case reported in 1984.176 A further relatively recent
case report of a medication error which led to a massive IV acetylcysteine dose
(2450mg/kg) in a 30month old patient was published in 2004. The overdose resulted
in status epilepticus, intracranial hypertension and death although due to the size of
the overdose the report could not establish whether death was a result of the
acetylcysteine overdose or the fluid and electrolyte imbalance that resulted from it.177
These reports highlight the specific risks associated with acetylcysteine
administration and the importance of provision of the correct prescribing information
72
in children. The inclusion of weight based tables providing volume and infusion rate
for children181 in children may help prevent such administration errors.
3.3.2. National Patient Safety Agency data
In 2010 the National Patient Safety Agency (NPSA) shared with the MHRA a report
summarising a large number of medication incidents (645) reported to the National
Reporting and Learning system (NRLS) relating to treatment with acetylcysteine
(Parvolex)
The report highlights that a
significant number of these errors relate to errors in administration of the medication
in terms of wrong dose or strength, wrong frequency, wrong quantity, wrong method
of preparation and wrong infusion rate. More recently the NPSA has provided an
update to its original report covering the period 2 September 2009 to 27 July 2011.
This shows a further 59 medication incident reports to the NRLS, broken down as
shown in Table 18.
Cause of incident
Wrong rate of infusion
Wrong infusion volume
Wrong infusion solution
Clinical documentation
Omitted or delayed dose
Wrong dose prescribed
Other
Total
Number of incidents
reported
23
8
7
6
5
5
5
59
%
39.0
13.6
11.9
10.2
8.4
8.4
8.4
Table 18: Summary of Updated Incident Reports for acetylcysteine reported to the
NPSA from 2 September 2007 to 27 July 2011.
In terms of the reported clinical outcome, 2 incidents were deemed ‘low harm’ and
the remaining 57 ‘no harm.’
These incident reports demonstrate that administration errors with intravenous
acetylcysteine continue to occur. Although none appear to have resulted in major
harm they represent a significant potential risk given the nature of paracetamol
toxicity and efficacy of acetylcysteine when administered correctly.
The nature of the incident reports is also instructive in that the complexity of
acetylcysteine dosing and administration was either the likely cause of the incident,
or at least represented a significant contribution to the error. For example:
73
These further incident reports to the NRLS illustrate that medication errors with
intravenous acetylcysteine continue despite an easy to use dose calculator available
on the TOXBASE website and reinforce the conclusion that there is a need to
simplify the posology and administration of intravenous acetylcysteine. Clearly these
errors have potentially extremely serious consequences if they result in the failure of
therapy. In addition the incidence of severe adverse drug reactions and fatalities
appears higher when acetylcysteine was administered in overdose.164
3.3.3. Conclusions
It is clear from the preceding sections that the prevalence of administration errors
with acetylcysteine is high. Errors predominantly centre on the calculation of either
the dose or the infusion volume although there have also been errors related to
omitted or delayed doses. However the study of Selvan et al179 would suggest that
the relatively simple measure of introducing a weight based dosing chart effectively
avoids these errors and such a chart is in routine use at King’s College Hospital.
This chart could be simplified further by increasing the size of the weight bands from
5kg to 10kg.
4.0.
EVIDENCE OF INTERPRETATION OF CURRENT SmPC GUIDANCE ON
FROM CLINICAL USE OF ACETYLCYSTEINE
There are now several sets of clinical data regarding the use of acetylcysteine in
practice which provide evidence in relation to the interpretation of the guidance as
stated in the current acetylcysteine Summary of Product Characteristics (SmPC).
4.1.
74
75
4.3.
Bristol data set
The below data was retrieved from the Bristol Self harm register and covered a 6
month period in 2010 (unpublished data; Bristol Self-Harm Surveillance Register,
Gunnell, D.J. and colleagues). During this period 220 patients with accurate blood
paracetamol concentrations were assessed of which 164 (74.5%) patients had both
an accurate time of self-harm recorded and a time at which the patient’s bloods were
taken. Half of the patients with available data had bloods taken exactly 4 hours after
the initial act of self-harm (figure 31)
Excluding the patients with bloods taken within 4 hours from their act of self-harm,
there were 11 (6.7%) patients above the normal treatment line and 30 patients
(18.3%) between the 100 and 200 mg/L treatment line. Of these patients 20/30 (66%)
were treated with acetylcysteine.
A total of 40 (24.4%) patients overall received acetylcysteine
350
Blood Paracetamol Concentration mg/kg
300
250
200
150
100
50
0
0:00
1:00
2:00
3:00
4:00
5:00
6:00
7:00
8:00
9:00 10:00 11:00 12:00 13:00 14:00 15:00 16:00
Hours from se lf-harm to bloods
Normal Risk
High Risk
Figure 31: Time from overdose to assessment of blood paracetamol level.
In the patients given acetylcysteine, 60% had an adverse reaction but the incidence
did not appear inversely related to the blood paracetamol level. Blood paracetamol
concentration was generally higher in those that had a reaction versus those that did
not (Table 21) but the number of cases are too small to draw clear conclusion with
confidence.
Outcome
N
Adverse
Non adverse
12
8
Mean time
between
overdose and
blood sampling
5.52
.33
Mean blood
paracetamol
(mg/kg)
Median blood
paracetamol
(mg/kg)
139
115
155
103
Table 21: Outcome of patients treated with acetylcysteine that were between the
high risk and normal risk lines
76
4.4.
Experience of a district general hospital.
To complement the previous data sets we have attempted to obtain similar
information from a district general hospital. Unfortunately the record of paracetamol
levels taken from 381 patients
is not
linked to treatment or not with acetylcysteine and the time of the sample with respect
to the time of overdose is not always reported. Of these 381 samples (Figure 31):
•
•
•
•
260 (68%) were sub therapeutic (<10 mg/L).
79 (20.7%) were between 10 and 99mg/L (14 between 75 and 99 mg/L).
33 (8.6%) were between 100 and 199 mg/L
9 (2.4%) >200mg/L
300
Number of patients
250
200
150
100
50
0
<10
10-99
100-200
>200
Serum Paracetamol level (mg/L)
Figure 31: Serum paracetamol levels in a cohort of patients presenting to a District
General Hospital between Nov 2008 and Jan 2009.
Hence in the majority of patients (68%) the levels were too low to be significant in
terms of toxicity and so the timing of presentation means decision to treat may have
77
been on the basis of history or dose taken. There were only 33 patients who
presented with levels between the 100 and 200 lines in this 3 month period equating
to approximately 10 patients a month in whom the decision to treat would have been
based on the presence or absence of risk factors. It is unfortunate that this data is
not currently linked to treatment but
other data would
suggest that it is likely that a substantial number of these patients would have been
treated with acetylcysteine. Interesting however a smaller percentage of patients
overall presented with levels >100mg/L at 4h
The comments attached to the paracetamol levels however support the unreliability
of patient history or potentially the variability of metabolism with alleged overdoses of
16g of paracetamol returning levels of 261 and 112 at 4h in two different patients.
The comments also suggest that when levels are subtherapeutic, there may be still
be instances where acetylcysteine is given based on the history of the amount
ingested.
4.4.1. Time taken between sampling and Reporting a Paracetamol Level.
Clearly efficient and appropriate treatment of paracetamol overdose with
acetylcysteine relies in part on the efficient measurement of serum paracetamol
levels by hospital laboratories. Information from one district general hospital
suggests that this can be very variable over a 12 month period.
4.5.
College of Emergency Medicine Audit.
The College of Emergency Medicine has carried out 3 audits of the treatment of
paracetamol overdose since 2004, the latest audit being 2008. The audit questions
are reproduced below:
78
Important points to note in the interpretation of the data are:
1.
2.
3.
4.
The treatment line was not defined in the audit and treatment may have
be based on either the high (100 line) or normal (200) risk line.
Staggered overdose was not defined within the audit.
Results are based on only 50 consecutive patients.
Due to the relatively low numbers of patients audited, errors in the
treatment of one or two patients can impact significantly on performance.
The audit results are attached in Appendix X. Key points to note are:
1.
2.
3.
4.
5.
6.
7.
In 2008, a median of 79% of cases reporting to the emergency
departments (ED) as a paracetamol overdose received a plasma
paracetamol level test (Table 7 of attached audit reproduced below as
Table 22).
In line with the previous data in 2008 on average only 17 % (11-22%) of
patients had levels above a treatment line. However, on average across
the EDs only 73% of these patients received acetylcysteine within 8h of
ingestion.
Consistently patients who presented with a staggered overdose and over
8h of ingestion did not receive acetylcysteine within 1h of arrival (NB: on
average only 8% of patients fell into this category but only 2% of these
were treated appropriately).
In some EDs staggered overdoses appear to represent a large number of
the patients audited. This may relate to a lack of clarity over the term
“staggered”.
In some EDs, a large number of samples were tested less than 4h after
the overdose.
There is a large variability in performance over the individual trusts. For
example in some trusts, only 20% of patients received acetylcysteine
within 8h of ingestion when it was required.
Overall only 80% of patients received the required treatment. In some
EDs between 15 and 25% of patients had serious omissions in treatment
although on average it was substantially less than this (chart 13 in
attached audit).
79
Table 22: National results for the treatment of paracetamol overdose since 2004
(CEM audit).
The key conclusions from this data set are that a relatively small percentage of
patients who present with a paracetamol overdose have a level above a treatment
line (~17%) which is in line with the other data sets. However there appears to be
variability across the trusts in terms of conformation with current guidelines which
may reflect difficulties in interpretation. Critically in some departments a large number
of samples were tested before the 4h cut off mark and in some only 20% of patients
for whom it was indicated received acetylcysteine within the optimal 8h period of
efficacy. It is likely that these results reflect a variability in interpretation of the
guidelines and subsequent treatment across the UK.
4.6.
Conclusions
It seems clear from the above data that there is considerable variability in
performance across EDs in terms of the treatment of paracetamol overdose and that
patients deemed to have taken a staggered overdose are at particular risk of delayed
treatment. In addition,
data
consistently suggest that a significant and possibly disproportionate number of
patients are being treated between the 100 and 200 lines reflecting either a cautious
80
approach or difficulty in applying the current guidelines. The cautious approach is
again supported by the fact that more than 50% of the patients treated over this
period were considered either to fall into the high risk category or to have unreliable
time of ingestions. There therefore provides some evidence in practice of departure
from national guidelines and therefore from the current approved SmPC for
acetylcysteine and other sources of guidance e.g. BNF.
5.0.
MAH REPORTS ON ACETYLCYSTEINE
The three companies who market IV acetylcysteine in the UK were asked to provide
all available information in relation to pharmacovigilance in addition to sales data and
details of the currently marked ampoule sizes. As the MA for the brand leader
Parvolex, UCB were asked to provide all available information supporting the current
posology and product formulation.
5.1.
UCB Pharma Ltd
5.2.
Martindale Pharma
Martindale Pharma provided up to date information on their pharmacovigilance cases
and worldwide sales usage data. Martindale have two ampoule sizes licensed, 10 or
20mL containing 200mg/mL of acetylcysteine but at present only market the 10mL
ampoule.
5.3.
Teva UK Limited
Teva UK supplied updated pharmacovigilance data which has been discussed
earlier. Teva only market a 10mL vial.
5.4.
MAH proposals to improve benefit risk of acetylcysteine
The three UK MA holders for acetylcysteine were also asked to make proposals to
improve the benefit risk of intravenous acetylcysteine. These proposals are
summarised as follows:
5.4.1. Acetylcysteine posology
To increase the duration of infusion of the initial loading dose of acetylcysteine from
15 minutes to 1 hour in order to reduce the risk of an ADR.
5.4.2. Identify patients at increased risk of a acetylcysteine ADR
The SmPC could better identify patients at risk of a acetylcysteine ADR, e.g. females
and those with asthma.
81
5.4.3. Weight-based dosing tables
To include a weight based dosing table in the acetylcysteine SmPC and technical
information leaflet (TIL).
5.4.4. Acetylcysteine Product Information
To harmonise the UK acetylcysteine SmPC in line with the brand leader.
In addition, acetylcysteine packs should include a technical information leaflet (TIL)
for healthcare professionals.
5.4.5. Pre-printed prescribing labels
To recommend the use of pre-printed prescribing labels such as those developed by
Glan Clwyd Hospital’s pharmacy in late 2002. These labels are self-adhesive and
can be attached to a patient’s main drug treatment chart. To complete the label, the
prescriber inserts the date of the prescription, the dose volume in mL of
acetylcysteine (using a weight-based table) and his or her signature. The nurse
completes the rest of the label.
5.4.6. Use of an integrated care pathway (ICP)
This is a locally produced multidisciplinary management plan that incorporates
guidelines (based on evidence-based practice for a specific group of patients) and
best practice to enhance care and documentation for a specific patient group.
5.4.7. Use of electronic prescribing
Electronic prescribing may increase the accuracy of prescriptions. An example is
provided by the system developed at Glan Clwyd Hospital in Wales and is available
on the hospital intranet. The system requires the prescriber to type in the patient’s
name, weight (in kg) and hospital number. The software then calculates the required
dose and prints out the acetylcysteine prescription (in the same format as the
treatment chart used in the hospital), which the prescriber then needs to sign and
date. Nursing staff then need to complete the time that administration of the infusion
was started and sign the prescription.
5.4.8. Computerised acetylcysteine physician order entry by template protocol
This is a system where the treating physician enters instructions for the treatment of
a patient and these are then communicated electronically to staff in other
departments, which in the case of paracetamol overdose would include the
pharmacy. The potential advantages of CPOE using order sets is that it includes
standardised ordering protocols, computerised weight-based dose calculation,
physician prompts for correct sequencing of orders, legible, and rapid communication
with pharmacy, and direct physician-to-pharmacist communication without
intermediaries.
5.4.9. Simplify the acetylcysteine posology.
Simplifying the acetylcysteine posology may reduce medication errors. A recent
study used a scenario of acetylcysteine application which assumed that the patient
presents to the hospital 2 h post-overdose, instead of 6 h, as per conventional
regimen.147 The investigators used a lower dosing rate of acetylcysteine infusion
initiated immediately on presentation and determined a dosing rate that gave an area
under the curve (AUC) of the concentration-time curve that was the same or greater
than that from the conventional regimen on 90% of occasions. Lower dosing rates of
acetylcysteine initiated immediately upon hospital presentation resulted in a similar
exposure to acetylcysteine. An infusion of 110 mg/kg over the first 5 h (22 mg/kg/h)
followed by the last two phases of the conventional regimen, or 200 mg/kg over 9 h
(22.6 mg/kg/h), followed by the last phase of the conventional regimen was used.
82
The investigators concluded that the novel dosing regimen allowed immediate
treatment of a patient using a lower dosing rate and this greatly simplified the current
dosing regimen.
6.0.
MODELLING BENEFIT RISK OF ACETYLCYSTEINE.
This analysis attempts to quantify the benefits and the risks relating solely to mortality
which would result from a recommendation to treat all patients presenting a with
paracetamol level above the “100mg/L at 4h line”. Various data sources have been
used in this analysis which will be discussed and the limitations of the analysis
highlighted. A quantitative assessment of the benefits and risks with regard to
mortality has then been conducted using these datasets.
6.1.
Available data sources and discussion of assumptions and limitations
Unfortunately the data required to make a quantitative analysis of the benefits and
risks of acetylcysteine use between the current two treatment lines in all patients are
not available from one source. Therefore several data sources have been used.
6.1.1. The number of patients presenting with paracetamol overdose in the UK
6.1.1.1. Gunnell D, Ho D, and Murray V. Emerg Med J. 2004; 21: 35-38.182
In this study data from the Hospital Episodes Statistics database, covering patients
aged 12+ in England from 1997-1999, is summarised with regards to the number of
admissions following a drug overdose and the number resulting in death.
