Time to onset in adverse drug reaction surveillance
1. Time to onset in adverse drug reaction surveillance
Ghazaleh Khodabakhshi
Faculty of Pharmacy
Department of Pharmaceutical Biosciences
Division of Toxicology
Masters Thesis, 2010-01-15
Supervisors: Kristina Star, the Uppsala Monitoring Centre and Staffan Hägg,
Linköping University
Examiner: Björn Hellman, Uppsala University
2. 2
1 Abstract
An important aspect of the causality assessment of adverse drug reactions (ADRs) is the time
span between administration of the drug and the clinical event, i.e. time to onset (TTO).
Today, case evaluations of reported ADRs are mainly based on the physician's experience of
similar reactions and the general knowledge about the suspected mechanism.
The aim of this study was to investigate whether the TTOs recorded on individual case safety
reports (ICSRs) in the WHO global ICSR database VigiBase correspond to what is
documented in the literature. Variations in TTO were intended to be investigated for gender,
age and ATC groups.
A selection of commonly drug induced and well-reviewed terms were chosen from the
MedDRA terminology: agranulocytosis, angioedema, hepatitis, serum sickness, Stevens-
Johnson syndrome and toxic epidermal necrolysis. This limited test sample from VigiBase
was analyzed regarding TTO at ADR level, age, gender and top ten reported ATC groups.
Median TTOs were obtained and compared to the literature.
The reported median TTOs studied corresponded well to the literature. Hepatitis exemplified
a shorter reported TTO than the chosen reference. Only slight variations were found across
the gender and age groups, while the ATC groups displayed marked differences in TTO. Long
TTOs were found for clozapine-induced agranulocytosis, angiotensin-converting enzyme
inhibitor-induced angioedema and statin-induced hepatitis. Short TTOs was observed for
antibiotics and non steroidal anti-inflammatory drugs reported with Stevens-Johnson
syndrome and toxic epidermal necrolysis.
This study suggests that spontaneous reports can be used as a source of information on TTO.
However, a wider set of ADRs must be studied before generalization of the obtained results
would be possible.
3. 3
2 Table of contents
1 Abstract..................................................................................................................................2
2 Table of contents ...................................................................................................................3
3 Glossary.................................................................................................................................5
4 ATC groups ...........................................................................................................................6
5 Introduction ...........................................................................................................................8
5.1 Pharmacovigilance and the WHO programme............................................................8
5.2 Time to onset in the causality assessment of case reports...........................................8
6 Aim........................................................................................................................................9
7 Selected adverse drug reactions.............................................................................................9
7.1 Agranulocytosis.........................................................................................................10
7.2 Angioedema ..............................................................................................................10
7.3 Hepatitis ....................................................................................................................11
7.4 Serum sickness ..........................................................................................................12
7.5 Stevens-Johnson syndrome and toxic epidermal necrolysis .....................................12
8 Methods ...............................................................................................................................14
8.1 Data extraction and criteria .......................................................................................14
8.2 Selection of adverse drug reactions and terminology ...............................................14
8.3 Definition of time to onset ........................................................................................15
8.4 Source of reference for time to onset ........................................................................15
8.5 Sensitivity analysis....................................................................................................16
8.6 Statistical analysis with R .........................................................................................16
9 Results .................................................................................................................................17
9.1 Report demographics.................................................................................................17
9.2 Time to onset by adverse drug reaction ....................................................................18
9.3 Time to onset by ATC group and age .......................................................................20
9.4 TTO by gender categories.........................................................................................28
5. 5
3 Glossary
(The explanations are found in the glossary of the WHO international collaborating centre for
adverse drug reactions at: http://www.who-umc.org/graphics/15338.pdf, if not otherwise is
stated).
Adverse drug reaction (ADR): “Any noxious, unintended and undesired effect of a drug
which occurs at a dose used in man for prophylaxis, diagnosis or therapy”.1
Anatomic Therapeutic Chemical classification system(ATC): Classification system where
substances are divided into different groups according to the organ or system on which they
act and their therapeutic, pharmacological and chemical properties.
Individual case safety report (ICSR): “A report that contains information describing a
suspected adverse drug reaction related to the administration of one or more medicinal
products to an individual patient”.
Medical Dictionary for Regulatory Activities (MedDRA): “The international medical
terminology developed under the auspices of the International Conference on Harmonization
of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH)”. 2
It is built up by five levels of hierarchy:
System Organ Class (SOC) - Distinguished by anatomical or physiological system, etiology
or purpose.
High Level Group Term (HLGT) – Subordinate to SOC, supraordinate descriptor for HLTs.
High Level Term (HLT) – Subordinate to HLGT, supraordinate descriptor for PTs.
Preferred Term (PT) – Represents a single medical concept.
Lowest Level Term (LLT) – Subordinate to a single PT as a synonym or lexical variant.
Pharmacovigilance: “The science and activities relating to the detection, assessment,
understanding and prevention of adverse effects or any other drug related problem”.
Rechallenge: “The point at which a drug is again given to a patient after its previous
withdrawal”.
Signal: “Reported information on a possible causal relationship between an adverse event and
a drug, the relationship being unknown or incompletely documented previously. Usually
more than a single report is required to generate a signal, depending upon the seriousness of
the event and the quality of the information”.
VigiBase: “The name for the WHO global ICSR database”.
VigiSearch: “This is a custom search service offered by the UMC to third-party inquirers for
which several types of standard presentation are available”.
6. 6
4 ATC groups
A01AD Other agents for local oral treatment
A07EC Aminosalicylic acid and similar agents
B01AC Platelet aggregation inhibitors excl. heparin
C01EB Other cardiac preparations
C09AA ACE inhibitors, plain
C10AA HMG-CoA reductase inhibitors
D06AX Other antibiotics for topical use
D10AF Antiinfectives for treatment of acne
D10AX Other anti-acne preparations for topical use
G02CC Antiinflammatory products for vaginal administration
H03BA Thiouracils
H03BB Sulfur-containing imidazole derivatives
J01CA Penicillins with extended spectrum
J01CE Beta-lactamase sensitive penicillins
J01CR Comb of penicillins, incl. beta-lactamase inhib.
