Clarification of Terminology in Drug Safety.3
Clarification of Terminology in Drug Safety.3
Clarification of Terminology in Drug Safety.3
0114-5916/05/0010-0851/$34.95/0
LEADING ARTICLE
Clarification of Terminology in
Drug Safety
Jeffrey K. Aronson1 and Robin E. Ferner2
1
2
Abstract
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A pharmaceutical formulation, also called a dosage form, is the form in which a medicinal product
is presented, for example as a tablet, capsule, elixir,
solution for injection, transdermal formulation,
cream, or ointment. The commonly used term,
preparation, is ambiguous, since it can refer to the
pure substance itself (for example, as prepared from
a plant) as well as the formulation.
When formulations are classified according to
the time over which the active substance is made
available to the body, two broad categories can be
distinguished: immediate-release formulations and
modified-release formulations. Other terms that are
subsumed by the term modified-release include
sustained-release, slow-release, long-release, controlled-release, timed-release, prolonged-release,
and delayed-release.
2005 Adis Data Information BV. All rights reserved.
853
1.3 Excipient
854
3. ADRs (from
medication
errors)
4. Medication errors
that cause harms
that are not ADRs
5. Medication errors
that dont cause
adverse events
3 + 4 + 5 = all medication errors
Fig. 1. A Venn diagram showing the relation between adverse
events, adverse drug reactions, and medication errors; adverse
drug events, as defined by Bates et al.,[6] would encompass areas
2 + 3 + 4. ADRs = adverse drug reactions.
The WHOs definition of an adverse drug reaction is a response to a drug that is noxious and
unintended and occurs at doses normally used in
man for the prophylaxis, diagnosis or therapy of
disease, or for modification of physiological function.[8]
This definition has been widely accepted but has
defects. One obvious defect is that adverse effects
can occur at doses other than those that are used in
the way that the definition describes, for example
after a test dose. Furthermore, the use of the word
noxious excludes adverse effects that may be inconvenient but not harmful.
Laurence[9] has suggested the following definition that specifically excludes minor unwanted reactions (for example, a slight dryness of the mouth),
effects that he says should not be dignified with the
designation adverse effect: a harmful or signifiDrug Safety 2005; 28 (10)
855
856
Table I. The history of classifications of adverse drug reactions based on dose relatedness and time course
Author(s), date
Wayne,[14] 1958
reactions
reactions
Hoigne et al.,[20] 1990
Aronson,[24] 2002
857
858
859
Response
Toxic
Collateral
Hypersusceptibility
Log dose
Fig. 2. A schematic representation of a log concentration-response
or dose-response curve that shows the concentrations or doses at
which toxic, collateral, and hypersusceptibility reactions occur.
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Table II. The dose, time, and susceptibility (DoTS) classification of adverse drug reactions (ADRs)[22]
ADR characteristic
Examples
Implications
Collateral reactions
Occur at standard therapeutic
concentrations
Hypersusceptibility reactions
Occur at subtherapeutic concentrations Penicillin allergy
in susceptible patients
Avoid
B. Time-related effects
Type of reaction
Time independent
Due to a change in dose or
concentration (pharmaceutical effects)
Administer slowly
Time dependent
Rapid (due to rapid administration)
Hypertension (digitalis)
Hypotension (iodipamide)
First dose (of a course)
Hypotension (1 adrenoceptor
antagonists and ACE inhibitors)
Careful history taking; if a reaction occurs, avoid reexposure; counsel the patient
Venous thromboembolism
(antipsychotic drugs)
Osteoporosis (corticosteroids)
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Examples
Implications
Retinopathy (chloroquine)
Tissue phospholipid deposition
(amiodarone)
Delayed
Carcinogenesis (ciclosporin,
diethylstilbestrol)
Teratogenesis (thalidomide)
C. Susceptibility factors
Source of susceptibility
Genetic
Porphyria
Neonates (chloramphenicol)
Alcohol intoxication
Phenytoin in pregnancy
Exogenous factors
Drug interactions
862
Late reactions (including withdrawal reactions): Late reactions occur rarely or not at all at
first, but the risk increases with continued or repeated exposure. They are typically collateral effects.
Examples include many of the adverse effects of
glucocorticoids and tardive dyskinesia with
dopamine receptor antagonists. Withdrawal reactions are late reactions that occur when, after prolonged treatment, a drug is withdrawn or its effective dose is reduced. They include opiate and
benzodiazepine withdrawal syndromes, hypertension after withdrawal of clonidine or methyldopa,
and acute myocardial infarction after -adrenoceptor antagonist (-blocker) withdrawal.