There were 233,756 admissions (an average of ~78,000 per year) for drug overdose.
6.1.1.2. Gunnell D, Bennewith O, Peters T, et al. J Pub Health. 2005; 27: 67-73.183
An 8-week audit of 32 random hospitals in England was completed 2001-2002 with
data collected on all presentations for self-harm in patients aged 18+.
There were 4,033 presentations for self-harm (~26,000 per year) with 3,198/4,026
(79%, ~21,000 per year) being for a drug overdose (and an additional 193 being for
overdose and laceration); 46% of presentations were admitted.
6.1.1.3. Hawton K, Bergen H, Casey D, et al. Soc Psych Psych Epi. 2007; 42: 513521.3
Data on self-harm presentations to 6 general hospitals in Oxford, Manchester, and
Leeds (two hospitals) were collected for the 18-month period March 2000 to August
2001.
7,344 patients presented following 10,498 episodes of self-harm with ~85% of
presentations involving self-poisoning. Paracetamol was the most commonly used
drug.
6.1.1.4. Prescott K, Stratton R, Freyer A, et al. BJCP. 2009; 68: 260-268.133
This one centre study, 04/2006 – 03/2007, looked at deliberate overdoses presenting
age 16+.
There were 1,598 overdoses reported as presenting to services with 770 (48%) of
these involving paracetamol (although only half of all overdoses involved only one
drug).
83
6.1.1.5. ONS 2011.
Data from the Office of National Statistics estimates that the population in England
1999-2001 was 49 million, in England and Wales was 52 million, and in the UK was
59 million.
These data suggest that there are between ~170,000 (Data from Gunnell et al.182,183:
78,000 admissions, 46% of presentations resulting in admission) and ~187,000 (data
from Hawton et al. 20073: extrapolated ~220,000 hospital attendances for self-harm,
approx 80% of which are self-poisoning presentations) for self-harm England per
year.
The data from Hawton et al. 20073 suggest that approximately 40% of presenting
overdoses involve paracetamol or paracetamol compounds.
This data can be extrapolated up to estimate figures for the whole of the UK.
ESTIMATE OF PARACETAMOL OVERDOSES IN UK ANNUALLY: 82,000 to 90,000
(CALCULATION (59/49)* [(170,000*0.4) to (187,000*0.4)])
This figure is only an estimate of the number of paracetamol overdoses presenting
per year in the UK overall. Differences in the demographics (e.g. age, location) of the
populations studied and the historical nature of the data mean that it is not possible
to exactly calculate the current annual number of presenting cases. In particular we
have made the assumption that the rates are the same in England and throughout
the rest of the UK. These limitations are compounded by the fact that data from
several sources has had to be combined in the calculation.
However, we can be reassured that there has been little change over time in the
number of presentations with paracetamol overdose from the paper by Hawton et al.
in 2004184. These authors investigated changes in self poisoning trends before and
after the changes in legislation in 1998 limiting the size of packs of analgesics. A
significant drop in the number of presentations in the year immediately following the
change was demonstrated but there was no evidence that this fall in numbers was
sustained and within 3 years the number of presentations seemed to have returned
to a similar level. It is also reassuring that the estimated figure is of a similar
magnitude across the different data sets considered.
6.1.2.
The number of people, presenting with a paracetamol overdose, whose
plasma paracetamol concentration falls between the “100” and “200” at 4h
treatment lines and an estimate of the proportion of these who do not
receive acetylcysteine
6.1.2.1. Prescott K, Stratton R, Freyer A, et al. BJCP. 2009; 68: 260-268.133
119/609 (20%) of the presenting paracetamol overdoses with serum paracetamol
levels recorded were between the “100” and “200” treatment lines. Of these, 39
(33%) were not admitted so it can be assumed that they were not treated. Despite
contacting the authors no further data on treatment with acetylcysteine is available.
6.1.2.2. Beer C, Pakravan N, Hudson M, et al. Q J Med. 2007; 100: 93-96.49
This study quotes data on 287 presentations collected in 1994 from six A&E
departments in North East England which showed that 19.4% had a serum
paracetamol level between the “100” and “200” treatment lines with data from
Newcastle in 2004 showing a similar figure of 18.8%.
84
Data from
Note: other more recent unpublished data suggests that 81% of patients who
presented with levels between the 100 and 200 mg/L treatment lines received
acetylcysteine.
6.1.2.3. Data from Bristol (Personal communication)
Data are from the BRI self-harm register covering the period 20/09/10 - 20/10/11. 164
(74.5%) patients had both an accurate time of self-harm recorded and a time at
which the patient’s bloods were taken. Half of the patients with available data had
bloods taken exactly 4 hours after the initial act of self-harm.
30/164 (18%) of patients fell between the two treatment lines and, of these, 67%
were treated with acetylcysteine.
The data therefore consistently suggest that approximately 20% of patients
presenting to services with a paracetamol overdose have serum paracetamol
concentrations between the current two treatment lines although this is probably the
lower end of a possible estimate. This estimate is reasonably consistent across all
the data sources.
The data also suggest that ~60-70% of patients presenting with a plasma
paracetamol concentration between the current two treatment lines were treated with
acetylcysteine i.e. were considered high risk assuming the current guidelines were
followed.
AN ESTIMATE PARACETAMOL OVERDOSES IN UK ANNUALLY WITH
PARACETAMOL CONCENTRATIONS BETWEEN THE TREATMENT LINES:
16,400 to 18,000
(CALCULATION 0.2*(82,000 to 90,000))
AN ESTIMATE NUMBER OF PEOPLE BETWEEN TREATMENT LINES NOT
RECEIVING acetylcysteine CURRENTLY: 4,920-7,200 i.e. 30-40%
(CALCULATION 0.3*16,400 to 0.4*18,000)
The main potential issues with the data regarding the number of patients with
paracetamol concentrations relate to possible inaccuracies due to regional
differences in overdose patterns and trends over time. However, the data presented
85
here appear to be reasonably consistent which suggests the estimate should be
reasonably reliable.
There might be similar concerns with the treatment data i.e. that treatment practice
had changed over time or that patterns of high risk or clinical practice are different
across the UK. There are likely to be differences in the proportion of high risk patients
in rural and urban areas.
Prescott et al20 estimated that 23% of patients presenting between the lines suffered
severe liver damage, although none of these patients died. If this is the case between
1032 and 1656 of the patients who are currently not treated are at risk of liver
damage in this patient group (calculation 0.23*4, 920 – 0.23*7200).
6.1.3.
The number of people, presenting with a paracetamol overdose, whose
plasma paracetamol concentration falls above the “200” treatment line or
who have a staggered paracetamol intake.
6.1.3.1. Beer C, Pakravan N, Hudson M, et al. Q J Med. 2007; 100: 93-96.49
This study quotes data on 287 presentations collected in 1994 from six A&E
departments in North East England which showed that 16.6% had a serum
paracetamol above the “200” treatment line and data from Newcastle in 2004
showing a figure of 10.2%.
6.1.3.2. Data from
6.1.3.3. Data from Bristol (Personal communication, as above)
Eleven (7%) of patients fell above the “200 line”.
All this data suggests that between 10-20% of patients had a level above the “200
line” and an additional 10-15% had staggered ingestion.
AN ESTIMATE OF PARACETAMOL OVERDOSES IN UK ANNUALLY WITH
PARACETAMOL CONCENTRATIONS ABOVE THE “200 LINE”: 8,200 to 30,000
(CALCULATION 0.1*82,000 to 0.3*90,000)
AN ESTIMATE OF PARACETAMOL OVERDOSES IN UK ANNUALLY WITH
PARACETAMOL CONCENTRATIONS ABOVE THE “200 LINE” OR BECAUSE OF
STAGGERED INGESTION: 9,020 to 34,500
(CALCULATION (8,200+(8,200*0.1) to (30,000+(30,000*0.15))
86
This data is subject to the same limitations with regard to differences and changes in
the quantity of paracetamol used in overdoses as that discussed in the previous
section. There seems to be a greater variation in the proportion of patients with
plasma paracetamol above the “200 line” than in the proportion between the two
treatment lines. This leads to quite a weak estimate in the number of patients
presenting with paracetamol concentrations above the 200mg/L at 4h line. Data on
the number of staggered overdoses is also limited.
6.2.
An estimate of the number of acetylcysteine associated deaths in the
UK
6.2.1. UK Yellow Card data
There have been 5 fatal ADR case reports for acetylcysteine given IV, IM SC,
parental, or via an unknown route for paracetamol overdose over more than 30 years
of treatment. Of these four had a confirmed fatality due to an anaphylactoid reaction
when acetylcysteine was administered. However, it should be noted that in one of
these cases the patient received an overdose dose of acetylcysteine of
approximately twice the recommended dose. For the remaining case,
.
Both of these cases have been included in this dataset for completeness.
Two cases of death reported by Mant et al164 in 1984 following an acetylcysteine
overdose have not been included in these figures. The deaths occurred some time
after the overdoses (10 days and 8hours respectively) and were in patients with
substantial paracetamol overdose of unclear timing. The authors state that it is
unclear the extent to which acetylcysteine was implicated in these deaths (for further
details see section 3.3.1).
AN ESTIMATE OF DEATHS FROM acetylcysteine AFTER PARACETAMOL
OVERDOSE IN UK ANNUALLY: 0.17
(CALCULATION 5/30)
Given the nature of the reaction and the fact that we are considering only fatal
outcomes it seems reasonable to conclude that we have most if not all of the relevant
fatal ADRs. However, sensitivity to this assumption should be considered as the level
of yellow card reporting is generally considered to be much lower. This data covers
over 30 years of treatment.
6.3.
An estimate of the number of deaths occurring in patients not treated
with acetylcysteine who have plasma concentrations between the
“100” and “200” treatment lines
6.3.1. Beer C, Pakravan N, Hudson M, et al. Q J Med. 2007; 100: 93-96 49.
Data from patients with paracetamol poisoning and severe liver dysfunction at
regional liver services in Newcastle and Edinburgh were reviewed. These two
services cover the populations of north-east England and Scotland, totalling about
9.0 million people, and the periods of study encompassed about 95 million personyears.
During the periods of study, 696 patients with possible paracetamol hepatotoxicity
were admitted to the two liver units. Just 6 patients, with no recorded features to
identify high risk, had a paracetamol concentration between the 100 and 200 lines.
87
One of these patients died after receiving acetylcysteine 33 hours after the overdose
followed by a liver transplantation.
6.3.2.
Data from
6.3.3. Hawton K, Simkin S, Deeks J, et al. BMJ. 2004: 329: 1076-1079.185
From all but one of the liver units in England and Scotland this study presented data
on numbers of patients admitted after paracetamol overdose, those listed for liver
transplant, and those undergoing transplantation, between 1996 and 2002.
Newcastle and Edinburgh liver units account for approximately 25% of the liver unit
admissions.
This data highlights that the number of deaths in patients from paracetamol overdose
who presented within 15 hours and who had a plasma paracetamol concentration
between 100 and 200 is extremely low. Extrapolating from the data
from Newcastle and Edinburgh we might expect there to be 4-5 deaths over a period
of ~10 years but this estimate has high levels of uncertainty.
6.3.4. MHRA data
There are 7 cases since 1992 known to the MHRA where a patient was not treated
with acetylcysteine and had a plasma paracetamol concentration between the two
treatment lines and died. One was initially thought to have a concentration lower than
the recommended treatment line but their subsequent clinical course suggested a
problem with the interpretation of this data. This is an estimate of ~0.35 per year
(7/20).
We will initially start with the highest estimate of the number of deaths but will later
consider the sensitivity to this.
AN ESTIMATE OF DEATHS FROM PARACETAMOL OVERDOSE IN UK
ANNUALLY WITH UNTREATED PARACETAMOL CONCENTRATIONS BETWEEN
THE TREATMENT LINES: 0.5
(CALCULATION 5/10)
This is a very rough estimate of the number of deaths in patients untreated between
the current two treatment lines and has many limitations.
6.4.
Quantitative analysis of benefit risk
In order to try and evaluate the benefits and risks with regard to mortality the data
presented above should be considered.
The data above estimates that;
•
there are 4,920-7,200 patients currently not treated with acetylcysteine each
year as they are not considered high risk and their plasma levels are between
the two treatment lines. Of these, we estimate 0.5 deaths annually.
88
•
there are 18,860-39,540 patients treated with acetylcysteine annually (9,02034,500 above the “200 line” or who have staggered ingestion and 9,840-5,040
between the two lines and considered high risk). Of these, we anticipate 0.17
will die due to a reaction to acetylcysteine.
•
If all the patients currently presenting with levels above the “100 line” were
treated with acetylcysteine this data would suggest that we would see an
additional 0.03-0.05 deaths a year due to a reaction to acetylcysteine
(extrapolating up based on the additional numbers of patients treated (4,9207,200 extra patients treated with acetylcysteine per year).
Thus if it is assumed that the anticipated 0.5 deaths due to untreated overdose do
not occur, this would result in a benefit with regards to mortality for lower treatment
i.e. 0.46-0.47 deaths/year or 1 death every 2.1-2.2 years.
However, it is important to acknowledge that the data used in this calculation has
many limitations. Not least the estimate of the number of acetylcysteine related
deaths from Yellow Card reports. Assuming all other estimates are valid, were we
only to have captured a third of the number of deaths associated with acetylcysteine
then the benefits would equal the risks in terms of mortality. We would however
expect a high level of reporting for fatal reactions although acetylcysteine has been
licensed for a long time.
If further the number of deaths in untreated patients between the two lines was only
0.35 then we only need have seen two/thirds of the deaths from acetylcysteine for
the benefit risk to be neutral.
Conversely, given that one of the known acetylcysteine death cases was
administered an acetylcysteine overdose which may have contributed to the death, a
situation that increased risk minimisation procedures should decrease the incidence
of in the future, it is possible that the risk of death associated with acetylcysteine use
is even lower. Using the lower estimate of 4 deaths/30 years would result in a
reduction of 1 death approximately every 2.1 years from lowering the treatment line.
There are several other major issues with this calculation, the impact of which are
very difficult to evaluate.
•
•
•
Potential changes in the profile of overdoses over time. Legislation brought in
1998 to reduce pack sizes significantly reduced the size of overdoses although
the effect of the legislation is thought to have varied across the UK. Some of the
data used here predates that legislation.
Geographical differences in the number and size of overdose and the time to
presentation. There are likely to be differences in the characteristics of the
patients and the overdoses they take depending on their rural or urban location.
Much of this data seems to come from urban centres and mainly from England.
•
As this analysis combines figures estimated from several different data sets the
potential error in the final figures is compounded.
•
The assumption that the rate of death associated with acetylcysteine will be the
same in those currently untreated is being made. Although usually not severe,
89
adverse reactions to acetylcysteine may be more common in patients with lower
plasma paracetamol concentrations.
•
The maximum estimated number of patients treated with acetylcysteine is still
lower (39,540) than might be expected from the most recent usage data (~60,000
patients annually). We are unable to determine how much of this usage is offlabel but it seems unlikely that it would be to this extent. It is possible that the use
in patients presenting with staggered ingestion is higher. If we are currently
underestimating acetylcysteine use then the estimated number of additional
deaths occurring if guidelines were changed would be lower.
•
Perhaps most importantly, further consideration should also be given to the
number of severe anaphylactic reactions to acetylcysteine and the number of
liver transplants needed or admission to liver units due to non-treatment of
patients above the “100 line” as these impact heavily on the overall benefit risk
profile. The issue of other ADRs associated with acetylcysteine requiring
hospitalisation is also important.
Overall, this data seems to suggest there is a slight benefit in favour of the
recommendation to treat all patients presenting with paracetamol levels greater than
100mg/L at 4h. However, this analysis is only with respect to mortality and given the
very small number of known deaths is not of a large magnitude.