J01DC Second-generation cephalosporins
J01DD Third-generation cephalosporins
J01FA Macrolides
J01EE Comb.sulfonamides and trimethoprim incl. derivatives
J01MA Fluoroquinolones
J05AG Non-nucleoside reverse transcriptase inhibitors
J07AM Tetanus vaccines
J07BC Hepatitis vaccines
L04AA Selective immunosuppressants
M01AB Acetic acid derivatives and related substances
M01AE Propionic acid derivatives
M02AA Antiinfl. prep., non-steroids for topical use
7. 7
M04AA Preparations inhibiting uric acid production
N01AB Halogenated hydrocarbons
N02BB Pyrazolones
N03AA Barbiturates and derivatives
N03AB Hydantoin derivatives
N03AF Carboxamide derivatives
N03AX Other antiepileptics
N05AH Diazepines, oxazepines and thiazepines
N06AA Non-selective monoamine reuptake inhibitors
N06AX Other antidepressants
N07BA Drugs used in nicotine dependence
S01AA Antibiotics
S01AX Other antiinfectives
S01BC Antiinflammatory agents, non-steroids
8. 8
5 Introduction
5.1 Pharmacovigilance and the WHO programme
It is today well accepted that some safety aspects of drugs will come to light first after their
introduction to the market 3 4. The concept was brutally demonstrated in the 1960’s through
the thalidomide disaster, giving rise to an expansion of the field of drug safety surveillance,
also referred to as pharmacovigilance. The World Health Organisation (WHO) Programme
for International Drug Monitoring was set up to enable early identification of adverse drug
reactions (ADRs) 5. It was first conducted in 1968 among 10 countries with existing national
spontaneous adverse reaction reporting centers coming together to share data, which was soon
developed into an international database of individual case safety reports (ICSRs) 6. Since
then, more than 95 countries have chosen to participate in the WHO programme. The
members contribute with reports from their respective national pharmacovigilance system.
The reports originate from a range of sources such as health professionals, patients and
pharmaceutical companies 6. In October 2009 there were a total of 4,888,246 reports in the
WHO global ICSR database system VigiBase, maintained and developed by the WHO
Collaborating Centre for Drug Monitoring, also known as the Uppsala Monitoring Centre
(UMC).
Ever since its outset, the primary function of pharmacovigilance has been to provide early
warnings in form of safety signals regarding previously undocumented ADRs 7. The
definition of a signal is “reported information on a possible causal relationship between an
adverse event and a drug, the relationship being unknown or incompletely documented
previously. Usually more than a single report is required to generate a signal depending upon
the seriousness of the event and the quality of the information” 8. It is the causality assessment
of aggregated data, that is the systematic study and interpretation of series of case reports, that
may lead to the generation of a signal 7. The UMC generates signals and distributes
summarized case reports of the issue to the national centers as well as pharmaceutical
companies for their own branded products 6.
5.2 Time to onset in the causality assessment of case reports
The temporal association between onset of the ADR and the initiation of drug treatment is an
important part of the causality assessment of case reports. In fact, the time interval between
drug intake and onset of ADR constitutes a major argument in various methods for
9. 9
standardized and structured causality assessment of case reports 9. Already in the late
seventies, one of the three questions in Karch and Lasagnas decision table for causality
assessment was if there were an appropriate interval between the agent and the event 10. In
1981, the importance of temporal association for causality assessment was pointed out at an
international conference in Switzerland 11. Among the nine points considered as the most
important in causality assessment, three were assigned to temporal relations between drug
intake and onset of the adverse reaction. Later on, the time relationship has often been
considered as the main reason for suspecting a drug and reporting the case as an adverse drug
reaction 9. Assessment of causality between a drug and an ADR where the time association is
of major concern is relevant in a range of settings, including that of national
pharmacovigilance centers. As two of the established national and regional centers within the
WHO programme were investigated 12 it turned out that neither of them had any guidelines on
time to onset when evaluating individual cases. Each report is assessed individually on the
basis of available information in the literature and clinical experience. The available
information about time to onset is limited for many ADRs, why it would be valuable to
investigate the compiled case reports of VigiBase regarding time to onset. As a first step in
exploring this source of information, a limited sample of ADRs may indicate the usefulness of
VigiBase data as a reference on time to onset in causality assessments.
6 Aim
The aim of this thesis was to investigate to what extent the time periods between start of drug
treatment and onset of suspected ADRs recorded on ICSRs in VigiBase correspond to what is
documented in the literature. Variations in TTO were intended to be investigated for gender,
age and ATC groups.
7 Selected adverse drug reactions
A selection of commonly drug induced diagnoses, well-reviewed in the literature, is studied to
provide a limited test sample from the database. The following sections describe the selected
ADRs and the literature findings on time to onset for the chosen ADRs; agranulocytosis,
angioedema, hepatitis, serum sickness, Stevens-Johnson syndrome and toxic epidermal
necrolysis. Tables I-V in the Appendix summarise the main literature findings for each ADR.
10. 10
7.1 Agranulocytosis
Drug-induced agranulocytosis is an idiosyncratic ADR, resulting in a severe reduction of
peripheral granulocytes, a specific type of white blood cell, in the blood. It is characterized by
a decrease in absolute neutrophil count to under 0.5 x 109 /L, 13 14 in response to immunologic
or cytotoxic mechanisms 15. In the majority of cases ANC is less than 0.1 x 109 /L, making the
condition life-threatening due to the occurrence of severe sepsis with deep infections (e.g.
pneumonia), septicemia and septic shock 16 in 60% of cases without intervention 17 18. In
1991, Benichou and Solal-Celigny published a report from an international consensus meeting
concerning drug-induced blood cytopenias, where standard designations and criteria for
causality assessment of agranulocytosis and related conditions were declared. In this report,
the first criteria for drug imputability of idiosyncratic agranulocytosis is onset during
treatment (not giving any measures on the duration of treatment) or within 7 days from
previous intake of the drug 13. Based on this, 7 days from initiation of treatment has been used
as the main reference for time to onset of drud-induced liver injury in recent literature 19 20. A
systemic review of published case reports on nonchemotherapy drug-induced agranulocytosis
estimated the time to onset per suspected causative drug 18. The median duration of treatment
before onset of agranulocytosis for different drugs ranged from 2-60 days and was longer than
1 month for 71% of the studied drugs. Clozapine is a well established causative drug of
agranulocytosis, assigned a median TTO of 56 days in the referenced study. The highest risk
of clozapine-induced agranulocytosis is documented for the initial 6-18 weeks of treatment 18.