Delayed reactions: Delayed reactions are observed some time after exposure, even if the drug is
withdrawn before the reaction appears. They are
typically collateral reactions. Examples are carcinogenesis (e.g. vaginal adenocarcinoma in women
whose mothers took diethylstilbestrol during pregnancy) and teratogenesis (e.g. phocomelia due to
thalidomide).
3.4 Susceptibility to Adverse Drug Reactions
3.4.1 Idiosyncrasy
3.4.2 Intolerance
also sometimes confusingly equated with hypersensitivity. We believe that the term intolerance has
no useful place in descriptions of adverse reactions
to medicinal products, although it may have a role in
describing adverse reactions to foods.[45]
3.4.3 Hypersensitivity
863
864
Table III. A proposed classification of the intensity of an adverse drug reaction, based on the need to change the dosage regimen of the
offending drug and the treatability of the reaction
Grade
A. No treatment required
B. Relieved or partly relieved by treatment
C. Not relieved by treatment
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Probable: 77 (12).
Possible: 43 (21).
In the same study highly variable percentages
were also assigned to different degrees of probability.
High probability: 87 (7).
Moderate probability: 61 (15).
Low probability: 17 (20).
Furthermore, in other studies widely different
percentages (standard deviations) were assigned to
the same words.[60] For example, the term possible
was assigned a chance of 43% (21) in one study[59]
and 27% (17) in another.[60] It is therefore better to
communicate probabilities in percentages (e.g. 5%)
or the corresponding fractions (0.05). The problem
of communicating such information to non-professionals has not been solved, but techniques include
comparisons with other risks (e.g. the annual risk of
dying in a road accident is 1 in 8000, by murder is 1
in 100 000, or by lightning is 1 in 10 000 000),[61]
visual analogues,[62] and other forms of analogy,[63]
such as tossing a coin to illustrate a 50% chance or
considering the relative chances of injuring yourself
by jumping from different storeys in a building.
6.2 Causal Probability of a Drug/Adverse
Effect Association Based on Series of Reports
Table IV. The relation between the frequency of an adverse event in patients taking a drug and the background frequency of the same event
together in determining the ease of proving the possible association
Incidence of an event in
patients taking the drug
Background incidence
of the event
Example
Common
Rare
Rare
Rare
Common
Common
Uncommon
Moderately common
None known
Impossible
Rare
Common
HRT = hormone replacement therapy.
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enough to substantiate a likely association. An example is the attribution of Fanconi syndrome to outdated tetracyclines.[70] At the other end of the spectrum, if a drug is uncommonly associated with an
adverse event that is otherwise common, anecdotal
reports will not be helpful in establishing the association. In such cases large trials or observational
studies are required. Of course, this is a purely
qualitative analysis and it is not clear if a useful
comparable quantitative version could be developed. But if it were, it would have to be based on
actual frequencies of events rather than verbal expressions of such frequencies, which are unreliable
(see section 7).
7. Defining the Frequency of Adverse
Drug Reactions
Risks and frequencies of adverse effects are often
discussed at the same time. However, although the
risk of an adverse effect in a population is the same
as its frequency in that population, the risk in an
individual need not be. It is possible for an individual, because of some susceptibility, to have a high
risk of an adverse effect that has a low frequency in
the population. It is, therefore, best to separate noTable V. Interpretation of words used to indicate frequencies
Word
Interpretation (range of
mean percentages)
References
Invariably/always
91100
59,60,71-74
Almost always
8594
71-74
Normally
7181
59,71,72
Usually
7084
71-73
Common(ly)
5669
71,73,75
64
71
Often
4271
71-74
Frequent(ly)
3672
60,71,73,75
Not infrequently
2435
71,73
Sometimes
1133
59,71,72,74
Occasionally
1721
71-73
On occasion
12
71
Infrequently
1214
73
Seldom
78
73
Rare(ly)
0.59
71-75
Very rare(ly)
0.83
74
Almost never
60
Exceptionally
0.41
74
Never
02
60,71-74
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Table VI. A verbal scale for describing frequencies, with some examples of causes of deaths that have those frequencies (reproduced from
Calman,[76] with permission from BMJ Publishing Group)
Verbal description of frequency
High
>1 : 100
Moderate
1 : 1001 : 1000
Smoking 10 cigarettes/day
Low
1 : 10001 : 10 000
Very low
Leukaemia
Minimal
Polio immunisation
Negligible
Struck by lightning
Table VII. The factors that contribute to an assessment of the benefit-harm balance in drug therapy. A drug that fulfills the criteria in the top
line has a very high benefit-harm balance, while one that fulfills the criteria in the bottom line has a very low benefit-harm balance. Most
drugs lie somewhere between the two extremes
Seriousness of the
Efficacy of the
Adverse reactions
Other drugs
indication
drug
seriousness
frequency
efficacy
safety
Life threatening
High
Trivial
Rare
Poor
Poor
Very high
Trivial
Poor
Serious
Frequent
Good
Good
Very low
Benefit-harm balance
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References
1. Buetow SA, Sibbald B, Cantrill JA, et al. Appropriateness in
health care: application to prescribing. Soc Sci Med 1997; 45:
261-71
2. Aronson JK. What is a clinical trial? Br J Clin Pharmacol 2004;
58: 61-3
3. Directive 2001/20/EC of the European Parliament and of the
Council of 4 April 2001 on the approximation of the laws,
regulations and administrative provisions of the member states
relating to the implementation of good clinical practice in the
conduct of clinical trials on medicinal products for human use.