7.0
COMMUNICATION STRATEGY
The subgroup on communications met on the 11th November 2011 and made a
number of suggestions with regard to the content and format of a discharge leaflet.
Further meetings of the group will be required to refine the communication strategy
once the recommendations have been agreed.
8.0
CONCLUSIONS
Whilst there are limitations, the data reviewed above provide persuasive evidence
that there are difficulties and inconsistencies in the interpretation of current guidelines
which reflect the UK SmPC for acetylcysteine, and these data therefore support the
need to revise the SmPC, patient information and hence guidelines. A number of
conclusions can be drawn.
8.1.
Benefit/Selecting Patient Population
i.
Acetylcysteine is a highly effective treatment in the prevention of
paracetamol induced hepatotoxicity. For maximum benefit treatment should
be initiated within 8h of the overdose. Although benefit is still derived in
patients who present late the efficacy is sharply reduced. This highlights the
need to provide treatment in a timely manner.
ii.
There is a high risk of hepatotoxicity for patients presenting with
paracetamol levels below the 200mg/L treatment line with case reports of
fatalities at levels around the 100 mg/L at 4 hours line.
iii.
There is evidence for significant biological variability in the metabolism of
paracetamol between individuals which cannot be predicted and is likely to
affect the toxic threshold.
90
iv.
There is evidence that practice varies significantly between different centres
across the UK. However, there would appear to be widespread substantial
treatment between the current normal (200mg/L at 4h) and high (100mg/L at
4h) risk lines which is either indicative of uncertainty in appropriate patient
selection in clinical practice or it may reflect that, in clinical practice, doctors
are erring on the side of caution or both.
v.
The introduction of the nomogram in the 1970’s suggested the prediction of
toxicity based on a timed blood plasma paracetamol level but its use is
fundamentally limited by:
a. It is dependent on an accurate time of ingestion. The nomogram is
therefore invalid if the time of overdose is unreliable or if the overdose is
staggered.
b. Factors which affect absorption of paracetamol may affect the accuracy
of the nomogram.
c. A range of risk factors which results in substantial individual variability in
the metabolism of paracetamol which cannot be predicted consistently
from the ingested dose and which significantly influence the risk of
toxicity. The evidence supporting the influence of risk factors on
paracetamol toxicity is poor and thus parameters are poorly defined.
d. Identification of the presence of risk factors is dependent upon an
accurate clinical history which is highly likely to be unreliable in this
patient population. Therefore this approach for the diagnosis of potential
toxicity has fundamental difficulties
vi.
Staggered overdose is not defined in the SmPC. Use of the nomogram is
not applicable for staggered overdose and all such patients should be
treated. It is critical that the term staggered is clearly defined.
vii.
Paracetamol half life is substantially slowed at an early time point in patients
with hepatotoxicity and could therefore be a useful additional measure of
toxicity particularly in those with levels close to the treatment lines. However,
problems associated with time of presentation and the time required to
receive the results of paracetamol levels means that for most centres having
two levels assessed within 8h of ingestion would be challenging.
viii.
Currently there are no novel biomarkers which could improve the diagnosis
of potential toxicity.
8.2.
Risk with acetylcysteine
i.
The adverse reactions associated with the infusion of acetylcysteine are
common (23-50%) usually mild and easily manageable. Currently ADRs are
generally easily managed by stopping the infusion and restarting at a lower
rate and/or with the administration of an anti-emetic/H1/H2 antagonist.
ii.
Very rarely (~1%) more serious anaphylactoid reactions occur which are
again usually readily managed with appropriate treatment. There is evidence
that patients with a history of asthma or atopy and those with lower
paracetamol levels are at increased risk of adverse reactions.
iii.
The majority of adverse reactions occur within the first hour of therapy when
plasma acetylcysteine levels are high. Sufficient evidence of efficacy is
available to support extending the time of the initial infusion from 15 minutes
91
to at least 60 minutes in order to reduce the incidence of more serious
anaphylactoid reactions.
8.3.
Medication Errors
i.
There is clear evidence that the use of acetylcysteine is associated with a
large number of administration errors which have potentially fatal
consequences if they result in a failure of therapy.
ii.
Reports of overdose due to medication errors resulting in severe
anaphylactoid reactions to acetylcysteine have been reported. Some of
these reactions have been fatal
iii.
There is a potentially greater risk of medication errors in children due to the
additional need to adjust the infusion volume.
iv.
There are a number of relatively simple measures that could be introduced
to decrease the incidence of administration errors.
8.4.
Balance of risks and benefits
i.
Although there is a high incidence of ADRS they are usually mild and
therefore the risk benefit profile of acetylcysteine is positive at paracetamol
levels >100mg/L. Below a level of 100mg/L the risk-benefit profile is less
clear particularly in the patient population more at risk of anaphylactoid
reactions.
ii.
From the data reviewed it is clear that there are several aspects of the
advice on the selection of paracetamol overdose patients and administration
of acetylcysteine that can be amended in order to further improve the
benefits and minimise the risks.
9.0
CHM ADVICE
IV acetylcysteine should be indicated in all patients in whom there is any doubt over
the time of ingestion of paracetamol or if a staggered overdose is suspected. The
term staggered overdose should be clearly defined. In the absence of any specific
evidence, ingestion of paracetamol over more than one hour should be considered
as “staggered overdose”.
1.
The assessment of risk factors for hepatotoxicity is poorly evidenced, lacks
precision and is difficult to apply in practice. Therefore all patients who present
with a paracetamol level on a treatment line ≥ 100mg/L at 4h and in whom time
of ingestion is verified should be treated with IV acetylcysteine.
2.
To minimise the risk of anaphylactoid reactions associated with acetylcysteine
the duration of the initial loading dose infusion should be increased from 15 to
60 minutes.
3.
Acetylcysteine should not be contra-indicated in patients who have had a
previous anaphylactoid reaction associated with acetylcysteine.
4.
To minimise the risk of administration errors a clear comprehensive weight
based dosage table should be included in the acetylcysteine product
information, supplemented by a technical leaflet for healthcare professionals,
92
and additional labels for recording patient-specific information on infusion bags
should be provided.
5.
Specific doses and infusion volumes for the paediatric population should be
recommended in the acetylcysteine product information.
6.
A larger vial size of acetylcysteine should be made available by the marketing
authorisation holders to minimise the risk of medication errors.
7.
The patient/family should be involved in the decision making process, especially
in those patients in whom treatment with acetylcysteine is not considered
indicated. This involvement should be supported by high quality patient
information, which should include information on acetylcysteine. Patients who
are discharged without treatment should be advised to return to hospital
immediately if they develop symptoms of hepatotoxicity, based on the model
leaflet developed by the group.
8.
The training of healthcare professionals should be the subject of a
comprehensive education strategy to be prepared in collaboration with key
stakeholders including the National Poisons Information Service, the College of
Emergency Medicine, the Royal College of Physicians and Royal College of
Nursing.
9.
Future research should be conducted in the following areas:
i.
Evidence based options for simplifying acetylcysteine posology.
ii.
Whether currently available biochemical markers might identify more
accurately those patients who are at risk of hepatotoxicity.
iii.
Identification of novel biomarkers of risk of hepatotoxicity.
iv.
The influence of pharmacogenomics on paracetamol induced hepatotoxicity
v.
To determine whether oral methionine has a role as:
a) Initial treatment for patients presenting with a paracetamol overdose
pending further assessment.
b) An alternative treatment for those patients for whom acetylcysteine is not
indicated but who have a measurable paracetamol level.
VRMM
25 JANUARY 2012
93
10.0.
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APPENDICES.
Appendix 1:
Appendix II:
Appendix III:
Appendix IV:
Appendix V:
Appendix VI:
Appendix VII:
Appendix VIII:
Appendix IX:
Appendix X:
Appendix XI:
Summary of Product Characteristics for Paracetamol
.
Summary of Product Characteristics for Parvolex.
Summary of treatment guidelines in Europe
NPIS Paracetamol Poisoning Leaflet.
FDA Package Insert
SmPC for methionine
College of Emergency Medicines Audit.
.
104
Appendix I
SUMMARY OF PRODUCT CHARACTERISTICS
1
NAME OF THE MEDICINAL PRODUCT
Panadol / Paracetamol Capsules
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each capsule contains Paracetamol Ph Eur 500.0 mg
3
PHARMACEUTICAL FORM
Capsule
4
CLINICAL PARTICULARS
4.1
Therapeutic indications
Panadol Capsules is a mild analgesic and antipyretic, and is recommended for the
treatment of most painful and febrile conditions, for example, headache including
migraine and tension headaches, toothache, backache, rheumatic and muscle pains,
dysmenorrhoea, sore throat, and for relieving the fever, aches and pains of colds and
flu.
4.2
Posology and method of administration
Adults and the elderly:
2 capsules up to 4 times a day.
These doses should not be repeated more frequently than every 4 hours and not more
than 4 doses should be given in any 24 hour period.
Not recommended for children under 12 years of age.
Oral administration only.
4.3
Contraindications
Hypersensitivity to paracetamol or any of the other constituents.
Appendix I
4.4
Special warnings and precautions for use
Care is advised in the administration of paracetamol to patients with renal or hepatic
impairment. The hazard of overdose is greater in those with non-cirrhotic alcoholic
liver disease.
Do not exceed the stated dose.
Patients should be advised to consult their doctor if their headaches become
persistent.
Patients should be advised not to take other paracetamol-containing products
concurrently.
If symptoms persist consult your doctor.
Keep out of the reach and sight of children.
Pack Label:
Immediate medical advice should be sought in the event of an overdose, even if you
feel well.
Do not take with any other paracetamol-containing products.
Patient Information Leaflet:
Immediate medical advice should be sought in the event of an overdose, even if you
feel well, because of the risk of delayed, serious liver damage.
4.5
Interaction with other medicinal products and other forms of interaction
The speed of absorption of paracetamol may be increased by metoclopramide or
domperidone and absorption reduced by colestyramine. The anticoagulant effect of
warfarin and other coumarins may be enhanced by prolonged regular daily use of
paracetamol with increased risk of bleeding; occasional doses have no significant
effect.
4.6
Pregnancy and lactation
Epidemiological studies in human pregnancy have shown no ill effects due to
paracetamol used in the recommended dosage, but patients should follow the advice
of their doctor regarding its use. Paracetamol is excreted in breast milk but not in a
clinically significant amount. Available published data do not contraindicate breast
feeding.
Appendix I
4.7
Effects on ability to drive and use machines
None.
4.8
Undesirable effects
Adverse events of paracetamol from historical clinical trial data are both infrequent
and from small patient exposure. Accordingly, events reported from extensive postmarketing experience at therapeutic/labelled dose and considered attributable are
tabulated below by system class. Due to limited clinical trial data, the frequency of
these adverse events is not known (cannot be estimated from available data), but postmarketing experience indicates that adverse reactions to paracetamol are rare and
serious reactions are very rare.
Post marketing data
Body System
Undesirable effect
Blood and lymphatic system
disorders
Thrombocytopenia
Immune system disorders
Anaphylaxis
Agranulocytosis
Cutaneous hypersensitivity reactions
including skin rashes, angiodema
and Stevens Johnson syndrome/toxic
epidermal necrolysis
Respiratory, thoracic and
mediastinal disorders
Bronchospasm*
Hepatobiliary disorders
Hepatic dysfunction
* There have been cases of bronchospasm with paracetamol, but these are more likely
in asthmatics sensitive to aspirin or other NSAIDs.
Appendix I
4.9
Overdose
Liver damage is possible in adults who have taken 10 g or more of paracetamol.
Ingestion of 5 g or more of paracetamol may lead to liver damage if the patient has
risk factors (see below).
Risk Factors:
If the patient
•
Is on long term treatment with carbamazepine, phenobarbitone, phenytoin,
primidone, rifampicin, St John’s Wort or other drugs that induce liver
enzymes.
•
Regularly consumes ethanol in excess of recommended amounts.
•
Is likely to be glutathione deplete e.g. eating disorders, cystic fibrosis, HIV
infection, starvation, cachexia.
Or
Or
Symptoms
Symptoms of paracetamol overdose in the first 24 hours are pallor, nausea, vomiting,
anorexia and abdominal pain. Liver damage may become apparent 12 to 48 hours
after ingestion. Abnormalities of glucose metabolism and metabolic acidosis may
occur. In severe poisoning, hepatic failure may progress to encephalopathy,
haemorrhage, hypoglycaemia, cerebral oedema and death. Acute renal failure with
acute tubular necrosis, strongly suggested by loin pain, haematuria and proteinuria,
may develop even in the absence of severe liver damage. Cardiac arrhythmias and
pancreatitis have been reported.
Management
Immediate treatment is essential in the management of paracetamol overdose.
Despite a lack of significant early symptoms, patients should be referred to hospital
urgently for immediate medical attention. Symptoms may be limited to nausea or
vomiting and may not reflect the severity of overdose or the risk of organ damage.
Management should be in accordance with established treatment guidelines, see BNF
overdose section.
Treatment with activated charcoal should be considered if the overdose has been
taken within 1 hour. Plasma paracetamol concentration should be measured at 4 hours
or later after ingestion (earlier concentrations are unreliable). Treatment with Nacetylcysteine may be used up to 24 hours after ingestion of paracetamol, however,
the maximum protective effect is obtained up to 8 hours post-ingestion. The
effectiveness of the antidote declines sharply after this time. If required the patient
should be given intravenous N-acetylcysteine, in line with the established dosage
schedule. If vomiting is not a problem, oral methionine may be a suitable alternative
for remote areas, outside hospital. Management of patients who present with serious
hepatic dysfunction beyond 24h from ingestion should be discussed with the NPIS or
a liver unit.
Appendix I
5
PHARMACOLOGICAL PROPERTIES
5.1
Pharmacodynamic properties
Paracetamol is an antipyretic analgesic. The mechanism of action is probably similar
to that of aspirin and dependant on the inhibition of prostaglandin synthesis. This
inhibition appears, however, to be on a selective basis.
5.2
Pharmacokinetic properties
Paracetamol is rapidly and almost completely absorbed from the gastro-intestinal
tract. The concentration in plasma reaches a peak in 30 to 60 minutes and the half life
in plasma is 1 to 4 hours after therapeutic doses. Paracetamol is relatively uniformly
distributed throughout most body fluids. Binding of the drug to plasma proteins is
variable; 20 to 50% may be bound at the concentrations encountered during acute
intoxication. Following therapeutic doses 90 to 100% of the drug may be recovered
in the urine within the first day. However, practically no paracetamol is excreted
unchanged, and the bulk is excreted after hepatic conjugation.
5.3
Preclinical safety data
There are no pre-clinical data of relevance to the prescriber which are additional to
that already included in other sections of the SPC.
6
PHARMACEUTICAL PARTICULARS
6.1
List of excipients
Maize starch, magnesium stearate, titanium dioxide, erythrosine, patent blue, gelatin.
Printing Ink: Shellac, propylene glycol and colour, black iron oxide (E 172)
6.2
Incompatibilities
None.
6.3
Shelf life
60 months.
Appendix I
6.4
Special precautions for storage
None.
6.5
Nature and contents of container
PVC 250µm / aluminium foil 30µm blister strips in cardboard cartons, containing 6,
12, 16, 24 or 32 capsules.
6.6
Special precautions for disposal
Not applicable.
7
MARKETING AUTHORISATION HOLDER
SmithKline Beecham (SWG) Limited
980 Great West Road
Brentford
Middlesex
TW8 9GS, U.K.
Trading as Sterling Health or GlaxoSmithKline Consumer Healthcare, Brentford,
TW8 9GS.
8
MARKETING AUTHORISATION NUMBER(S)
PL 00071/0220
9
DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
09/06/2005
10
DATE OF REVISION OF THE TEXT
01/04/2010
Appendix I
Appendix III
1.