In the European Union, weekly neutrophil counts are mandated during the first 18 weeks (six
months in the United States), followed by biweekly monitoring up to one year and thereafter
every four weeks throughout the drug treatment 21.
7.2 Angioedema
Angioedema is an abrupt, transient swelling of the skin and mucous membranes,
conventionally classified according to the pathophysiological mechanism causing the
condition 22. Among the various classes of angioedema, the allergic histamine-mediated,
pseudoallergic (cyclooxygenase inhibition-mediated) and bradykinin-mediated may be caused
by certain drug groups 23-25. Allergic angioedema is typically accompanied by urticaria, both
usually occurring within 1-2 hours of exposure to the offending drug. The onset is reliant on
previous sensitization with the allergen or cross-reactive substances 22. Severe cases of
allergic angioedema can lead to anaphylaxis, with a typical time to onset of minutes 25. A
11. 11
variety of nonsteroidal anti-inflammatory drugs (NSAID), including aspirin as the most
common one, can cause angioedema through pseudoallergic reactions. While superficially
resembling allergic angioedema, these ADRs are often explained by the pharmacological
properties of the drug 23 26. Generally, the NSAID-induced angioedema is due to the inhibition
of prostaglandin production (especially prostaglandin E2), which results in an excess of
leukotrienes 27. As the clinical manifestations do not differ significantly, neither does the time
to onset; mucosal and/or cutaneous angioedema occurs within minutes of exposure to the
offending NSAID 24. Unlike allergic and pseudoallergic angioedema, bradykinin-mediated
angioedema is not associated with urticaria. This type of drug-induced angioedema is
associated with angiotensin-converting enzyme inhibitors (ACEI) 28. Early literature findings
based on ADR reporting29 and clinical case series28 have typically suggested ACEI-associated
angioedema to occur during the first week of treatment, whereas another set of case reports
have acknowledged late onset and irregular course of the adverse event 30-33.
7.3 Hepatitis
The recognition and diagnosis of drug-induced liver injury are usually delayed due to the
often asymptomatic process and the ability to mimic the entire spectrum of clinicopathologic
features of chronic and acute liver diseases 34-36. Recent reviews tend to distinguish between
predictable and unpredictable drug-induced liver injury 35 37 38. Acetaminophen (paracetamol)
poisoning is an example of the predictable and strongly dose-dependent adverse events 34.
Time to onset for liver injury induced by this drug is stated to range from hours to a few days
34 38, more precisely from 24 to 48 hours for biochemical signs of liver damage to become
apparent 39. The unpredictable liver injuries are divided into immune mediated and
idiosyncratic, where the latency to onset is approximated to be intermediate (1-8 weeks, with
rapidly recurring positive rechallenge) and long (up to 1 year), respectively 37 40 41. In an
ongoing prospective multicenter observational study of the Drug-Induced Liver injury
Network the first 300 subjects enrolled treated with a range of drugs (acetaminophen
excluded) were stated to have a median time to onset of 42 days for drug-induced liver injury.
The range of duration between first exposure to the implied drug and recognition of
symptoms were 20-117 days 36.
12. 12
7.4 Serum sickness
The term serum sickness refers to a typical type III hypersensitivity reaction to heterologous
proteins mediated by immune-complex formation, which was originally observed by injection
of sera 42. Serum sickness-like reactions are associated with drugs such as penicillins,
cephalosporins including cefaclor as the most risky substance of the group, minocycline and
propranolol 43. Although clinically similar with fever, urticaria, polyarthalgias and
lymphadenopathy the absence of vasculitis, renal lesions, hypocomplementaemia and immune
complexes distinctly differ serum sickness-like reactions from “true” serum sickness 44.
Despite of the distinction, the usage of this terminology is found to be inconsistent in the
literature. In this study, the term serum sickness also refers to serum sickness-like reactions,
due to the terminology used for encoding this ADR in VigiBase.
As to the matter of time to onset for serum sickness, there are several different suggestions
found in the literature. The reaction is stated to develop 1-3 weeks after initial administration
of the causative drug and reoccur within 12-36 hours when rechallenged 44 45. In the 17th
edition of Harrison’s Principles of internal medicine, the occurrence of common characteristic
symptoms of serum sickness and serum sickness-like reactions are declared within a range of
7-10 days after primary exposure and 2-4 days after secondary exposure, that is rechallenge46.
A recently published case series on serum sickness-like reaction associated with influenza
vaccination found the median TTO of the adverse events to be 9 days, with a range of 7-14
days 47. This is consistent with previous estimates and will be used as a measure of this
particular TTO.
7.5 Stevens-Johnson syndrome and toxic epidermal necrolysis
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but severe
mucocutaneous ADRs, with widespread epidermal necrosis and keratinocyte apoptosis
resulting in epidermis detachment 48 49. While there are no generally accepted criteria for
distinction between SJS and TEN, they represent the two ends of a severity spectrum for what
is widely, but not universally, considered to be a single disease 48. Mounting evidence
suggests that SJS and TEN have common causes and mechanisms 50 and that the principal
difference lies in the extent of detached and detachable epidermis. SJS is classified as a loss of
epidermis affecting less than 10% of the total body surface area, whereas the classification
13. 13
TEN requires involvement of 30% or more. The overlap of these two conditions cover
epidermal detachment between 10-30% 48.
The assessment of TTO for these ADRs has typically been based on case reports from
hospitalized patients, where the time course between drug intake and appearance of the
adverse reaction is stated. Literature findings from case reports generally state the TTO for
SJS and TEN as 1-15 days, with recurrence within 48 hours of rechallenge, that is
reintroduction of drug therapy 51 52.
In the first case-control study to assess the risks of SJS and TEN related to medications it was
found that the first weeks of treatment had the highest risks for developing SJS or TEN.