Off J Eur Commun 2001; L121: 34-44 [online]. Available
from URL: http://www.eortc.be/Services/Doc/clinical-EUdirective-04-April-01.pdf [Accessed 2003 Sep 26]
4. Inman WH. Postmarketing surveillance of adverse drug reactions in general practice. I: search for new methods. BMJ (Clin
Res Ed) 1981; 282: 1131-2. II: Prescription-event monitoring
at the University of Southampton. BMJ (Clin Res Ed) 1981;
282: 1216-7
5. Kramer MS, Leventhal JM, Hutchinson TA, et al. An algorithm
for the operational assessment of adverse drug reactions. I:
Background, description, and instructions for use. JAMA
1979; 242: 623-32
6. Bates DW, Cullen DJ, Laird N, et al. Incidence of adverse drug
events and potential adverse drug events: implications for
prevention. ADE Prevention Study Group. JAMA 1995; 274:
29-34
7. Dunn N. 10-minute consultation: adverse drug event. BMJ
2003; 326: 1018
8. World Health Organization. International drug monitoring: the
role of national centres. Technical Report Series No 498.
Geneva: WHO, 1972
9. Laurence D, editor, Carpenter J, contributor. A dictionary of
pharmacology and allied topics. Amsterdam: Elsevier, 1998
10. Stephens MBD, Talbot JCC, Routledge PA, editors. The detection of new adverse drug reactions. 4th ed. London: Macmillan, 1998: 32-44
11. Ferner RE, Aronson JK. Errors in prescribing, preparing, and
giving medicines: definition, classification, and prevention. In:
Aronson JK, editor. Side effects of drugs. Annual 22. Amsterdam: Elsevier, 1999
12. Edwards IR, Aronson JK. Adverse drug reactions: definitions,
classification, diagnosis, management, surveillance. Lancet
2000; 356: 1255-60
13. Hartigan-Go KY, Wong JQ. Inclusion of therapeutic failures as
adverse drug reactions. In: Aronson JK, editor. Side effects of
drugs. Annual 23. Amsterdam: Elsevier, 2000: xxvii-xxxiii
14. Wayne EJ. Problems of toxicity in clinical medicine. In: Walpole AL, Spinks A, editors. The evaluation of drug toxicity.
London: J & A Churchill Ltd, 1958: 1-11
15. Levine RR. Factors modifying the effects of drugs in individuals. In: Pharmacology: drug actions and reactions. Boston
(MA): Little, Brown and Co, 1973: 261-91
16. Wade OL, Beeley L. Adverse reactions to drugs. 2nd ed.
London: William Heinemann Medical Books Ltd, 1976: Chapter II
17. Rawlins MD, Thompson JW. Pathogenesis of adverse drug
reactions. In: Davies DM, editor. Textbook of adverse drug
reactions. Oxford: Oxford University Press, 1977: 44
18. Rawlins MD, Thompson JW. Pathogenesis of adverse drug
reactions. In: Davies DM, editor. Textbook of adverse drug
reactions. 2nd ed. Oxford: Oxford University Press, 1981: 11
19. Grahame-Smith DG, Aronson JK. The Oxford textbook of
clinical pharmacology and drug therapy. Oxford: Oxford University Press, 1984: 134
20. Hoigne R, Jaeger MD, Wymann R, et al. Time pattern of allergic
reactions to drugs. Agents Actions Suppl 1990; 29: 39-58
869
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Correspondence and offprints: Dr Jeffrey K. Aronson, University Department of Clinical Pharmacology, Radcliffe
Infirmary, Woodstock Road, Oxford, OX2 6HE, UK.
E-mail: jeffrey.aronson@clinpharm.ox.ac.uk