Name of the Medicinal Product
Parvolex Solution for Infusion.
2.
Qualitative and Quantitative Composition
Acetylcysteine
200mg/ml.
For excipients, see 6.1.
3.
Pharmaceutical Form
Solution for infusion.
4.
Clinical Particulars
4.1
Therapeutic indications
For the treatment of paracetamol overdosage.
4.2
Posology and method of administration
The injection is administered by intravenous infusion. The following infusion fluids may
be used: 5% dextrose, 0.9% sodium chloride, 0.3% potassium chloride with 5% glucose,
or 0.3% potassium chloride with 0.9% sodium chloride.
Adults:
An initial dose of 150mg/kg body weight of acetylcysteine is infused in 200ml of the
recommended infusion fluid over 15 minutes, followed by 50mg/kg in 500ml infusion
fluid over the next 4 hours, then 100mg/kg in 1 litre infusion fluid over the next 16 hours.
(This gives a total dose of 300mg/kg in 20 hours.)
Children:
Children should be treated with the same doses and regimen as adults; however, the
quantity of intravenous fluid used should be modified to take into account age and
weight, as fluid overload is a potential danger. The National Poisons Centres in the UK
have provided the following guidance:
Children weighing 20kg or more:
150mg/kg intravenous infusion in 100ml infusion fluid over 15 minutes; then 50mg/kg in
250ml infusion fluid over 4 hours; then 100mg/kg in 500ml infusion fluid over 16 hours.
Children under 20kg:
Volumes for infusion of the above doses are the responsibility of the prescriber and
should be based on the daily maintenance requirements of the child by weight.
Critical times:
Parvolex UK
1
June 2005
Appendix III
Acetylcysteine (Parvolex®) is very effective in preventing paracetamol-induced
hepatotoxicity when administered during the first 8 hours after a paracetamol overdose.
When administered after the first 8 hours, the protective effect diminishes progressively
as the overdose-treatment interval increases. However, clinical experience indicates that
acetylcysteine can still be of benefit when administered up to 24 hours after paracetamol
overdose, without any change in its safety profile. It may also be administered after 24
hours in patients at risk of severe liver damage. In general, for patients presenting later
than 24 hours after a paracetamol overdose, guidance should be sought from a National
Poisons Centre.
Treatment 'nomogram':
Plasma paracetamol concentration in relation to time after the overdose is commonly
used to determine whether a patient is at risk of hepatotoxicity and should, therefore,
receive treatment with an antidote such as acetylcysteine.
For the majority of otherwise healthy patients, a line joining points of 200mg/l at 4 hours
and 30mg/l at 15 hours on a semilogarithmic plot is used. (Treatment line A - see graph.)
This line can be extended to 24 hours after overdose, based on a paracetamol half-life of
4 hours. It is recommended that patients whose plasma paracetamol concentrations fall
on or above this line receive acetylcysteine. If there is doubt about the timing of the
overdose, consideration should be given to treatment with acetylcysteine.
Patients with induced hepatic microsomal oxidase enzymes (such as chronic alcoholics
and patients taking anticonvulsant drugs) are susceptible to paracetamol-induced
hepatotoxicity at lower plasma paracetamol concentrations (see section 4.4 - Special
Warnings and Precautions for Use) and should be assessed against treatment line B (see
graph).
In patients who have taken staggered overdoses, blood levels are meaningless in relation
to the treatment graph. These patients should all be considered for treatment with
acetylcysteine.
NB: Blood samples taken less than 4 hours after a paracetamol overdose give unreliable
estimates of the serum paracetamol concentration.
Parvolex UK
2
June 2005
Appendix III
Plasma paracetamol concentrations in relation to time after overdosage as a guide to
prognosis.
From guidelines agreed by National Poisons Centres - June 1995.
Parvolex is indicated in patients with values on or above the appropriate treatment line.
4.3
Contraindications
Hypersensitivity to any ingredient in the preparation.
4.4
Special warnings and special precautions for use
Precautions:
Administer with caution in patients with asthma or a history of bronchospasm.
Liver enzyme-inducing drugs; chronic alcohol abuse:
Patients taking drugs that induce liver enzymes, such as some anticonvulsant drugs (e.g.
phenytoin, phenobarbitone, primidone and carbamazepam) and rifampicin, and patients
who routinely consume alcohol above recommended levels are believed to be at risk of
hepatotoxicity from paracetamol poisoning at lower plasma paracetamol concentrations
than other patients. It is recommended that such patients whose plasma paracetamol
Parvolex UK
3
June 2005
Appendix III
concentrations fall on or above a treatment line joining 100mg/l at 4 hours after overdose
and 15mg/l at 15 hours after overdose on a semilogarithmic plot (i.e. treatment line B see graph), be given acetylcysteine.
Other patients predisposed to toxicity:
Patients suffering from malnutrition, for example, patients with anorexia or AIDS, may
have depleted glutathione reserves. It has been recommended that paracetamol overdose
in such patients be treated as for chronic alcohol consumers or patients taking
anticonvulsant drugs (treatment line B - see graph).
4.5
Interaction with other medicinal products and other forms of Interaction
There are no known interactions.
4.6
Pregnancy and lactation
The safety of acetylcysteine in pregnancy has not been investigated in formal prospective
clinical trials. However, clinical experience indicates that use of acetylcysteine in
pregnancy for the treatment of paracetamol overdose is effective. Prior to use in
pregnancy, the potential risks should be balanced against the potential benefits.
4.7
Effects on ability to drive and use machines
There are no known effects on ability to drive and use machines.
4.8
Undesirable effects
'Anaphylactoid' or 'hypersensitivity-like' reactions have been reported. They include
nausea/vomiting, injection-site reactions, flushing, itching, rashes/urticaria, angioedema,
bronchospasm/respiratory distress, hypotension, and rarely, tachycardia or hypertension.
These have usually occurred between 15 and 60 minutes after the start of infusion. In
many cases, symptoms have been relieved by stopping the infusion. Occasionally, an
antihistamine drug may be necessary. Corticosteroids may occasionally be required.
Once an anaphylactoid reaction is under control, the infusion can normally be restarted at
the lowest infusion rate (100mg/kg in 1 litre over 16 hours).
In rare instances, the following side-effects have occurred: coughing, chest tightness or
pain, puffy eyes, sweating, malaise, raised temperature, vasodilation, blurred vision,
bradycardia, facial or eye pain, syncope, acidosis, thrombocytopenia, respiratory or
cardiac arrest, stridor, anxiety, extravasation, arthropathy, arthralgia, deterioration of
liver function, generalised seizure, cyanosis, lowered blood urea. Rare instances of
fatality have also occurred.
Hypokalaemia and ECG changes have been noted in patients with paracetamol poisoning
irrespective of the treatment given. Monitoring of plasma potassium concentration is,
therefore, recommended.
If any side-effects to Parvolex® (acetylcysteine) develop, advice should be sought from a
National Poisons Centre to ensure that the patients receives adequate treatment of the
paracetamol overdose.
Parvolex UK
4
June 2005
Appendix III
4.9
Overdose
There is a theoretical risk of hepatic encephalopathy. Overdosage of acetylcysteine has
been reported to be associated with effects similar to the 'anaphylactoid' reactions noted
in section 4.8 (Undesirable Effects), but they may be more severe. General supportive
measures should be carried out. Such reactions are managed with antihistamines and
steroids in the usual way. There is no specific antidote.
5.
Pharmacological Properties
5.1
Pharmacodynamic properties
Acetylcysteine is considered to reduce the hepatic toxicity of NAPQI (n-acetyl-p-benzoquinoneimine), the highly reactive intermediate metabolite following ingestion of a high
dose of paracetamol, by at least two mechanisms. First, acetylcysteine acts as a precursor
for the synthesis of glutathione and, therefore, maintains cellular glutathione at a level
sufficient to inactivate NAPQI. This is thought to be the main mechanism by which
acetylcysteine acts in the early stages of paracetamol toxicity.
Acetylcysteine has been shown to still be effective when infusion is started at up to 12
hours after paracetamol ingestion, when most of the analgesic will have been metabolised
to its reactive metabolite. At this stage, acetylcysteine is thought to act by reducing
oxidised thiol groups in key enzymes.
When acetylcysteine treatment is begun more than 8 to 10 hours after paracetamol
overdose, its efficacy in preventing hepatotoxicity (based on serum indicators) declines
progressively with further lengthening of the overdose-treatment interval (the time
between paracetamol overdose and start of treatment). However, there is now evidence
that it can still be beneficial when given up to 24 hours after overdose. At this late stage
of paracetamol hepatotoxicity, acetylcysteine's beneficial effects may be due to its ability
to improve systematic haemodynamics and oxygen transport, although the mechanism by
which this may occur has yet to be determined.
5.2
Pharmacokinetic properties
Following intravenous administration of acetylcysteine using the standard 20-hour
intravenous regimen, plasma levels of 300 to 900mg/l have been reported to occur shortly
after the start of the infusion, falling to 11 to 90mg/l at the end of the infusion period.
Elimination half-lives of 2 to 6 hours have been reported after intravenous dosing, with
20 to 30% of the administered dose being recovered unchanged in the urine.
Metabolism appears to be rapid and extensive. There is no information on whether
acetylcysteine crosses the blood-brain barrier or the placenta, or whether it is excreted in
breast milk.
Parvolex UK
5
June 2005
Appendix III
5.3
Preclinical safety data
None stated.
6.
Pharmaceutical Particulars
6.1
List of excipients
Disodium Edetate
Sodium Hydroxide
Water for Injections
6.2
Incompatibilities
Acetylcysteine is not compatible with rubber or metals, particularly iron, copper and
nickel. Silicone rubber and plastic are satisfactory for use with Parvolex®.
A change in the colour of the solution to light purple has sometimes been noted and is not
thought to indicate significant impairment of safety or efficacy.
6.3
Shelf life
3 years.
6.4
Special precautions for storage
Store below 25°C.
6.5
Nature and contents of container
Clear, Type I glass, 10ml snap ring ampoules. 10 x 10ml ampoules are packed in
cartons.
6.6
Instructions for use and handling
Acetylcysteine to be diluted for intravenous infusion using either 5% dextrose, 0.9%
sodium chloride, 0.3% potassium chloride with 5% glucose, or 0.3% potassium chloride
with 0.9% sodium chloride. The volumes to be used are as directed in section 4.2.
7.
MARKETING AUTHORISATION HOLDER
UCB Pharma Limited
208 Bath Road
Slough
Berkshire
SL1 3WE
UK
Parvolex UK
6
June 2005
Appendix III
8.
MARKETING AUTHORISATION NUMBER(S)
PL 00039/0410
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
14 October 1992, 31 October 1997, June 2002
10.
DATE OF REVISION OF THE TEXT
June 2005
11.
Legal Category
POM
Parvolex UK
7
June 2005
Appendix IV
Country
Methods of assessing Risk
Denmark
All patients suspected of paracetamol
overdose are treated.
Linear Rumack-Matthew nomogram
used. For the management of
staggered overdose, level +
additional lab findings (mainly
transaminase level) considered.
Alcohol considered a risk factor but
treatment decision based on clinical
and lab (mainly transaminase)
evaluation
Rumack nomogram (150mg/L single
line). Paediatric presentations where
dose unsure considered toxic in
addition to self harm cases.
Rumack-Matthew nomogram used –
Greece
Italy
Slovakia
Latvia
No nomogram used.
<8h treatment if paracetamol
level>therapeutic or if no level
available if dose of paracetamol dose
>150mg/kg. (Further details below*)
Ireland
UK nomogram used with normal and
high risk treatment line (starting at
200 and 100 mg/L respectively).
Consideration of risk factors as in
UK.
Rumack nomogram (150mg/L single
line)
Not available
Rumack-Matthew nomogram
(150mg/L single line). If risk factors
present (chronic alcohol use, liver
insufficiency and use of CYOP 2E1
inducers, treatment is initiated at
levels >75mg/L.
Hungary
Austria
Netherlands
Finland
Portugal
Rumack Matthew nomogram with
high risk line 25% below normal line.
(High risk patients: chronic alcohol
consumption, use of enzyme
inducing medicines, eating disorder,
malnutrition)
All paracetamol exposures > 150
mg/kg (or 7.5g regardless of weight)
or 200mg/kg in children are treated
with NAC until plasma paracetamol
level available. Once paracetamol
level is available 3 risk categories
(low, probable or potential) are
established and the decision is made
to continue or suspend treatment.
Additional risk factors are only
NAC posology and Administration
IV usage. Standard posology
IV administration. Standard posology.
IV usage. Standard posology
IV administration – standard IV
posology for severe (>300mg/L at 4h).
In less severe cases oral
administration preferred.
IV usage. Standard posology.
Infusion stopped when paracetamol
level is < therapeutic.
IV usage. Standard posology
IV administration preferred.
IV administration. Standard posology
IV administration. Standard posology
IV administration. Standard posology
IV administration. Standard posology
Appendix IV
Sweden
France
Belgium
Norway
Germany
Spain
Iceland
Slovenia
considered when exposure to supra
therapeutic concentrations takes
place for more than 24h.
Nomogram (Rumack-Matthew
nomogram with 150mg/L 4h value).
Following factors are used to
categorise a patient as high risk:
alcoholism, starvation, dehydration,
impaired liver function or concomitant
use of enzyme inducing medications.
No consensus on use of a nomogram
among hospitals
Nomogram (lines not specified). Risk
factors include malnutrition, enzyme
inducing medications, alcohol use
(woman >14 units; man >21 units).
Treatment decision based on dose
(adults and children >6yrs):
<4h: 150mg/kg or ≥12yrs
If high risk: ≥ 75mg/kg or ≥6g/24h.
If staggered ingestion (>24h):
≥150mg/kg/24hs or ≥7.5g/24h.
If time of ingestion known, UK
nomogram used with two lines
(normal and high risk). Risk factors
Not stated
Variable policy. Plasma paracetamol
measurements not consistently used.
Where taken, nomogram used. Line
at either 150 or 100 mg/L depending
on risk. High risk defined as
alcoholics, CYP450 inducers,
metabolic impairments or
concomitant liver disease. NAC may
be given in some hospitals while
awaiting results if there is a suspicion
that >6g has been ingested.
Nomogram used as in UK with
normal and high risk treatment line
(starting at 200 and 100 mg/L
respectively). High risk denoted as
glutathione depletion, hepatic
enzyme induction, ongoing liver
disease and alcoholics.
Rumack-Matthew nomogram used –
2 lines high and normal risk line.
High risk line 25% below normal line.
High risk not defined other than
induction of CYP450 enzymes.
IV administration. Standard posology
Oral product not licensed. IV
administration preferred in case of
vomiting. Standard NAC posology
IV administration. Standard posology.
IV administration. Standard posology.
No official recommendation or national
guideline
IV usage preferred. Standard
posology
IV NAC standard protocol
Oral NAC preferred (maintenance
dose continued for 3 days. If
persistent vomiting, IV administered
(standard therapy).
* Further details of Latvian treatment:
1. <8 h - NAC i/v if paracetamol plasma level is higher than therapeutic. If
paracetamol plasma level test is not available during the first 8 h NAC is
administered (if the dose of paracetamol p/o >150 mg/kg). NAC infusion is
stopped when paracetamol level is <therapeutic. After NAC discontinuation
plasma levels of ASAT/ALAT, prothrombin time, creatinine should be tested.
Appendix IV
2. 8 - 18 h - without delay NAC is initiated if the dose of paracetamol p/o >150
mg/kg. Tests: plasma levels of paracetamol, prothrombin time, ASAT/ALAT,
creatinine, bilirubin, acid and alkaline balance. NAC infusion is stopped when
paracetamol level is <therapeutic.
3. 18 - 24 h - NAC standard therapy if the dose of paracetamol is >150 mg/kg.