Although specific measures were not given, the high risks of drug groups such as
anticonvulsants, oxicam-NSAIDs and corticosteroids as well as allopurinol were associated
with recently initiated therapy (≤2 months duration) 53. In a second and multinational case-
control study the time relationship between SJS/TEN and initiation of the responsible
medication was evaluated more specifically. The study stated that SJS and TEN most often
begin more than 4 and up to 28 days after the initial use of drugs classified as highly
suspected to cause SJS and TEN. Among these drugs nevipramine, lamotrigine,
carbamazepine, phenytoin, phenobarbital, sulfasalazine, allopurinol, oxicam-NSAIDs,
cotrimoxazole and other anti-infective sulfonamides were included. The above stated TTO
was suggested after correction for confounding by indication. The authors recognized the high
potential of confounding time to onset of SJS/TEN by using fever or pain as marker of the
initiation day, in the absence of more specific signs 54.
14. 14
8 Methods
8.1 Data extractionand criteria
This descriptive study covers data up to August 28, 2009, extracted from VigiBase via the
VigiSearch tool version 1. The information in VigiBase originates from multiple sources and
the likelihood that a medicine caused the ADR may vary from case to case.
All reports containing the defined terms (see the next section) were extracted from the
database after considering the exclusion criteria in Table 1. As a first criterion, all reports
containing incomplete dates for TTO were excluded. To avoid the complexity of multiple
drug use in this study, we focused exclusively on reports with a single drug suspected to cause
the ADR(s). Furthermore, reports with negative TTOs or TTOs exceeding the patients age
were excluded, as well as reports with non-classified drug names. The last exclusion criterion
concerned suspected approximated dates to avoid uncertain TTOs. Approximated dates
originate from certain national centers where incomplete dates are automatically denoted to
the first day of the month or the first day of the year. All reports containing such dates
(day=01 or month and day=0101) were excluded from the analysis.
Table 1. Exclusion criteria for reports
Exclusion criteria
Incomplete dates for TTO, e.g. missing day and/or month
for start of drug treatment or onset of ADR
Multiple suspected drugs
Negative TTO or TTO>age
Missing drug name
Dates suspected to have been approximated
8.2 Selectionof adverse drug reactions and terminology
The study is limited to the review of six selected ADRs, primarily of type B (patient
reactions): agranulocytosis, angioedema, hepatitis, serum sickness, Stevens-Johnson
syndrome and toxic epidermal necrolysis. Classical type A ADRs (drug actions) were
15. 15
avoided, as they are known to be dose dependent 55 and therefore may be more directly related
to changes in drug dosages during treatment.
The ADRs were studied encoded by terms from the Medical Dictionary for Regulatory
Activities (MedDRA) 2. It is built up by five levels of hierarchy, out of which the self-
descriptive preferred terms (PTs) are used to define each of the six ADRs studied. The PTs
contain a range of Lowest Level Terms (LLTs), reflecting the same medical concept as the
corresponding PT, expressed by synonyms and lexical variants 56. After a review of all LLTs
for the respective six PTs in MedDRA, LLTs indicating that the ADR had been aggravated
(e.g. angioedema aggravated) or were too specific/unspecific, were excluded. Such LLTs
were found for the PTs angioedema and hepatitis. The studied PTs and their LLTs are listed in
appendix Table VII, where all excluded LLTs are denoted.
8.3 Definitionof time to onset
In this study, time to onset is defined as the time span between the reported start of drug
therapy and reported onset of the ADR. Considering the nature of data being used, time to
onset can be given as time to first symptom of the ADR, or time to diagnosis (the time span
from start of drug therapy to diagnosis of the ADR). It is plausible to assume that there may
occur some variability among spontaneous reports regarding what they actually refer to, as
either of the two above definitions may be in use.
8.4 Source of reference for time to onset
A summary of the TTOs further used in this study and their references based on the
background literature search is available in Table 2. These will be referred to as referenced
TTOs throughout this paper, in contrast to the reported TTOs obtained in this study. The
choice of which references to use is based on the type of study and year of publication. Case-
control or prospective studies are selected above literature reviews or case reports, while
recently published studies are preferred above older ones.
Table 2. Referenced time to onsets
Adverse drug reaction Time to onset Study type Reference
Agranulocytosis 1-2 months Case reports review Andersohn et al. 2007
Angioedema
Allergic 1-2 hours Literature review Greaves and Lawlor 1991
16. 16
Pseudoallergic
Bradykinin-mediated
<1 hour
1 week
Literature review
ADR reports
Kaplan and Greaves 2005
Hedner et al. 1992
Hepatitis
Predictable
Unpredictable
1-2 days
42 days
Literature review
Prospectivestudy
Chun et al.2009
Chalasani et al. 2008
Serum sickness 7-10 days
9 days
Handbook
Case series
Harrison’s Principles 2008
Apisarnthanarak et al. 2009
Stevens-Johnson syndrome
Toxic epidermal necrolysis
4-28 days
4-28 days
Case-control
Case-control
Mockenhaupt et al. 2008
Mockenhaupt et al. 2008
8.5 Sensitivityanalysis
As the suspected estimated TTOs were excluded from the study a sensitivity analysis was
performed to investigate the impact of the excluded data on the resulting TTO. To enable the
sensitivity analysis a dataset was extracted in an extended version, essentially including all
reports with any information on date of start for drug treatment and date of onset of ADR,
including incomplete dates, for the studied MedDRA terms. The criteria of a single suspected
drug, no negative TTOs or TTOs higher than age and no missing drug names were applied
also to this dataset. Incomplete dates only containing year were estimated to 0701, while dates
missing day were appointed to the 15th. As VigiBase is known to contain estimated dates
assigned to the first of the year, as well as the first of the month, all dates with 0101 were set
to 0701 and dates with day 01 were set to 15. The adjustment of incomplete and estimated
dates to mid-year and mid-month was made to minimize the systematic error caused by these
dates.
8.6 Statistical analysis withR
The statistical analyses were performed using R, an advanced computing system originating
from the R project started by Ross Ihaka and Robert Gentlemen at the University of
Auckland. R is “an integrated suite of software facilities for data manipulation, calculation
and graphical display” according to official sources 57. It provides a wide variety of statistical
and graphical techniques, designed around a coded computer language.