Tests: plasma levels of paracetamol, prothrombin time, ASAT/ALAT,
creatinine, bilirubin, phosphates, acid and alkaline balance. Tests are repeated
after the discontinuation of NAC. Tests are not normal or symptoms exist: 100
mg/kg NAC/1l 5% dextrose/16 hours; the dose is repeated until recovery.
4. >24 h - Tests: plasma levels of paracetamol, prothrombin time, ASAT/ALAT,
creatinine, bilirubin, fosfates, acid - alkaline balance. NAC standard therapy if
the dose of paracetamol is >150 mg/kg. Tests are repeated. Decide on NAC
administration if there is risk of acute hepatic insufficiency (10 mg/kg NAC/1l
5% dextrose/16 hours, the dose is repeated).
Standard Acetylcysteine Posology
Intravenous infusion (adult and child >12 yrs)
Dose Sequence
Acetylcysteine
(mg/kg body weight)
Volume of 5% glucose
for dilution
Duration of infusion
1
150
200 mL
15 min
2
50
500 mL
4 hours
3
100
1000 mL
16 hours
If for any reason glucose is unsuitable, 0.9% sodium chloride solution may be substituted.
Oral
Loading dose of 140mg/kg. Advised to administer 70mg/kg every 4 h for 72h.
Paracetamol Poisoning
Assessment
National Poisons
Information Service
The National Poisons Information Service (NPIS) is a network of dedicated units
commissioned by the Health Protection Agency through its Centre for Radiation,
Chemical and Environmental Hazards. The NPIS provides information on the
diagnosis and management of poisoning to health professionals in the UK.
PRODUCED BY
Health Protection Agency
Centre for Radiation, Chemical and Environmental Hazards
Chilton
Didcot
Oxfordshire OX11 0RQ
United Kingdom
www.hpa.org.uk
August 2011
Printed on chlorine-free paper
Appendix V
Appendix V
National Poisons
Information Service
Paracetamol Poisoning Assessment
ONLY to be used in conjunction with www.toxbase.org
Paracetamol poisoning requires two assessments: susceptibility and dose
In addition, all deliberate ingestions need psychological review
INITIAL blood tests: paracetamol concentration, U&E, creatinine, LFTs, FBC, INR or PT
END of treatment blood tests: U&E, creatinine, LFTs, FBC, INR or PT
1Susceptibility
Assessment
2
Patients may be at higher
risk of toxicity if they are:
Normal risk: toxic dose >150 mg/kg – use the normal treatment line on the nomogram
a
Estimate the dose ingested
a few days, e.g. due to recent depression,
febrile illness (children), dental pain or eating
disorders (anorexia/bulimia)]
•
cystic fibrosis, AIDS, cachexia, alcoholism,
hepatitis C or children with ‘failure to thrive’
Clinical clues – history, low urea, urinary
ketones positive, abnormal LFTs
High risk: toxic dose >75 mg/kg – use the high‑risk treatment line on the nomogram
If intentional, always measure the paracetamol concentration. If accidental, estimate the risk of toxicity and consider the need to measure the paracetamol concentration
Single ingestion
malnourished, have nutritional deficiency and/or
chronic debilitating illness and are therefore likely
to be glutathione deplete, e.g.
• acute or chronic starvation [not eating for
Dose Assessment
Time delay from ingestion to
presentation
Staggered/multiple ingestion
200
If more than 24 hours since last ingestion
1.3
•
190
1.2
180
0–4 hours
Normal treatment
Take initial blood tests (see box above)
170
Wait until 4 hours have elapsed to take initial blood tests
(see box above)
•
•
1.1
160
4–8 hours
150
Take initial blood tests (see box above). Then assess risk of
toxicity using nomogram. Treat if appropriate
140
1.0
• on long-term treatment with drugs such as
carbamazepine, phenobarbital, phenytoin,
primidone, rifampicin, rifabutin, efavirenz,
nivirapine, St John’s Wort or other drugs that
induce liver enzymes
• regularly consume alcohol in excess of
recommended amounts
Clinical clues – history, abnormal LFTs, INR,
elevated GGT (if available)
Perform risk assessment (see Susceptibility Assessment). If
potentially toxic dose ingested, start acetylcysteine without
waiting for blood results to return. The initial toxicity
assessment is based on the stated paracetamol dose and
risk assessment (see Susceptibility Assessment)
Take initial blood tests (see box above)
Re-assess the need for acetylcysteine using paracetamol
nomogram when results become available
If patient has a reduced conscious level or there is no
history available, treat with acetylcysteine
Over 36 hours
If jaundiced or acute hepatic tenderness, treat with
acetylcysteine
NPIS units find almost half their
patients are at high risk
In all other cases, do not give acetylcysteine immediately
but take initial blood tests (see box above). Assess blood
results when available and treat with acetylcysteine if
abnormal (see www.toxbase.org)
0.8
120
110
0.7
100
0.6
90
80
0.5
70
60
Prognostic accuracy
after 15 hours uncertain
50
40
Plasma paracetamol, mmol/litre
have hepatic enzyme induction or evidence of
ongoing liver injury, e.g.
Plasma paracetamol, mg/litre
b
if normal, no need for acetylcysteine
if abnormal (see www toxbase.org), start treatment
with acetylcysteine
0.9
130
8–36 hours
if jaundiced or acute hepatic tenderness, treat
with acetylcysteine
If less than 24 hours since last ingestion
Perform a toxicity estimate for dose ingested (mg/kg)
over the last 24 hours. If potentially toxic dose, start
acetylcysteine without waiting for blood results to return.
Toxicity assessment is based on the stated paracetamol
dose and risk assessment (see Susceptibility Assessment)
Take initial blood tests in all patients (see box above),
even those with a potentially non-toxic ingested dose
0.4
Assess blood results and treat with acetylcysteine if
abnormal, or if paracetamol is detectable. Do not use the
nomogram (see www.toxbase.org)
0.3
If in doubt, treat with acetylcysteine
High-risk treatment
30
0.2
20
Treat
0.1
10
0
0
0
2
4
6
8
10
12
14
16
Hours after ingestion
18
20
22
24
After a full course of acetylcysteine, take END
of treatment blood tests (see box above) and
assess the need for further acetylcysteine
If after reading this and consulting www.toxbase.org you are still uncertain, you should call the NPIS on 0844 892 0111 (24 hours)
© Health Protection Agency 2011 Prepared by NPIS Edinburgh on behalf of the NPIS and HPA
Appendix VI
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use Acetadote
safely and effectively. See full prescribing information for Acetadote.
--------------------------------CONTRAINDICATIONS-------------------------------Patients with previous anaphylactoid reaction to acetylcysteine (4)
ACETADOTE (acetylcysteine) Injection
Initial U.S. Approval: 2004
• Monitor as acute flushing and erythema of the skin may occur; usually
-------------------------WARNINGS AND PRECAUTIONS--------------------------
-----------------------------RECENT MAJOR CHANGES----------------------------Adverse Reactions, Postmarketing Safety Study (6.1)
12/2008
------------------------------INDICATIONS AND USAGE----------------------------Acetadote, administered intravenously within 8 to 10 hours after ingestion of a
potentially hepatotoxic quantity of acetaminophen, is indicated to prevent or
lessen hepatic injury (1)
associated with the loading dose; often resolves spontaneously despite
continued infusion (5.1)
• Monitor for serious anaphylactoid reactions; infusion may be interrupted until
treatment of anaphylactoid symptoms has been initiated (5.1)
• Should be used with caution in patients with asthma, or where there is a
history of bronchospasm (5.2)
• Total volume administered should be adjusted for patients less than 40kg and
for those requiring fluid restriction (5.3)
----------------------DOSAGE AND ADMINISTRATION -------------------------Patients >40 kg (2.1):
Loading Dose: 150 mg/kg in 200 mL of diluent administered over 60 min
Dose 2: 50 mg/kg in 500 mL of diluent administered over 4 hr
Dose 3: 100 mg/kg in 1000 mL of diluent administered over 16 hr
Patients >20- <40 kg (2.1):
Loading Dose: 150 mg/kg in 100 mL of diluent administered over 60 min
Dose 2: 50 mg/kg in 250 mL of diluent administered over 4 hr
Dose 3: 100 mg/kg in 500 mL of diluent administered over 16 hr
Patients <20 kg (2.1):
Loading Dose: 150 mg/kg in 3 mL/kg of body weight of diluent administered
over 60 min
Dose 2: 50 mg/kg in 7 mL/kg of body weight of diluent administered over 4 hr
Dose 3: 100 mg/kg in 14 mL/kg of body weight of diluent administered over 16
hr
--------------------------------ADVERSE REACTIONS--------------------------------Most common adverse reactions (incidence >2%) are rash, urticaria/facial
flushing and pruritus (6.1)
-----------------------DOSAGE FORMS AND STRENGTHS-----------------------Vials: 200 mg/mL, 30 mL (20% solution) (3)
See 17 for PATIENT COUNSELING INFORMATION
To report SUSPECTED ADVERSE REACTIONS, contact Cumberland
Pharmaceuticals Inc. at 1-877-484-2700 or FDA at 1-800-FDA-1088 or
www.fda.gov/medwatch.
--------------------------------DRUG INTERACTIONS--------------------------------No drug-drug interaction studies have been conducted. (7)
-------------------------USE IN SPECIFIC POPULATIONS------------------------Pregnancy: This drug should be used during pregnancy only if clearly needed
(8.1)
Nursing Mothers: Unknown if drug is excreted in human milk (8.3)
Pediatric Use: See dose adjustment for patients < 40 kg (2)
Revised: 12/2008
FULL PRESCRIBING INFORMATION: CONTENTS*
1
INDICATIONS AND USAGE
1.1 Acetaminophen Assays Interpretation and Methodology – Acute
Ingestion
1.2 Acetaminophen Assays Interpretation and Methodology –
Repeated Supratherapeutic Ingestion
2
DOSAGE AND ADMINISTRATION
2.1 Administration Instructions (Three-Bag Method: Loading, Second
and Third dose)
2.2 Renal Impairment
2.3 Hepatic Impairment
3
DOSAGE FORMS AND STRENGTHS
4
CONTRAINDICATIONS
5
WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid Reactions
5.2 Monitoring Patients with Asthma
5.3 Volume Adjustment: Patients <40kg and Requiring Fluid
Restriction
6
ADVERSE REACTIONS
6.1 Clinical Studies Experience
Acetadote® (acetylcysteine) Injection
7
8
10
11
12
13
14
16
17
DRUG INTERACTIONS
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing mothers
8.4 Pediatric use
8.5 Geriatric use
OVERDOSAGE
DESCRIPTION
CLINICAL PHARMACOLOGY
12.1 Mechanism of action
12.3 Pharmacokinetics
NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
13.3 Reproductive and Developmental Toxicology
CLINICAL STUDIES
HOW SUPPLIED/STORAGE AND HANDLING
PATIENT COUNSELING INFORMATION
*Sections or subsections omitted from the Full Prescribing Information are not
listed.
Package Insert, page 1 of 7
Appendix VI
FULL PRESCRIBING INFORMATION
1
INDICATIONS AND USAGE
Acetadote, administered intravenously within 8 to 10
hours after ingestion of a potentially hepatotoxic quantity of
acetaminophen, is indicated to prevent or lessen hepatic injury
[see Dosage and Administration (2) and Acetaminophen
Assays – Interpretation and Methodology (1.1, 1.2)].
On admission for suspected acetaminophen overdose, a
serum blood sample should be drawn at least 4 hours after
ingestion to determine the acetaminophen level and will serve
as a basis for determining the need for treatment with
acetylcysteine. If the patient presents after 4 hours postingestion, the serum acetaminophen sample should be
determined immediately.
Acetadote should be administered within 8 hours from
acetaminophen ingestion for maximal protection against
hepatic injury for patients whose serum acetaminophen levels
fall above the “possible” toxicity line on the Rumack-Matthew
nomogram (line connecting 150 mcg/mL at 4 hours with 37.5
mcg/mL at 12 hours); [see Acetaminophen Assays –
Interpretation and Methodology (1.1, 1.2)]. If the time of
ingestion is unknown, or the serum acetaminophen level is not
available, cannot be interpreted, or is not available within the
8 hour time interval from acetaminophen ingestion, Acetadote
should be administered immediately if 24 hours or less have
elapsed from the reported time of ingestion of an overdose of
acetaminophen, regardless of the quantity reported to have
been ingested.
The aspartate aminotransferase (AST, SGOT), alanine
aminotranferase (ALT, SGPT), bilirubin, prothrombin time,
creatinine, blood urea nitrogen (BUN), blood glucose, and
electrolytes also should be determined in order to monitor
hepatic and renal function and electrolyte and fluid balance.
NOTE: The critical ingestion-treatment interval for
maximal protection against severe hepatic injury is between 0
– 8 hours. Efficacy diminishes progressively after 8 hours and
treatment initiation between 15 and 24 hours post-ingestion of
acetaminophen yields limited efficacy. However, it does not
appear to worsen the condition of patients and it should not be
withheld, since the reported time of ingestion may not be
correct.
Interpretation of Acetaminophen Assays
1. When results of the plasma acetaminophen assay are
available, refer to the nomogram in Figure 1 to determine
if plasma concentration is in the potentially toxic range.
Values above the line connecting 200 mcg/mL at 4 hours
with 50 mcg/mL at 12 hours (probable line) are associated
with a probability of hepatic toxicity if an antidote is not
administered.
2. If the predetoxification plasma level is above the line
connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at
12 hours (possible line), continue with maintenance doses
of acetylcysteine. It is better to err on the safe side and
thus this line, defining possible toxicity, is plotted 25%
below the line defining probable toxicity.
3. If the predetoxification plasma level is below the line
connecting 150 mcg/mL at 4 hours with 37.5 mcg/mL at
12 hours (possible line), there is minimal risk of hepatic
toxicity, and acetylcysteine treatment may be
discontinued.
Estimating Potential for Hepatotoxicity: The following
depiction of the Rumack-Matthew nomogram has been
developed to estimate the probability that plasma levels in
relation to intervals post-ingestion will result in
hepatotoxicity.
Figure 1. Rumack-Matthew Nomogram: Plasma or Serum
Acetaminophen Concentration vs. Time Post Acetaminophen
Ingestion (Rumack BH, Matthew H. Acetaminophen
poisoning and toxicity. Pediatrics. 1975;55:871-876 and
Rumack BH, Peterson RC, Kock GG, Amara IA.
Acetaminophen overdose. 662 cases with evaluation of oral
acetylcysteine treatment. Arch Intern Med. 1981;141:380385.)
1.1 Acetaminophen Assays Interpretation and
Methodology – Acute Ingestion
The acute ingestion of acetaminophen in quantities of 150
mg/kg or greater may result in hepatic toxicity. However, the
reported history of the quantity of a drug ingested as an
overdose is often inaccurate and is not a reliable guide to
therapy of the overdose. Therefore, plasma or serum
acetaminophen concentrations, determined as early as
possible, but no sooner than four hours following an acute
overdose, are essential in assessing the potential risk of
hepatotoxicity. If an assay for acetaminophen cannot be
obtained, it is necessary to assume that the overdose is
potentially toxic.
Acetadote® (acetylcysteine) Injection
Package Insert, page 2 of 7
Appendix VI
1.2 Acetaminophen Assays Interpretation and
Methodology – Repeated Supratherapeutic Ingestion
Repeated Supratherapeutic Ingestion (RSI) is defined as
ingestion of acetaminophen at doses higher than those
recommended for extended periods of time. The nomogram
does not apply to patients with RSI. Treatment is based on the
acetaminophen and elevated AST/ALT levels indicative of
potential toxicity due to acetaminophen.