In this study, R was systematically used to program graphs for density plots and box plots,
using the functions “densityplot” and “boxplot”. The density plots were based on the 90th
percentile of data, as it contained extreme outliers disturbing the analysis. The default setting
17. 17
of R was used for defining outliers in the box plots, applying the conventionally accepted
definition Q3+1,5 (Q3-Q1) for the upper limit of outliers. Q1 denotes the first quartile (25%)
of data and Q3 the third (75%).
Data was analyzed regarding ADR at PT level, gender, age and the ten most reported
suspected ATC groups for each ADR. For the age analysis, data was divided into four
categories: <2 years, 2-17 years, 18-64 years and ≥65. The top ten reported ATC groups for
each PT were selected by listing the number of unique reports for the respective ATC group.
The third level of the ATC hierarchy was used, in which the included substances are
appointed pharmacological subgroups. Each substance can belong to one single or multiple
pharmacological subgroups.
9 Results
9.1 Report demographics
When applying the exclusion criteria in Table 2, 45,561 reports were selected for the study.
The number of reports for each studied ADR is presented in Table 3 by gender and age
groups. The total number of unique reports is smaller than the sum of reports for each ADR,
due to 320 reports containing multiple ADRs. Reports lacking information on gender or age
were consequently not included in the gender and age analyses, respectively.
Table 3. Number of reports for each studied ADR
ADR term Total
ADR
Female Male Gender
missing
<2
yrs
2-17
yrs
18-64
yrs
>65
yrs
Age
missing
Agranulocytosis 5484 2942 2475 67 46 182 3325 1757 174
Angioedema 20930 12753 7840 337 321 2097 13142 4199 1171
Hepatitis 8961 4948 3891 122 56 436 5670 2442 357
Serum sickness 1908 1010 854 44 206 650 831 101 120
SJS 6531 3474 2979 78 97 923 3962 1234 315
TEN 2067 1170 867 30 27 202 1115 627 96
Total (unique
reports)
45561 26111 18778 672 744 4464 27839 10302 2212
18. 18
Data for each PT is displayed in density plots, giving an overview of the distribution of
reports with TTO in number of days. The data is also presented in box plots, demonstrating
the differences in TTO regarding type of ADR, gender, age and top 10 reported ATC groups.
In the upcoming sections, the results will first be presented with an overview of all ADRs.
The ATC groups and age analyses for each ADR are presented together to facilitate visual
comparisons between the box plots.
9.2 Time to onset by adverse drug reaction
The density plots below (Figure 1) denote the distribution of TTO for each ADR of interest,
where the peaks represent TTOs with the highest number of reports. As the data is heavily
skewed with some very high TTOs disturbing visualization, data points beyond the 90th
percentile for the respective ADR are omitted. The TTO data for agranulocytosis is
concentrated to the 80 first days of treatment, with a bimodal pattern within the first month.
Angioedema has an immediate maximum density on the same day as the prescription rapidly
declining during the first five days. Hepatitis reaches its maximum density on the fifth day
followed by a steady decline until day 50, beyond which point there are very few
observations. Serum sickness displays a bimodal pattern with peaks at 1 and 7 days, the latter
having a notably higher estimated density. Stevens-Johnson syndrome and toxic epidermal
necrolysis follow similar patterns with regards to shape and range of TTO data distribution:
an early peak in estimated density is found within the first three days, followed by a tendency
of bimodality after ten
days.
19. 19
Figure 1. Density plots on TTO data distribution for each studied ADR.
A common box plot on TTO for the six studied ADRs is presented in Figure 2. TTO data for
agranulocytosis is the most widespread among the ADRs studied, resulting in a wide range of
observations within the limit of the whiskers. The observed median TTO is 35 days, with the
first quartile at 16 and the third quartile at 59 days. The abrupt onset and consistent pattern of
angioedema is demonstrated by the first quartile at 0 days and median at 1. Similar to
agranulocytosis, also hepatitis presents a wide range of TTO observations. The median is 19
days, while Q1 and Q3 are found at 6 and 49 days respectively. Serum sickness has the
smallest proportion of data in this study (visualized by the small width of the box), with a
median TTO at 8 days. The similarities between TTO data for SJS and TEN are evident also
in this graph, with the main difference being the larger width of the SJS box, indicating a
higher number of reports for this ADR. Median TTO is 8 days for SJS and 7 for TEN, while
the first and third quartiles are equal for both boxes at 2 and 17 days, respectively.
20. 20
Figure 2. Box plots of each adverse drug reaction
9.3 Time to onset by ATC group and age
Median TTO for the top ten ATC groups reported for agranulocytosis (Figure 3) range from 7
days for pyrazolones (N02BB) to 66 days for diazepines, oxazepines and thiazepines
(N05AH). The latter ATC group accounts for 25% of all reports on agranulocytosis and
mainly contains clozapine data (99%). The markedly large proportion of data in N05AH
among the studied ATC groups is visualized by the width of the box. This group displays a
notably wide range of late TTOs and has the highest observed median. The low median TTO
of the pyrazolones (N02BB) is followed by sulfonamides and trimethoprim (J01EE) at 12
days. Both these groups present a deviating short median TTO compared to the remaining
studied ATC groups. As to the age analysis, median TTO differs between each age group
(Figure 4). To relate the observed difference in median TTO to the drugs used, the most
prevalent drugs in each age group were investigated. Within the age category 18-64, 37% of
the data was found to be based on clozapine. The corresponding percentage clozapine data in
the age group ≥65 was markedly lower, only 7%. Children <2 years were noted to have a low
median TTO at 11.5 days. 26 of 46 reports in this age category were on antibiotics, 10 of
which belonging to J01EE. This explains most of the observed difference for this age group.
21. 21
Figure 3. TTO by top ten reported ATC groups for agranulocytosis
Figure 4. TTO by age groups for agranulocytosis
The majority of the studied ATC groups for angioedema have a median TTO of 0 days and
third quartile at 1 day (Figure 5). Among these groups, ibuprofen is found to dominate the
ATC groups C01EB, D10AX, G02CC and M01AE (one substance can belong to multiple
ATC groups). ACEI-induced angioedema has a distinctly different pattern of TTO, with
median at 7 days and third quartile at 43 days followed by a range of widespread
observations. Among the age group ≥65 years (Figure 6), there is a higher proportion of
reports with ACEI (C09AA) than in the other age groups, which can explain the higher TTO.
22. 22
Figure 5. TTO by top ten reported ATC groups for angioedema
Figure 6. TTO by age groups for angioedema
Among the top ten ATC groups reported for hepatitis the highest median TTO of 55 days is
found for C10AA; the hydroxy-methylglutaryl-coenzyme A reductase (HMG CoA reductase)
inhibitors, commonly referred to as statins. The remaining nine ATC groups have markedly
lower medians, ranging from 5-21 days (Figure 7). Median TTO of 21 days belongs to the
acetic acid derivatives and related substances (M01AB), followed by non steroidal anti-
inflammatory drugs (NSAIDs) for topical use (M02AA) at 17 days. Note that M02AA will
23. 23
include all NSAID drugs that have at least one topical indication. Thus, it will also contain
several commonly used NSAIDs which may have been given through other routes of
administration, e.g. diclofenac, ibuprofen, naproxen and indometacin. A median TTO of 15
days is noted for N06AA, the non-selective monoamine reuptake inhibitors. The lowest
median TTO at 5 days is observed for the halogenated hydrocarbons (N01AB), a group
mainly based on halothane data (284/352 observations). Mutual erythromycin is found to be
the main basis for the ATC groups D06AX (other antibiotics for topical use), D10AF
(antiinfectives for treatment of acne) and S01AA (antibiotics). Acetaminophen (paracetamol)
accounts for 86 reports among the 8961 studied for hepatitis. Median TTO for the age
categories is stepwise increased with higher age (Figure 8).
Figure 7. TTO by top ten reported ATC groups for hepatitis
24. 24
Figure 8. TTO by age groups for hepatitis
The majority of the median TTOs for the top ten reported ATC groups of serum sickness are
found within the range of 7-10 days (Figure 9). Tetanus vaccines (J07AM) stand out with a
short median TTO of 2 days followed by hepatitis vaccines at 4 days. High median TTOs are
observed for the group of other antidepressants (N06AX) and drugs used in nicotine
dependence (N07BA), both mainly based on mutual bupropion data. Second-generation
cephalosporins (J01DC) account for a large proportion of data, compared to the other ATC
groups studied. No distinct differences in median TTO is noted depending on age, although
TTO observations for age categories 18-64 and ≥65 years have wider ranges compared to for
children<18 years (Figure 10).
25. 25
Figure 9. TTO by top ten reported ATC groups for serum sickness
Figure 10. TTO by age groups for serum sickness
There are two clusters of median TTOs for SJS among the studied ATC groups (Figure 11).
One cluster contains ATC groups with antibiotics and NSAIDs (J01CA, J01EE, M02AA,
S01AA and S01BC), presenting median TTOs at 4 days or less. J01EE is the ATC group
containing the largest proportion of data, mainly based on sulfamethoxazole/trimethoprim.
The remaining five ATC groups are subgroups of anticonvulsants (N03AB, N03AF and
N03AX), non-nucleoside reverse transcriptase inhibitors (J05AG) and preparations inhibiting
26. 26
uric acid production (M04AA). These groups all have median TTOs above 10 days. Median
TTOs for the age categories are overall similar with the exception of ages<2 years, which
have a notably shorter latency (Figure 12). The four dominating ATC groups of this age
category (J01CA, J01CE, J01EE and N03AA) were further investigated by comparing the
TTO they each induce in all studied age categories. No major variations were found in the age
distribution of these ATC groups, but the trend of low TTOs for ages <2 were noted (results
not presented).
Figure 11. TTO by top ten reported ATC groups for Stevens-Johnson syndrome
27. 27
Figure 12. TTO by age groups for Stevens-Johnson syndrome
The top ten most prevalent ATC groups repeated with toxic epidermal necrolysis match well
to those observed for SJS (Figure 13). The only two groups differing from those of SJS are
J01MA and S01AX, both based on data from ciprofloxacin, norfloxacin and levofloxacin,
which are all included in these ATC groups. Again, two clusters of TTOs are formed where
the preparations inhibiting uric acid production (M04AA) and anticonvulsants (N03AB,
N03AF and N03AX) have median TTOs above 10 days. The remaining ATC groups’ median
TTOs are found at six days or less. Piroxicam, diclofenac and indometacin are found to be the
dominating drugs of M02AA and S01BC. J01EE is still the most common ATC group. The
latter group is mainly based on sulfamethoxazole/trimethoprim, just as previously observed
for SJS. No distinct differences are found for median TTO among the age categories (Figure
14).
28. 28
Figure 13. TTO by top ten reported ATC groups for toxic epidermal necrolysis
Figure 14. TTO by age groups for toxic epidermal necrolysis
9.4 TTO by gender categories
The gender comparisons did not display any major differences in TTO among men versus
women, wherefore the results are not included here but can be found in the Appendix, Figure
I-VI.
29. 29
9.5 Sensitivityanalysis
In this sub-study, TTOs based on explicitly incomplete dates as well as dates suspected to
have been approximated to the first of the month or the first of the year were included. The
concern was that incomplete dates would be more common in association with long TTOs, so
that their exclusion from the analysis would lead to a bias in the direction of shorter TTO. The
ADRs were analyzed regarding the reported TTOs and resulted in an overall similar outcome
to what was found only using the complete dates. The median TTOs for angioedema and
serum sickness were unchanged while median TTOs for SJS and TEN increased with one and
two days, respectively. Agranulocytosis showed an increase of median TTO from 35 to 39
days. The largest impact was made on the median TTO of hepatitis, which increased with 9
days from 19 to 28.
10 Discussion
The reported TTOs for the majority of the studied ADRs correspond well to the literature
findings previously referred to in this paper. More strikingly, variations in TTO for the same
ADR among different ATC groups are also reflected in VigiBase.
All median TTOs reported are within the expected range of days, with the one exception of
hepatitis which has a notably shorter latency than the reference TTO. In the prospective study
by Chalasani and colleagues the median TTO was 42 days 36, while the median reported TTO
for hepatitis is observed to be 19 days in this study. Other references in the literature have
stated drug- induced liver injury to occur 1-8 weeks after the initiation of drug therapy 38,
which provides a TTO range including the reported median of 19 days.