For specific
treatment information regarding the clinical management of
repeated supratherapeutic acetaminophen overdose, please
contact your regional poison center at 1-800-222-1222, or
alternatively, a special health professional assistance line for
acetaminophen overdose at 1-800-525-6115.
2
Figure 2. Acetadote Treatment Flow Chart
Table 1. Three-Bag Method Dosage Guide by Weight,
patients > 40 kg
Estimate time of
acetaminophen ingestion
< 24 h since overdose
Draw serum for acetaminophen
level at 4 h post-ingestion or as
soon as possible thereafter *#
PLOT LEVEL ON
NOMOGRAM
If time of ingestion is unknown
or patient is considered
unreliable, consider empiric
initiation of acetylcysteine
Plasma level plots
BELOW
treatment line***
Plasma level plots
ABOVE
treatment line***
Stop acetylcysteine
if initiated earlier
Administer
acetylcysteine
*Acetaminophen levels drawn less than 4 hours post-ingestion
may be misleading.
# With an extended-release preparation, an acetaminophen
level drawn less than 8 hours post-ingestion may be
misleading. Draw a second level at 4 to 6 hours after the
initial level.
If either falls above the toxicity line,
acetylcysteine treatment should be initiated.
***Acetylcysteine may be withheld until acetaminophen assay
results are available as long as initiation of treatment is not
delayed beyond 8 hours post-ingestion. If more than 8 hours
post-ingestion, start acetylcysteine treatment immediately.
Acetadote® (acetylcysteine) Injection
DOSAGE AND ADMINISTRATION
The total dose of Acetadote is 300 mg/kg administered
over 21 hours. Please refer to the guidelines below for dose
preparation based upon patient weight.
2.1 Administration Instructions (Three-Bag Method:
Loading, Second and Third Dose)
Patients >40 kg (Table1):
Loading Dose: 150mg/kg in 200mL of diluent◊
administered over 60 min
Second Dose: 50mg/kg in 500mL of diluent administered
over 4 hr
Third Dose: 100mg/kg in 1000mL of diluent
administered over 16 hr
Body
Weight
(kg)
100
90
80
70
60
50
40
(lb)
220
198
176
154
132
110
88
LOADING Dose
150 mg/kg in
◊
200 mL diluent
over 60 min
Acetadote (mL)
75
67.5
60
52.5
45
37.5
30
SECOND Dose
50 mg/kg in
500mL diluent
over 4 hours
THIRD Dose
100 mg/kg in
1000mL diluent
over 16 hours
Acetadote (mL)
25
22.5
20
17.5
15
12.5
10
Acetadote (mL)
50
45
40
35
30
25
20
The total volume administered should be adjusted for patients
less than 40 kg and for those requiring fluid restriction:
Patients >20 - <40 kg (Table 2):
Loading Dose: 150 mg/kg in 100 mL of diluent◊
administered over 60 min
Second Dose: 50 mg/kg in 250 mL of diluent
administered over 4 hr
Third Dose: 100 mg/kg in 500 mL of diluent administered
over 16 hr
Table 2. Three-Bag Method Dosage Guide by Weight,
patients >20 - < 40 kg
Body Weight
LOADING Dose
150 mg/kg over 60
minutes
(kg)
(lb)
Acetadote
(mL)
30
25
66
55
22.5
18.75
Diluent
(mL)
100
100
◊
SECOND Dose
50 mg/kg over 4
hours
THIRD Dose
100 mg/kg over 16
hours
Acetadote
(mL)
Diluent
(mL)
Acetadote
(mL)
Diluent
(mL)
7.5
6.25
250
250
15
12.5
500
500
Patients <20 kg (Table 3):
Loading Dose: 150mg/kg in 3mL/kg of body weight of
diluent◊ administered over 60 min
Second Dose: 50mg/kg in 7mL/kg of body weight of
diluent administered over 4 hr
Third Dose: 100mg/kg in 14mL/kg of body weight of
diluent administered over 16 hr
Package Insert, page 3 of 7
Appendix VI
Table 3. Three-Bag Method Dosage Guide by Weight,
patients < 20 kg
Body Weight
LOADING Dose
150 mg/kg over 60
minutes
(kg)
(lb)
Acetadote
(mL)
20
15
10
44
33
22
15
11.25
7.5
◊
Diluent
(mL)
◊
60
45
30
SECOND Dose
50 mg/kg over 4
hours
THIRD Dose
100 mg/kg over 16
hours
Acetadote
(mL)
Diluent
(mL)
Acetadote
(mL)
Diluent
(mL)
5
3.75
2.5
140
105
70
10
7.5
5
280
210
140
Acetadote is hyperosmolar (2600 mOsm/L) and is compatible
with 5% Dextrose (D5W), ½ Normal Saline (0.45% Sodium
Chloride Injection, ½ NS), and Water for Injection (WFI).
Single dose vial, preservative-free, discard unused portion. If
vial was previously opened, do not use for I.V. administration.
Stability studies indicate that the diluted solution is stable for
24 hours at controlled room temperature.
Note: The color of Acetadote may turn from essentially
colorless to a slight pink or purple once the stopper is
punctured. The color change does not affect the quality of the
product.
2.2 Renal Impairment
No data are available to determine if a dose adjustment in
patients with moderate or severe renal impairment is required.
2.3 Hepatic Impairment
Although there was a threefold increase in acetylcysteine
plasma concentrations in patients with hepatic cirrhosis, no
data are available to determine if a dose adjustment in these
patients is required. The published medical literature does not
indicate that the dose of acetylcysteine in patients with hepatic
impairment should be reduced.
3
DOSAGE FORMS AND STRENGTHS
Acetadote (acetylcysteine) Injection is available as a 20%
solution (200mg/mL) in 30 mL single dose glass vials.
Acetadote is sterile and can be used for I.V. administration.
4
CONTRAINDICATIONS
Acetadote is contraindicated in patients with previous
anaphylactoid reactions to acetylcysteine.
5
WARNINGS AND PRECAUTIONS
5.1 Anaphylactoid Reactions
Serious anaphylactoid reactions, including death in a
patient with asthma, have been reported in patients
administered acetylcysteine intravenously.
Acute flushing and erythema of the skin may occur in
patients receiving acetylcysteine intravenously. These
reactions usually occur 30 to 60 minutes after initiating the
infusion and often resolve spontaneously despite continued
infusion of acetylcysteine. Anaphylactoid reactions (defined as
the occurrence of an acute hypersensitivity reaction during
acetylcysteine administration including rash, hypotension,
wheezing, and/or shortness of breath) have been observed in
patients receiving I.V. acetylcysteine for acetaminophen
overdose and occurred soon after initiation of the infusion [see
Adverse Reactions (6.1)]. If a reaction to acetylcysteine
Acetadote® (acetylcysteine) Injection
involves more than simply flushing and erythema of the skin,
it should be treated as an anaphylactoid reaction. This usually
entails administering antihistaminic drugs and in severe cases
may require administration of epinephrine. In addition, the
acetylcysteine infusion may be interrupted until treatment of
the anaphylactoid symptoms has been initiated and then
carefully restarted. If the anaphylactoid reaction returns upon
reinitiation of treatment or increases in severity, intravenous
acetylcysteine should be discontinued and alternative patient
management should be considered.
5.2 Monitoring patients with asthma
Acetadote should be used with caution in patients with
asthma, or where there is a history of bronchospasm.
5.3 Volume Adjustment: Patients <40kg and
Requiring Fluid Restriction
The total volume administered should be adjusted for
patients less than 40 kg and for those requiring fluid
restriction. To avoid fluid overload, the volume of diluent
should be reduced as needed [see Dosage and Administration
(2)]. If volume is not adjusted fluid overload can occur,
potentially resulting in hyponatremia, seizure and death.
For specific treatment information regarding the clinical
management of acetaminophen overdose, please contact your
regional poison center at 1-800-222-1222, or alternatively, a
special health professional assistance line for acetaminophen
overdose at 1-800-525-6115.
6
ADVERSE REACTIONS
6.1 Clinical Studies Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the
clinical trials of a drug cannot be directly compared to rates in
the clinical trials of another drug and may not reflect the rates
observed in practice.
In the literature the most frequently reported adverse
reactions attributed to I.V. acetylcysteine administration were
rash, urticaria and pruritus. The frequency of adverse
reactions has been reported to be between 0.2% and 20.8%,
and they most commonly occur during the initial loading dose
of acetylcysteine.
Loading Dose/Infusion Rate Study
The incidence of drug-related adverse reactions occurring
within the first 2 hours following acetylcysteine administration
reported in a randomized study in patients with acetaminophen
poisoning is presented in Table 4 by preferred term. In this
study patients were randomized to a 15-minute or a 60-minute
loading dose regimen.
Within the first 2 hours following I.V. acetylcysteine
administration, 17% developed an anaphylactoid reaction
(18% in the 15-minute treatment group; 14% in the 60-minute
treatment group) in this randomized, open-label, multi-center
clinical study conducted in Australia to compare the rates of
anaphylactoid reactions between two rates of infusion for the
I.V. acetylcysteine loading dose. [see Warnings (Section 5)
and Clinical Studies - Loading Dose/Infusion Rate Study
(Section 14)].
Package Insert, page 4 of 7
Appendix VI
Table 4. Incidence of Drug-Related Adverse Reactions
Occurring Within the First 2 Hours Following Study Drug
Administration by Preferred Term: Loading
Dose/Infusion Rate Study
*Respiratory symptoms are defined as presence of any of the
following: cough, wheezing, stridor, shortness of breath, chest
tightness, respiratory distress, or bronchospasm.
Treatment Group
Number of Patients
Cardiac disorders
Severity:
Tachycardia NOS
Gastrointestinal
disorders
Severity:
Nausea
Vomiting NOS
Immune System
Disorders
Severity:
Anaphylactoid
reaction
Respiratory,
thoracic and
mediastinal
disorders
Severity:
Pharyngitis
Rhinorrhoea
Rhonchi
Throat tightness
Skin & subcutaneous
tissue disorders
Severity:
Pruritus
Rash NOS
Vascular disorders
Severity:
Flushing
Unkn=Unknown
7
15-min
n=109
5 (5%)
Unkn Mild Moderate Severe
4 (4%) 1 (1%)
60-min
n=71
2 (3%)
Unkn Mild
Moderate
2 (3%)
16 (15%)
Unkn
1 (1%)
Mild Moderate Severe
6 (6%)
2 (2%) 11 (10%)
Unkn
Mild Moderate Severe
Mild
1 (1%)
2 (3%)
Unkn
Mild
Severe
Moderate
Severe
4 (6%)
5 (7%)
1 (1%)
10 (14%)
2 (2%) 6 (6%) 11 (10%) 1 (1%)
2 (2%)
Mild Moderate Severe
1 (1%)
1 (1%)
8
Unkn
20 (18%)
Unkn
Severe
7 (10%)
Moderate
1 (1%)
4 (6%)
2 (3%)
Unkn
Mild
Moderate
Severe
1 (1%)
1 (1%)
6 (6%)
Unkn
Mild Moderate Severe
1 (1%)
3 (3%) 2 (2%)
2 (2%)
Unkn Mild Moderate Severe
1 (1%) 1 (1%)
5 (7%)
Unkn
Mild
Moderate
2 (3%)
3 (4%)
3 (4%)
Unkn Mild
Moderate
2 (3%)
1 (1%)
Severe
Severe
Postmarketing Safety Study
A large multi-center study was performed in Canada
where data were collected from patients who were treated with
I.V. NAC for acetaminophen overdose between 1980 and
2005. This study evaluated 4709 adult cases and 1905
pediatric cases. The incidence of anaphylactoid reactions in
adult (overall incidence 7.9%) and pediatric (overall incidence
9.5%) patients is presented in Tables 5 and 6.
Table 5. Distribution of reported reactions in adult
patients receiving I.V. NAC
Reaction
Urticaria/Facial Flushing
Incidence (%)
% of Patients
(N=4709)
6.1%
Pruritus
4.3%
Respiratory Symptoms*
1.9%
Edema
1.6%
Hypotension
0.1%
Anaphylaxis
0.1%
Table 6. Distribution of reported reactions in pediatric
patients receiving I.V. NAC
Reaction
Urticaria/Facial Flushing
Incidence (%)
% of Patients
(N=1905)
7.6%
Pruritus
4.1%
Respiratory Symptoms*
2.2%
Edema
1.2%
Anaphylaxis
0.2%
Hypotension
0.1%
®
Acetadote (acetylcysteine) Injection
DRUG INTERACTIONS
No drug-drug interaction studies have been conducted.
USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
Pregnancy Category B
There are no adequate and well-controlled studies of
Acetadote in pregnant women. However, limited case reports
of pregnant women exposed to acetylcysteine during various
trimesters did not report any adverse maternal, fetal or
neonatal outcomes.
There are published reports on four pregnant women with
acetaminophen toxicity, who were treated with oral or
intravenous acetylcysteine at the time of delivery.
Acetylcysteine crossed the placenta and was measurable
following delivery in serum and cord blood of three viable
infants and in cardiac blood of a fourth infant at autopsy (22
weeks gestational age who died 3 hours after birth). No
adverse sequelae developed in the three viable infants. All
mothers recovered and none of the infants had evidence of
acetaminophen poisoning.
Reproductive and developmental toxicity studies
performed in rats at oral doses up to 6.7 times the
recommended human intravenous dose and in rabbits at doses
up to 3.3 times the recommended human intravenous dose
revealed no evidence of impaired fertility or embryofetal
toxicity. [see Reproductive and Developmental Toxicology
(13.3)]
8.3 Nursing mothers
It is not known whether Acetadote is present in human
milk. Because many drugs are excreted in human milk,
caution should be exercised when acetylcysteine is
administered to a nursing woman. Based on the
pharmacokinetics of acetylcysteine, it should be nearly
completely cleared 30 hours after administration. Nursing
women may consider resuming nursing 30 hours after
administration.
8.4 Pediatric use
No adverse effects were noted during I.V. infusion with
acetylcysteine at a mean rate of 4.2 mg/kg/h for 24 hours to 10
preterm newborns ranging in gestational age from 25 to 31
weeks and in weight from 500 to 1380 grams in one study or
in 6 newborns ranging in gestational age from 26 to 30 weeks
and in weight from 520 to 1335 grams infused with
acetylcysteine at 0.1 to 1.3 mg/kg/h for 6 days. Elimination of
acetylcysteine was slower in these infants than in adults; mean
elimination half-life was 11 hours. There are no adequate and
well-controlled studies in pediatric patients.
8.5 Geriatric use
The clinical studies do not provide a sufficient number of
geriatric subjects to determine whether the elderly respond
differently.
10 OVERDOSAGE
Single intravenous doses of acetylcysteine at 1000 mg/kg
in mice, 2445 mg/kg in rats, 1500 mg/kg in guinea pigs, 1200
mg/kg in rabbits and 500 mg/kg in dogs were lethal.
Package Insert, page 5 of 7
Appendix VI
Symptoms of acute toxicity were ataxia, hypoactivity, labored
respiration, cyanosis, loss of righting reflex and convulsions.
11 DESCRIPTION
Acetylcysteine injection is an intravenous (I.V.)
medication for the treatment of acetaminophen overdose.
Acetylcysteine is the nonproprietary name for the N-acetyl
derivative of the naturally occurring amino acid, L-cysteine
(N-acetyl-L-cysteine, NAC). The compound is a white
crystalline powder, which melts in the range of 104° to 110°C
and has a very slight odor. The molecular formula of the
compound is C5H9NO3S, and its molecular weight is 163.2.
Acetylcysteine has the following structural formula:
H
CH3
N
SH
O
COOH
Acetadote is supplied as a sterile solution in vials containing
20% w/v (200 mg/mL) acetylcysteine. The pH of the solution
ranges from 6.0 to 7.5. Acetadote contains the following
inactive ingredients: 0.5 mg/mL disodium edetate, sodium
hydroxide (used for pH adjustment), and Sterile Water for
Injection, USP.