Bearing in mind the nature of spontaneous reports, it is more likely for events with short
latency to be detected and reported as suspected ADRs as they are easier to relate to the drug
treatment 60. This trend is reflected in the medians obtained. All observed median TTOs at
ADR level are within the expected range, but found in the earlier time frame. Hepatitis, being
the one ADR deviating from the expected TTO, also presents with a shortened latency in this
study. This observation could not be explained by the occurrence of acetaminophen in the
dataset, as the reports on this substance accounted for less than 1% of the studied hepatitis
data. A related issue is that coincidental adverse events are more likely to be reported as
suspected ADRs if they correspond to the expected time to onset for that reaction – this may
lead to a confirmation bias.
30. 30
However, when reviewing the TTOs of specific ATC groups, there are examples of a longer
reported TTO than that in the literature. Clozapine-induced agranulocytosis is one such
example in this study, where the reported TTO is longer than the literature reference. In a
systematic review of case reports, Andersohn and colleagues found the median TTO of
clozapine-induced agranulocytosis at 56 days 18. Comparing the reported median of 66 days
for the ATC group diazepines, oxazepines and thiazepines (N05AH) where clozapine is the
dominant drug, the reference suggests ten days shorter latency. Hence, clozapine-induced
agranulocytosis was found with a slightly longer latency in this study than the reference based
on the same drug.
There are several other circumstances of importance affecting the reported TTOs in this study.
Special monitoring of drugs is one such factor contributing to the reporting patterns, where
clozapine and agranulocytosis again provide a good example. Continuous white blood cell
counts are routinely monitored during the entire clozapine treatment, due to the strong
association of agranulocytosis to this particular drug21. The continuous monitoring of drug
therapies can evidently enable the detection of late-onset ADRs, otherwise unlikely to be
reported as such. In the literature, there are documented cases of late-onset clozapine-induced
agranulocytosis detected after 11 years of therapy with continuous monitoring 59. In the
absence of other medicines intensively monitored for this ADR, it is difficult to discern to
what extent clozapine really does have a different time to onset than other drugs. Intensive
monitoring of hospitalized patients may on the other hand lead to an earlier detection of
diagnoses where observed symptoms normally would be presented at a later stage in the
disease process. The intensive monitoring provides a group of hospitalized patients where
asymptomatic ADRs, such as e.g. hepatitis, may be detected and reported in an early stage.
When analyzing the top reported ATC groups, it seemed as the duration of drug treatment had
a considerable impact on the reported TTO. Hepatitis provides a good example, where all
median reported TTOs below or equal to ten days are based on the antibiotic erythromycin,
the general anesthetic halothane or combinations of penicillins. These drugs share the
common feature of short term treatments, compared to the long term or chronic treatments
expected with the statins, which account for the longest median TTOs observed. Late-onset
ADRs require long term treatments for providing a sustained time span between drug start and
the event of ADR. However, the correlation between length of treatment and TTO is not
consistent. The antidepressive non-selective monoamine reuptake inhibitors causative of
31. 31
hepatitis have a relatively short median TTO of 15 days, although long term treatment of the
indication is expected. The overall observation for the studied data is that the duration of
treatment needs to be considered when analyzing TTO.
The substances represented within each ATC group need to be considered when interpreting
the TTO box plots, as each substance can be represented in several ATC groups. The ATC
group of topical NSAIDs (M02AA) is recurrent among the top ten reported groups for all
studied ADRs except serum sickness. M02AA groups a variety of NSAIDs such as
diclofenac, ibuprofen and piroxicam. These substances belong to different ATC subgroups of
systemic NSAIDs, forming a large group when accumulated in the topical category M02AA.
The dominating drugs in different age groups may also determine the overall TTO pattern.
Children <2 years reported with agranulocytosis are one such example, where half of the
reports for this age group are on antibiotics and analgetics/antipyretics with short median
TTOs in the ATC analysis. The short reported median TTO for antibiotics in the ATC group
J01EE does not correspond with the median TTO of other referenced antibiotics. Andersohn
and colleagues found the median TTO in a variety of antibiotics to range between 22-25 days
18, compared to 12 days in this current study. The differences in TTO may be due to the
specific drugs being studied or the drug exposure itself, as in immune-mediated drug-induced
agranulocytosis where the occurrence of antibodies is dependent on a prior exposure to the
drug. Repeated and intermittent exposure to certain drugs, such as β-lactam penicillins, is
suggested to cause rapid granulocyte destruction mediated by preexisting antibodies. In the
presence of the drug, antibodies may bind to the target cells and recruit complement. Other
non-immune mediated mechanisms involve direct damage to the bone marrow
microenvironment, resulting in agranulocytosis after prolonged exposure 20. The data used in
this study does not contain any information regarding first or second exposure to the
suspected drugs, why the role of drug exposure can not be determined.
In the literature, distinction between immune mediated and non-immune mediated reactions
have also been made for drug induced angioedema and hepatitis, where the immunological
reactions present with shorter latency 24 35 60. For angioedema, immunologic reactions are
reliant on a pre-sensitizing exposure and antibody formation 24. However, allergic hepatitis
may be induced by multiple mechanisms and is not dependent of secondary exposure to the
same extent 60. Halothane, erythromycin and the dominating penicillin amoxicillin-clavulanic
acid all have been suggested to cause immune mediated liver injury 37, which may be
32. 32
reflected in the short reported TTOs observed for hepatitis. As for the statins and diclofenac,
both immune mediated and non-immune mediated mechanisms of induction have been
suggested to induce hepatotoxicity 34 61 62. These drugs present the highest reported median
TTOs for hepatitis in this study. The ATC groups of angioedema reveal another example,
where the deviating long TTO induced by ACE-inhibitors is non-immune mediated 23.
Median TTO at one week followed by a wide range of later observations correspond well to
the literature 30-33.
The study design only including complete dates is expected to result in shortened TTOs for
the ADRs studied, since reports with longer time spans are more likely to have estimated or
incomplete dates. However, the sensitivity analysis shows that the bias of estimated and
incomplete dates is small. The increase of median TTO with 9 days for hepatitis may be a
result of the relatively large proportion of data added when including estimated and
incomplete dates for this ADR. Data for hepatitis increased with 30%, which accounts for the
highest gain of reports after inclusion of suspected estimated date reports among the studied
ADRs. This may be an indication of data quality problems for the preferred term, due to a
large amount of reports with long TTOs being estimated.