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of action
Acetaminophen Overdose:
Acetaminophen is absorbed from the upper
gastrointestinal tract with peak plasma levels occurring
between 30 and 60 minutes after therapeutic doses and usually
within 4 hours following an overdose. It is extensively
metabolized in the liver to form principally the sulfate and
glucoronide conjugates which are excreted in the urine. A
small fraction of an ingested dose is metabolized in the liver
by isozyme CYP2E1 of the cytochrome P-450 mixed function
oxidase enzyme system to form a reactive, potentially toxic,
intermediate metabolite. The toxic metabolite preferentially
conjugates with hepatic glutathione to form nontoxic cysteine
and mercapturic acid derivatives, which are then excreted by
the kidney.
Recommended therapeutic doses of
acetaminophen are not believed to saturate the glucuronide
and sulfate conjugation pathways and therefore are not
expected to result in the formation of sufficient reactive
metabolite to deplete glutathione stores. However, following
ingestion of a large overdose, the glucuronide and sulfate
conjugation pathways are saturated resulting in a larger
fraction of the drug being metabolized via the cytochrome P450 pathway and therefore, the amount of acetaminophen
metabolized to the reactive intermediate increases. The
increased formation of the reactive metabolite may deplete the
hepatic stores of glutathione with subsequent binding of the
metabolite to protein molecules within the hepatocyte
resulting in cellular necrosis.
Acetadote® (acetylcysteine) Injection
Acetylcysteine I.V. Treatment:
Acetylcysteine has been shown to reduce the extent of
liver injury following acetaminophen overdose. It is most
effective when given early, with benefit seen principally in
patients treated within 8-10 hours of the overdose.
Acetylcysteine likely protects the liver by maintaining or
restoring the glutathione levels, or by acting as an alternate
substrate for conjugation with, and thus detoxification of, the
reactive metabolite.
12.3 Pharmacokinetics
Distribution:
The steady-state volume of distribution (Vdss) and the
protein binding for acetylcysteine were reported to be 0.47
liter/kg and 83%, respectively.
Metabolism:
Acetylcysteine may form cysteine, disulfides and
conjugates in vivo (N, N’-diacetylcysteine, N-acetylcysteinecysteine, N-acetylcysteine-glutathione, N-acetylcysteineprotein, etc). Based on published data, it was reported that
after an oral dose of 35S-acetylcysteine, about 22% of total
radioactivity was excreted in urine after 24 hours. No
metabolites were identified.
Elimination:
After a single intravenous dose of acetylcysteine, the
plasma concentration of total acetylcysteine declined in a
poly-exponential decay manner with a mean terminal half-life
The mean clearance (CL) for
(T1/2) of 5.6 hours.
acetylcysteine was reported to be 0.11 liter/hr/kg and renal CL
constituted about 30% of total CL.
Special Populations:
Gender: Adequate information is not available to assess if
there are differences in pharmacokinetics (PK) between males
and females.
Pediatric: The mean elimination T1/2 of acetylcysteine is
longer in newborns (11 hours) than in adults (5.6 hours).
Pharmacokinetic information is not available in other age
groups.
Pregnant Women: In four pregnant women with
acetaminophen toxicity, oral or I.V. acetylcysteine was
administered at the time of delivery. Acetylcysteine was
detected in the cord blood of 3 viable infants and in cardiac
blood of a fourth infant sampled at autopsy. [see Pregnancy
(8.1)]
Hepatic Impairment: In subjects with severe liver damage,
i.e., cirrhosis due to alcohol (with Child-Pugh score of 7-13),
or primary and/or secondary biliary cirrhosis (with Child-Pugh
score of 5-7), mean T1/2 increased by 80% while mean CL
decreased by 30% compared to the control group.
Renal Impairment: Pharmacokinetic information is not
available in patients with renal impairment.
Geriatric Patients: Adequate information on acetylcysteine
PK in geriatric patients is not available.
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of
Fertility
Long-term studies in animals have not been performed to
evaluate the carcinogenic potential of acetylcysteine.
Acetylcysteine was not genotoxic in the Ames test or the
in vivo mouse micronucleus test. It was, however, positive in
Package Insert, page 6 of 7
Appendix VI
the in vitro mouse lymphoma cell (L5178Y/TK+/-) forward
mutation test.
Treatment of male rats with acetylcysteine at an oral dose
of 250 mg/kg/day for 15 weeks (0.8 times the recommended
human dose of 300 mg/kg) did not affect the fertility or
general reproductive performance.
13.3 Reproductive and Developmental Toxicology
Reproduction studies were performed in rats at oral doses
up to 2000 mg/kg/day (6.7 times the recommended human
dose of 300 mg/kg) and in rabbits at oral doses up to 1000
mg/kg/day (3.3 times the recommended human dose of 300
mg/kg) and revealed no evidence of impaired fertility or harm
to the fetus due to acetylcysteine [see Pregnancy (8.1)].
14 CLINICAL STUDIES
Loading Dose/Infusion Rate Study
A randomized, open-label, multi-center clinical study was
conducted in Australia to compare the rates of anaphylactoid
reactions between two rates of infusion for the I.V.
acetylcysteine loading dose. One hundred nine subjects were
randomized to a 15 minute infusion rate and seventy-one
subjects were randomized to a 60 minute infusion rate. The
loading dose was 150 mg/kg followed by a maintenance dose
of 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours.
Of the 180 patients, 27% were male and 73% were female.
Ages ranged from 15 to 83 years, with the mean age being
29.9 years (+13.0).
A subgroup of 58 subjects (33 in the 15-minute treatment
group; 25 in the 60-minute treatment group) was treated
within 8 hours of acetaminophen ingestion. No hepatotoxicity
occurred within this subgroup; however with 95% confidence,
the true hepatotoxicity rates could range from 0% to 9% for
the 15-minute treatment group and from 0% to 12% for the
60-minute treatment group.
Observational Study
An open-label, observational database contained
information on 1749 patients who sought treatment for
acetaminophen overdose over a 16-year period. Of the 1749
patients, 65% were female, 34% were male and <1% was
transgender. Ages ranged from 2 months to 96 years, with
71.4% of the patients falling in the 16-40 year old age bracket.
A total of 399 patients received acetylcysteine treatment. A
post-hoc analysis identified 56 patients who (1) were at high
or probable risk for hepatotoxicity (APAP >150 mg/L at the
four hours line according to the Australian nomogram) and (2)
had a liver function test. Of the 53 patients who were treated
with I.V. acetylcysteine (300 mg/kg I.V. acetylcysteine
administered over 20-21 hours) within 8 hours, two (4%)
developed hepatotoxicity (AST or ALT>1000U/L). Twentyone of 48 (44%) patients treated with acetylcysteine after 15
hours developed hepatotoxicity. The actual number of
hepatotoxicity outcomes may be higher than what is reported
here.
For patients with multiple admissions for
acetaminophen overdose, only the first overdose treated with
I.V. acetylcysteine was examined. Hepatotoxicity may have
occurred in subsequent admissions.
Evaluable data were available from a total of 148
pediatric patients (less than 16 years of age) who were
admitted for poisoning following ingestion of acetaminophen,
of whom 23 were treated with I.V. acetylcysteine. Of the 23
patients who received I.V. acetylcysteine treatment, 3 patients
Acetadote® (acetylcysteine) Injection
(13%) had an adverse reaction (anaphylactoid reaction, rash
and flushing, transient erythema). There were no deaths of
pediatric patients. None of the pediatric patients receiving
I.V. acetylcysteine developed hepatotoxicity while two
patients not receiving I.V. acetylcysteine developed
hepatotoxicity. The number of pediatric patients is too small
to provide a statistically significant finding of efficacy,
however the results appear to be consistent to those observed
for adults.
Postmarketing Safety Study [see 6.1 Clinical Studies
Experience]
16 HOW SUPPLIED/STORAGE AND HANDLING
Acetadote (acetylcysteine) Injection is available as a 20%
solution (200mg/mL) in 30 mL single dose glass vials.
Acetadote is sterile and can be used for I.V. administration. It
is available as follows:
• 30 mL vials, carton of 4 (NDC 66220-107-30)
Do not use
administration.
previously
opened
vials
for
I.V.
Note: The color of Acetadote may turn from essentially
colorless to a slight pink or purple once the stopper is
punctured. The color change does not affect the quality
of the product.
The stopper in the Acetadote vial is formulated with a
synthetic base-polymer and does not contain Natural
Rubber Latex, Dry Natural Rubber, or blends of Natural
Rubber.
Storage
Store unopened vials at controlled room temperature, 20°
to 25°C (68° to 77°F) [See USP Controlled Room
Temperature].
17 PATIENT COUNSELING INFORMATION
Sensitivity to acetylcysteine: Patients should be advised to
report to their physician any history of sensitivity to
acetylcysteine [see Contraindications (4)].
Asthma: Patients should be advised to report to their
physician any history of asthma [see Warnings and
Precautions (5)].
For all questions concerning adverse reactions associated with
the use of this product or for inquiries concerning our
products, please contact us at 1-877-484-2700.
For specific treatment information regarding the clinical
management of acetaminophen overdose, please contact your
regional poison center at 1-800-222-1222, or alternatively, a
special health professional assistance line for acetaminophen
overdose at 1-800-525-6115.
Manufactured for:
Cumberland Pharmaceuticals Inc.
Nashville, TN 37203
*Sections or subsections omitted from the Full Prescribing
Information are not listed.
Package Insert, page 7 of 7
Appendix VII
MCA PLUS
**TITLE****************************
Page: 1
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Requested by:**ID*
PL No:****PLNO**************
Holder:***HOLDER*********************************************************
Formulation No:***FORMNO
Licensed name(s):
**MORE**
**LN1*******************************************************
**LN2*******************************************************
**LN3*******************************************************
**LN4*******************************************************
**LN5*******************************************************
1.
NAME OF THE MEDICINAL PRODUCT
Methionine 500mg Film Coated Tablets
2.
QUALITATIVE AND QUANTITATIVE COMPOSITION
Each tablet contains 500 mg methionine
For excipients, see 6.1.
3.
PHARMACEUTICAL FORM
Film coated tablet
White oval,19 x 9 mm, film-coated tablet, with Pharma Nord logo stamped on each side.
4.
CLINICAL PARTICULARS
4.1.
Therapeutic indications
Methionine 500mg Film Coated Tablets are indicated for the oral treatment of paracetamol
overdosage if IV n-acetylcysteine is not available, or if the patient cannot tolerate nacetylcysteine.
4.2.
Posology and method of administration
Paracetomol overdose: The first dose should be given within ten hours of paracetamol
ingestion and subsequent to any emesis being induced.
Adults and the elderly, adolescents 13 to 18 years old, and children 7 to 12 years old: An
initial dose of five tablets (2.5 g) followed by five tablets every four hours up to a total dose
of twenty tablets (10 g).
Children (up to 6 years old): An initial dose of two tablets (1 g) followed by two tablets
every four hours up to a maximum of eight tablets (4 g).
Appendix VII
MCA PLUS
**TITLE****************************
4.3.
Page: 2
**/***/****
Requested by:**ID*
Contraindications
Methionine 500mg Film Coated Tablets are contraindicated in patients with known
hypersensitivity to methionine or to any of the excipients.
Methionine 500mg Film Coated Tablets should not be used for the treatment of paracetamol
overdose if more than ten hours have elapsed since the time of suspected overdose.
Methionine 500mg Film Coated Tablets is contraindicated in patients with metabolic
acidosis, renal tubular acidosis, hyperuricaemia (including predisposition), hyperuricuria,
uric acid calculi, cystine calculus diathesis, oxalosis and congenital metabolic disorder
(homocyteinuria)
4.4.
Special warnings and special precautions for use
Methionine may aggravate hepatic encephalopathy in patients with established liver
damage, therefore Methionine 500mg Film Coated Tablets should be used with caution in
patients with severe liver disease.
Large doses (10 - 20 grams per day) of methionine have been reported to precipitate acute
psychotic episodes in patients with schizophrenia therefore Methionine 500mg Film Coated
Tablets should be used with care in such patients.
This product includes maltodextrin, a dietary source of glucose. Patients with rare glucosegalactose malabsorption should not take this medicine.
4.5.
Interactions with other medicinal products and other forms of interaction
An increase in effectiveness due to lengthening of the plasma half-life, may be observed
with substances which are reabsorbed more powerfully by the kidneys as a result of
acidification of the urine e.g. ampicillins, carbenicillins, sulphonamides, nitrofurantoin,
nalidixic acid.
The effect of the anti-parkinsonian agent, levodopa may be reduced.
4.6.
Pregnancy and lactation
The safety in human pregnancy or during lactation of the administration of large amounts of
methionine, that would normally not be found in a balanced diet, has not been established.
Methionine 500mg Film Coated Tablets should only be used during pregnancy or lactation
if the potential benefits out weigh any potential risks.
4.7.
Effects on ability to drive and use machines
Appendix VII
MCA PLUS
**TITLE****************************
Page: 3
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Methionine may cause drowsiness. Patients should be advised that their ability to drive or
operate machinery may be affected.
4.8.
Undesirable effects
Large doses of methionine may cause nausea, vomiting, drowsiness and irritability.
Daily doses of 6 to 20g can cause neurological changes and precipitate encephalopathy in
patients with hepatic cirrhosis especially if portal hypertension is present.
4.9.
Overdose
Large doses of methionine cause nausea, vomiting, drowsiness and irritablity. General
supportive measures should be taken. Activated charcoal may be used to adsorb some of the
methionine.
5.
PHARMACOLOGICAL PROPERTIES
5.1.
Pharmacodynamic properties
Pharmacotherapeutic group: Antidotes, ATC code: VO3A B26
Methionine is an amino acid which is an essential constituent of the diet.
The pharmacodynamics of methionine in the treatment of paracetamol overdose is based on
knowledge of the biochemical basis of paracetamol toxicity. Paracetamol is metabolised to a
chemically unstable intermediate which is rapidly detoxified by conjugation with reduced
glutathione. In paracetamol overdose the reduced glutathione is rapidly depleted and the
unstable intermediate becomes covalently bound to hepatic proteins, thus precipitating
hepatic necrosis. Methionine enhances the synthesis of glutathione and is used in the
treatment of paracetamol poisoning to prevent hepatic damage.
5.2.
Pharmacokinetic properties
Methionine is absorbed from the gastrointestinal tract. About 80% of the ingested
methionine is converted to inorganic sulphate which is excreted in the urine. Following oral
administration in humans, methionine is well absorbed. Methionine is degraded via a transsulphuration and a transamination pathway. Methionine degradation via the transsulphuration pathway forms cysteine which is a precursor of glutathione and consequently
helps to restore and maintain glutathione levels in paracetamol overdose.
5.3.
Preclinical safety data
There are no preclinical data of relevance to the prescriber other than those already provided
in other sections of the SPC.
Appendix VII
MCA PLUS
**TITLE****************************
6.
PHARMACEUTICAL PARTICULARS
6.1.
List of excipients
Page: 4
**/***/****
Requested by:**ID*
The excipients in the tablet core are:
Microcrystalline cellulose
Maltodextrin
Sodium croscarmellose
Talc
Silica (colloidal anhydrous)
Magnesium stearate.
The tablet coating comprises:
Hypromellose
Talc
Titanium dioxide (E 171)
6.2.
Incompatibilities
Not applicable
6.3.
Shelf life
Two years
6.4.
Special precautions for storage
Do not store above 25°C. Keep blister in the outer carton.
6.5.
Nature and contents of container
Methionine 500mg Film Coated Tablets are packaged in blister consisting of transparent
PVC/PVdC and aluminium foil backing. A blister tray of 20 tablets is packed in a cardboard
outer.
6.6.
Instruction for use and handling (and disposal)
No special requirements
7.