Using literature findings as a reference for TTO requires a set of considerations to be made.
Two aspects of importance are the diagnosis of the ADR and the studied drugs on which TTO
is based. The observed deviating TTO of hepatitis may be due to the diagnosis used in the
comparing reference, which includes a wide range of drug induced liver injuries 36. Hepatitis
itself is a broad term, providing basis for caution when being analyzed as one homogenous
ADR. For SJS and TEN, the distinction of diagnosis is mainly based on the percentage of
affected body surface area 48. As these two terms represent different severity levels of the
same disease, there is reason to assume a certain overlap in the diagnosing and reporting of
SJS and TEN. The review of TTO for these terms can trigger doubt as to the true causality of
some reported cases. When Mockenhaupt and colleagues excluded cases with onset of SJS
and TEN before four days of drug exposure, their previously observed association between
analgesics/antipyretics and the ADR disappeared. They suggest that SJS and TEN most
commonly start after at least four days of drug treatment and that this time span should be
considered when assessing individual cases for causality 54. Curiously, the ATC groups with
median TTOs of 4.5 days or less for SJS and TEN in this study are either antibiotics or
NSAIDs. Both these drug groups may be used in infections, suggesting that they may be
33. 33
confounded by indication and/or the underlying disease. Infections or a combination of
infections and drugs have been implicated as causative of SJS and TEN 63. The basis for using
4 days as a cut-off for causality in Mockenhaupts study is not clearly outlined in the paper 54.
Case reports and previous case-control studies have stated TTO for SJS and TEN to range
from 1-15 days and up to two months 52 53.
Age was not found to influence the outcome of TTO in the majority of cases. However, young
age (<2 years old) was noted to present a short TTO for the studied ADRs. When further
investigating the drugs reported for age groups <2 years, they mainly originated from ATC
groups having an overall shorter TTO. However, for SJS the shorter TTO of the youngest was
not fully explained by the drugs used. The major drugs for the age category <2 years with SJS
were phenobarbital, sulfamethoxazole/trimethoprim, amoxicillin and
phenoxymethylpenicillin. Accordingly, anticonvulsants, sulfonamides and penicillins are
suspected causative agents for 90% of SJS cases in children 64. All these drugs were also
found among the top prevalent drugs used by the age category 2-17, whereas the median TTO
is six days later than for the younger group. In this case, the observed difference in median
TTO is indicated to depend on age rather than the type of drug and needs further
investigation.
There are several limitations to this study. The ATC analyses reveal that the reported TTOs
can differ markedly among the reported drug groups of an ADR. The influence of specific
drugs on the displayed TTO for each ATC group has only been partially explored in this
study, why further investigations of TTO on substance level are needed. Furthermore, the
reporting of TTO at day 0 needs to be questioned for all the studied ADRs, although the
impact on angioedema might have been limited as allergic reactions are expected to occur
within hours. The assignment of ADR onset to the same day as drug start may represent
missing information. However, 84% of the 11193 reports with TTO at 0 days are found for
angioedema. Moreover, as this study only included a few ADR terms and excluded reports
containing multiple suspected drugs, further investigations are needed before these results can
be generalized.
11 Conclusion
This study shows that TTOs reported to VigiBase for the included ADRs correspond well to
the literature. For specific ADRs, interesting differences between ATC groups were identified
34. 34
in the reported TTO. Only slight variations were found across the gender and age groups,
when the ATC groups were accounted for. The study suggests that spontaneous reports can be
used as a source of information on TTO. However, further investigations are needed before
TTO information in this type of data can be generated for large scale use.
12 Acknowledgments
Thanks to Tomas Bergvall for helping me with data extractions, Ola Caster for patient
guidance on R software, Ralph Edwards, Richard Hill and Ronald Meyboom for expert
clinical advice, Niklas Norén for input on study design and Staffan Hägg for great supervision
of the project. Finally, a special thanks to Kristina Star for extensive support, guidance and
mentorship in every step of the way.
The information used in this study does not represent the opinion of the World Health
Organisation.
35. 35
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Appendix
Table I. Literature findings on time to onset for agranulocytosis.
Time to onset Study type Reference
7 days Consensus meeting Benichou and Solal Celigny 1991
1-2 months Case reports Andersohn et al. 2007
Table II. Literature findings on time to onset for angioedema.
Time to onset Study type Reference
1-2 hours* Literature review Greaves and Lawlor 1991
<1 hour** Literature review Kaplan and Greaves 2005
1 week*** ADR reports Slater et al. 1988; Hedner et al. 1992
*Allergic, **Pseudoallergic, ***Bradykinin mediated
Table III. Literature findings on time to onset for hepatitis.
Time to onset Study type Reference
1-2 days* Literature review Chun et al. 2009
1-8 weeks** Literature review Abboud and Kaplowitz 2007
<1 year*** Literature review Abboud and Kaplowitz 2007
42 days Prospectiveobservational Chalasani et al. 2008
*Predictable, **Immune mediated, ***Idiosyncratic
Table IV. Literature findings on time to onset for serum sickness.
Time to onset Study type Reference
1-3 weeks Literature review Valeyrie-Allanore et al. 2007
7-10 days Book Harrison’s Principle of internal medicine
9 days Case reports Apisarnthanarak et al. 2009
39. 39
Table V. Literature findings on time to onset for SJS and TEN.
Time to onset Study type Reference
1-15 days Case reports Revuz et al. 1987; Teo et al. 2009
≤2 months Case-control Roujeau et al. 1995
4-28 days Case-control Mockenhaupt et al. 2008
Table VI. The studied MedDRA PTs and their respective LLTs. * denotes LLTs for which no reports
matched the inclusion criteria of the study. ** denotes LLTs that were removed from the PT.
PT LLTs
Agranulocytosis Agranulocytosis
Angina agranulocytic
Acute agranulocytosis
Neutropeniamalignant*
Angioedema Acute angio oedema
Acute angio edema
Angio-edema
Angioedema
Angioneurotic edema
Angioneurotic oedema
Edema angioneurotic
Edema Quincke's
Giant hives
Giant urticaria
Quincke's edema
Quincke's oedema
Urticaria giant
Allergic angioedema
Oedema angioneurotic
Oedema Quincke's