MARKETING AUTHORISATION HOLDER
Appendix VII
MCA PLUS
**TITLE****************************
Page: 5
**/***/****
Requested by:**ID*
Pharma Nord (UK) Ltd.,
Telford Court,
Morpeth,
NE61 2DB
UK
8.
MARKETING AUTHORISATION NUMBER
PL 15702/0001
9.
DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
8th June 2005
10.
DATE OF REVISION OF THE TEXT
Appendix X
The College of
Emergency Medicine
CEM Clinical Audits:
Paracetamol Overdose 2008
All Trusts Report 2008
INT. GROUP:
COMP. SET:
YEAR(S):
DATABASE:
All trusts
All trusts
2008, 2004
cemp_2008_paracetamol.xls
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
Introduction
This report shows results from an audit of the treatment of patients presenting in Emergency
Departments (EDs) with a paracetamol overdose against the clinical standards of the College of
Emergency Medicine (CEM) Clinical Effectiveness Committee. It compares your department
with 126 other departments that made audit returns.
6,021 cases from 127 Emergency Departments were included in the 2008 audit.
This report has been prepared by the Care Quality Commission in partnership with the College.
History of the audits
This audit follows on from the successful earlier audits of ED treatment of paracetamol overdose
in 2004 and 2005. There have been similar audits of the treatment of fractured neck of femur,
pain in children, urinary retention and moderate/severe asthma in adults. These audits were
developed in association with the CEM, initially by the Audit Commission’s Acute Hospital
Portfolio and then by the Healthcare Commission as part of its programme of service reviews.
The Care Quality Commission is continuing this work as part of its work on clinical quality.
In September 2008, letters were sent to nominated contact Consultants and audit departments
in each trust asking them to participate in the latest round of audits. Audit tools were made
available on the Healthcare Commission and CEM websites.
Participants were asked to collect data from ED notes on 50 or more patients presenting with a
paracetamol overdose. The audit tool summarised the data entered automatically. These
summaries were then e-mailed to the College, who passed them to the Commission for the
preparation of this report.
Next Steps
Should you think that any of the figures or charts in this report misrepresent the results of your
audit, please inform CEM by e-mailing [email protected] or telephoning
020 7067 1269.
Details of CEM audits for 2009 will be circulated shortly with a view to starting them in August
2009. The Care Quality Commission’s support for the CEM audits will now be provided through
its work on clinical quality with the view to publishing the results as comparative data. Some
more information can be found at
http://www.collemergencymed.ac.uk/CEM/Clinical Effectiveness Committee/CEC Standards and Audit
None - Coll. Emergency Medicine Audits
2
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
Results for this department since 2004
The paracetamol overdose audit is now in its third cycle, and the table below shows your results for
each round. It allows you to see quickly whether performance in your department is improving.
The table also includes the national results for 2008 (in blue type) so that you can quickly compare
your department’s results against the performance of the other departments that took part in the audit.
The median shows the results of the “average” department, while the lower and upper quartiles
indicate departments that were noticeably below or above average.
The charts from page 5 to the end of the report allow more considered comparisons to be made.
Table 1: ED’s results since 2004 compared with national results for 2008
Results for this department
Results for 2008
lower
quartile
median
upper
quartile
48
50
50
10
14
18
4
8
12
72
79
88
3
8
13
Where tested within 8 hours of
ingestion and plasma concentration
above treatment level
11
17
22
of which received N-acetylcysteine
(NAC) within of 8 hours ingestion
4
8
14
2
8
14
0
2
4
73
83
90
6
10
20
0
0
3
2008
Case mix
Number of patients audited
Who presented within 1 hour of
ingestion (%)
Who took a staggered dose (%)
Assessment and Treatment (%)
Received plasma paracetamol level
test
of which plasma level tested earlier
than 4 hours after ingestion
Where dose >12g and over 8 hours
since ingestion or staggered
ingestion
of which % received NAC within 1
hour of arrival
Compliance of treatment with guidelines (%)
Yes - recommended treatment
received
No - recommended treatment
partially received
No - serious omissions in treatment
2005
2006
Note: the median and quartiles are descriptive statistics. When results are sorted into numerical order, the median is the
value where half (50%) the values are less than it and half are greater. Similarly, the lower quartile represents the quarterway value (25%), and the upper quartile the three-quarters value (75%).
None - Coll. Emergency Medicine Audits
3
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
National results since 2004
The table below summarises national performance since 2004. It uses three measures to
summarise the variation between departments in performance. The median indicates performance
in an average department. The lower quartile indicates departments that performed less well. The
upper quartile shows the results achieved by the better performing departments. The table below
presents an overview of national and local performance.
Table 2: National results since 2004
Results for 2008
Results for 2005
Results for 2004
lower
quartile
median
upper
quartile
lower
quartile
median
upper
quartile
lower
quartile
median
upper
quartile
48
50
50
30
30
33
30
32
40
10
14
18
10
13
23
10
14
19
4
8
12
2
6
10
0
6
10
72
79
87
70
77
87
69
79
87
3
8
13
4
5
11
4
7
13
11
17
22
7
10
15
6
10
17
50
73
86
53
67
100
50
68
100
2
8
14
7
13
17
7
13
19
0
2
4
0
0
30
0
0
29
90
76
83
88
63
75
84
Case mix
Number of patients audited
Who presented within 1 hour
of ingestion (%)
Who took a staggered dose
(%)
Assessment and Treatment (%)
Received plasma
paracetamol level test
of which plasma level tested
earlier than 4 hours after
ingestion
Where tested within 8 hours
of ingestion and plasma
concentration above
treatment level
of which received Nacetylcysteine (NAC) within 8
hours of ingestion
Where dose >12g and over 8
hours since ingestion or
staggered ingestion
of which % received NAC
within 1 hour of arrival
Compliance of treatment with guidelines (%)
Yes - recommended
73
83
treatment received
No - recommended treatment
6
10
partially received
No - serious omissions in
0
0
treatment
Other
No. of departments
participating in audit
128
20
3
33
171
The charts in the following pages allow more considered comparisons to be made.
None - Coll. Emergency Medicine Audits
4
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
Case mix 1
Chart 03: Patients presenting within 60 minutes of ingestion
Usually few patients arrive at an ED within one hour
of ingestion. If they do they may be treated with
charcoal.
100
% of pts audited
80
The median value was 14%, but in a 10% of
departments it was 24% or more.
60
40
20
0
Results for All trusts within All trusts
Chart 03T: Trend in patients presenting
within 60 minutes of ingestion
% within 1 hour of ingestion
(100=base yr median)
210
U.Quartile
160
Median
110
L.Quartile
60
2004
2005
2008
This trend chart shows how those presenting with
an overdose at your ED has changed over
successive audits compared to patients presenting
at other EDs. All values shown on a trend chart are
in relation to the national median score in the first
audit (i.e. a current score greater than 100
represents a rise on the national result of the first
audit).
The thick red line (your results) shows how your
patients are changing compared to other
departments. Where the line is moving away from
the median line, those presenting at your ED’s case
mix is diverging from the “average”.
Results for All trusts
Chart 04: Patients who took a staggered dose
Like chart 03 this is a contextual measure as if a
staggered dose was taken affects how a patient is
assessed and treated.
30
% of pts audited
25
The median value was 8%, but in a tenth of
departments it was 17% or more.
20
15
10
5
0
Results for All trusts within All trusts
None - Coll. Emergency Medicine Audits
5
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
Case mix 2
Chart 04T: Trend in patients who took a staggered dose
% staggered dose (100=base
yr median)
200
U.Quartile
150
100
Median
50
L.Quartile
0
2004
2005
This chart shows how this aspect of case mix is
changing compared to case mix at other
departments.
The red line compares patients who took a
staggered OD in your ED with the national median
score in the first audit, which is shown as 100.
Compared to 2004 there has been a slight rise in
patients who took a staggered dose. (The 2005
results, which are based on 32 EDs, should be
treated with caution.)
2008
Results for All trusts
Chart 01: No. of patients audited
For the 2008 round of audits departments were
asked to sample 50 patients, however a quarter of
EDs did not audit this number. Some only covered
30 patients, which was the sample number for the
2004 and 2005 audits.
No. of patients
80
60
40
20
0
Results for All trusts within All trusts
Chart 02: Time taken to complete the audit
This measure uses the dates of the first and last
presentations included in the audit and reflects how
frequently patients present with an overdose of
paracetamol.
40
No. of weeks
30
The median was 16 weeks, and some larger EDs
completed the audit within a month. However
others took over 6 months as they extended the
data collection period in order to find 50 cases for
the audit.
20
10
N.B. Some very high values may reflect inaccurate
start dates being supplied. Values above 40 have
been capped.
0
Results for All trusts within All trusts
None - Coll. Emergency Medicine Audits
6
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
Assessment & Treatment - plasma concentration test
Chart 05: Plasma paracetamol level tested
Chart 06: Where plasma tested earlier than 4
hours after ingestion
80
80
% of pts tested
100
% of pts audited
100
60
40
60
40
20
20
0
0
Results for All trusts within All trusts
Results for All trusts within All trusts
This plasma test was taken for 79% of patients (chart 05, where a high value is good), and in 10% of these
patients it occurred less than four hours before ingestion (chart 06, low value is good).
As charts 05 and 06 show practice in some departments was very good: all patients were tested and no test
occurred less than 4 hours after ingestion. The charts also show that in a sizeable minority of departments
practice needs to improve as in 25% of departments over a quarter of patients did not receive a plasma level.
Chart 06 only denominator is no. of patients where plasma level tested
Chart 05T: Trend in testing of plasma
concentration
Chart 06T: Trend in plasma tested earlier than
4 hours after ingestion
250
U.Quartile
110
100
Median
90
Of which % where 4 hours
not allowed (100=base yr
median)
% who received plama level
test (100=base yr median)
120
U.Quartile
200
150
Median
100
50
L.Quartile
80
2004
2005
Results for All trusts
2008
L.Quartile
0
2004
2005
2008
Results for All trusts
These trend charts measures performance by comparing your department, shown by the thick red line, to
the median in the first audit (2004) which has a value of 100.
For chart 05T, where high values are good, there has been a modest improvement since 2004.
For chart 06T, where low values are good, the performance of the better trusts is has improved a little,
however performance in other EDs has slipped back slightly, and the difference between the performance of
the better and poorer EDs is widening.
None - Coll. Emergency Medicine Audits
7
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
Assessment & Treatment - Less than 8 hours from ingestion
Chart 07: Plasma tested within 8 hours AND
concentration above treatment level
Chart 08: Patients receiving NAC within 8
hours of ingestion
100
% pts above treatment level
etc.
% of pts audited
40
30
20
10
0
80
60
40
20
0
Results for All trusts within All trusts
Results for All trusts within All trusts
Chart 07T: Trend in test within 8 hours of
ingestion AND above treatment level
Chart 08T: Trend in patients receiving NAC
within 8 hours of ingestion
150
U.Quartile
150
100
Median
50
Of which % who received
NAC within 8 hours
ingestion (100=base yr
median)
% within 8 hrs ingestion and
plasma above treatment
level (100=base yr median)
200
U.Quartile
130
110
Median
90
L.Quartile
0
2004
2005
L.Quartile
70
2004
2008
Results for All trusts
2005
2008
Results for All trusts
Treatment with NAC, N-acetylcysteine, is most effective when undertaken within 8 hours of ingestion and
EDs should aim to treat 90% of relevant patients within this time.
Across the audit 17% of patients received a plasma test within 8 hours where the concentration was above
the treatment level (chart 07). 69% of these patients received NAC within 8 hours of ingestion (Chart 08).
The trend for those tested and over the treatment line (chart 07T) shows a small rise since 2004.
The trend for NAC treatment (chart 08T) shows that the median, representing a typical ED, has improved
slightly from 2004, however the lower quartile, representing more poorly performing EDs has not changed,
and the upper quartile, representing better performing EDs has fallen noticeably. (Detailed comparisons with
2004 data show fewer EDs achieved either 0% or 100%).
(For these charts your ED is shown by the thick red line.)
In both charts 7 and 8 there is significant variation between departments. EDs where fewer than 80% of
patients receive NAC within 8 hours of ingestion should investigate the reasons for this.
For Chart 08 the denominator is no. patients tested within 8 hours
of ingestion and where the level was above the treatment line.
None - Coll. Emergency Medicine Audits
8
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
Assessment & Treatment - More than 8 hours from ingestion
Chart 09: Patients where dose >12g, >8hours
since ingestion or staggered dose
Chart 10: Patients where dose >12g etc &
receiving NAC within 60 minutes of arrival
60
% pts where dose >12g etc
50
% of pts audited
50
40
30
20
10
0
40
30
20
10
0
Results for All trusts within All trusts
Results for All trusts within All trusts
Chart 09T: Trend in dose >12g, > 8hours
since ingestion or staggered dose
Chart 10T: Trend in NAC treatment within 60
minutes
300
U.Quartile
100
Median
50
Of which % received NAC
within 1 hr of arrival
(100=base yr median)
% more then 8 hrs or
staggered and > 12g
(100=base yr median)
150
250
U.Quartile
200
150
Median
100
50
L.Quartile
0
2004
2005
Results for All trusts
2008
L.Quartile
0
2004
2005
2008
Results for All trusts
For patients present 8 or more hours after ingestion treatment should start within one hour to limit liver
damage.
Charts 09 and 09T provide context for performance in starting treatment within 60 minutes. Chart 9 shows
that a small proportion of patients present 8 or more hours after ingestion. It was 10% for the whole audit,
but for some EDs it was over 20%.
Charts 10 and 10T measure performance. In at least half the EDs participating in the audit, only a few
patients were involved ( in your ED). This meant delays in treating one or two patients, had a big impact on
performance.
In Chart 10T good performance is indicated if the thick red line (your results) is now either above the line
denoting the upper quartile performance of all participating EDs, or is converging towards it.
The lower quartile for all years was zero (0) and runs along the x-axis.
Denominator for chart 10 is no. patients where dose >12g,
more than 8 hrs since ingestion or staggered dose
None - Coll. Emergency Medicine Audits
9
Appendix X
CEM clinical audits
PARACETAMOL OVERDOSE 2008
Compliance of treatment with guidelines
Chart 11: Patients receiving recommended
treatment
Chart 11T: Trend in patients receiving the
recommended treatment
120
% who received
recommended treatment
(100=base yr median)
100
% of pts audited
80
60
40
20
U.Quartile
110
100
Median
90
L.Quartile
0
80
2004
Results for All trusts within All trusts
Chart 12: Patients partially receiving
recommended treatment
2005
2008
Results for All trusts
Chart 13: Patients where serious omissions in
treatment
80
30
% of pts audited
% of pts audited
25
60
40
20
15
10
20
5
0
0
Results for All trusts within All trusts
Results for All trusts within All trusts
Ideally all patients should receive the recommended treatment. Overall only 80% received the
recommended treatment. Chart 11 shows that in 75% of EDs this occurred for less than 90% of patients. In
6% of EDs less than 50% of patients received the recommended treatment.
Chart 11T shows the trend of very modest improvement. Good performance is indicated if the thick red line
(your results) is now either above the line denoting the upper quartile performance of all participating EDs,
or is converging towards it.
Charts 12 and 13 are counterparts to chart 11. Chart 12 considers patients who have not received the
recommended treatment, which should be under 10%. Chart 13 covers where there were serious omissions,
which should be 0%.
Across the whole audit 12% of patients partially received the recommended treatment, and there were
serious omissions in 3% of cases. There was though significant variation between EDs.
Departments should look at their results shown Table 1 on page 3 and should investigate where the
proportion receiving the recommended treatment is less than 80%, or those partially receiving
the recommend treatment is more than 10%, or there were serious omissions in treatment.
None - Coll. Emergency Medicine Audits
10