BMJ 2018;363:k4051 doi: 10.1136/bmj.

k4051 (Published 6 November 2018) Page 1 of 9

Practice

BMJ: first published as 10.1136/bmj.k4051 on 6 November 2018

PRACTICE

CLINICAL UPDATES

Adverse drug reactions

Robin E Ferner honorary professor of clinical pharmacology 1, Patricia McGettigan reader in
clinical pharmacology and medical education 2
1West Midlands Centre for Adverse Drug Reactions, City Hospital, Birmingham B18 7QH, UK; 2William Harvey Research Institute, Queen
Mary University of London, London EC1M 6BQ, UK

poisoning, and medication errors. The US Food and Drug

. Downloaded from http://www.bmj.com/ on 6 November 2018 by guest. Protected by copyright.

What you need to know
• Prescribers need to balance the possibility of causing harm against
the probability of benefit
• Some drugs cause characteristic adverse reactions, whereas
others cause non-specific or bizarre effects
• Some adverse drug reactions occur within minutes of
administration, whereas others can present years after treatment
• The dose of the drug, time since starting treatment, and potential
susceptibility of the patient can help determine if adverse drug
reactions enter the differential diagnosis
• Report suspected serious or unusual adverse drug reactions to the
national medicines regulator; you don’t have to be certain in order
to report
No medicine is entirely safe, so the therapeutic benefit needs to
be balanced against the risk of an adverse drug reaction. The
pharmacovigilance environment has changed in the past two
decades, with biological therapies, complex multidrug regimens,
genetic testing, “big data,” and new regulation for drug safety.1 In
this clinical update we describe some principles that guide
prevention, recognition, and response to adverse drug reactions.
Administration (FDA) defines an adverse drug reaction as
any untoward medical occurrence associated with the use of
a drug in humans “for which there is a reasonable possibility
that the drug caused the adverse event.”4
How common are serious adverse
drug reactions?
Well established clinically serious 5 reactions to commonly
prescribed drugs are uncommon: simvastatin probably
causes rhabdomyolysis in one patient in 10 000. 6 However,
adverse drug reactions are underreported in most countries,
making it difficult to assess the burden and take preventive
action. In Europe, the proportion of acute hospital admissions
caused by adverse drug reactions in 17 studies ranged from
0.5% to 12.8%, and the proportion of hospital patients
developing an adverse drug reaction in 10 studies ranged
from 1.7% to 50.9%.7Figure 1 depicts standard nomenclature
in Europe for the likely frequency of adverse reactions.

Sources and selection criteria How are new adverse drug

We searched Medline for “exp drug-related side effects and adverse reactions/”,
which gave 103 893 hits. We limited the search to 2008 onwards; to “exp drug-
related side effects and adverse reactions/classification, diagnosis, diagnostic
imaging, etiology, genetics, prevention, and control”; and to core medical journals,
which gave 1236 titles to look through. We also used the UK Medicines and
Healthcare products Regulatory Agency’s Drug Safety Update, the US Food and
Drug Administration’s MedWatch alerts, the journal Reactions Weekly, Meyler’s
Side Effects of Drugs Annual, and our own reference collections to identify
relevant articles.
What is an adverse drug reaction?
Medicines have unintended side effects, and if any of these is harmful, the
patient has an adverse drug reaction.2 The European Medicines Agency
(EMA) defines an adverse drug reaction as “a response to a medicinal
product which is noxious and unintended.”3 This definition now extends
beyond the licensed use of a drug to include adverse reactions from off-
label use,
reactions uncovered?
Adverse reaction reports
Pre-licensing clinical trials are often too small to uncover
uncommon but important harms. There is sometimes a long
delay before the adverse effects of a drug are known, so
spontaneous reporting schemes and case reports by astute
physicians are important.8 Patients may now report adverse drug
reactions directly to many schemes,9 and the internet has made
reporting faster and easier than in the past.10 Dedicated adverse
drug reaction managers11 and clinical pharmacist champions also
help.12 Spontaneous reports generate “signals”—suspicions of a
link between a drug and a clinical outcome worthy of further
study.13 The EMA’s Eudravigilance database and the World
Health Organization’s Vigibase contain vast numbers of drug

Correspondence to: R E Ferner r.e.ferner@bham.ac.uk

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BMJ 2018;363:k4051 doi: 10.1136/bmj.k4051 (Published 6 November 2018)
reaction reports that can be screened to detect signals.
Informal social media reports may uncover novel
adverse drug reactions14 and help to understand
serious reactions from the patient’s perspective.15
Database studies
Large linked databases16-18 allow clinical events to be correlated
with drug prescriptions in substantial cohorts of patients. Newer
statistical methods, including self controlled and propensity
scoring designs and disproportionality statistics, help to interpret
these data.19 They complement information from clinical trials and
systematic reviews, which often emphasise drug efficacy and fail
to distinguish adverse drug reactions from other adverse
events.20 21 Healthcare professionals suggested a link between
the influenza vaccine Pandemrix and narcolepsy.22 The evidence
was strengthened by a retrospective cohort study in Finnish
primary care databases, which showed that narcolepsy was 12.7
times commoner in vaccinated children (95% confidence interval
6.1 to 30.8 times), although only 1 in 10 000 children came to
harm.23 The manufacturer let the market authorisation lapse, so
the vaccine is no longer marketed.
Risk management plans
Risk management plans now form part of applications for a
European marketing authorisation. They are another route to
discovering adverse drug reactions. They describe the
adverse reaction risks predicted at the time of marketing a
new drug, the measures to mitigate them, and the information
needed prospectively to refine risk estimates. They are
especially important for orphan drugs and other medicines
approved under fast track procedures “designed to facilitate
the development, and expedite the review of drugs to treat
serious conditions and fill an unmet medical need.” 24-27
Warnings
If a significant adverse drug reaction is uncovered, regulators
can require that the relevant summary of product characteristics
adds appropriate warnings; sometimes the drug is withdrawn. 28
Warnings are more likely to be added post-marketing to the
summaries of product characteristics (labels) of fast tracked
medicines than medicines authorised by the standard route.29
How is an adverse drug
reaction diagnosed?
Patients may not link symptoms to their medicines, so adverse
drug reactions can go undiagnosed unless the prescriber
specifically asks about them. Even then, the symptoms may be
due to a cause other than the drug.30 Since adverse drug
reactions sometimes hide behind common presenting symptoms
and sometimes present bizarrely, a good drug history will help to
establish if they should figure in the differential diagnosis.
Algorithms to determine whether a drug caused a reaction are
fallible, and none is universally accepted.31-33
Does the presentation fit into a
recognised pattern?
Some clinical presentations are characteristic. Patients will often
attribute new symptoms or signs to medicines they have recently
started. They are likely to be correct if they have developed
common adverse effects such as sleepiness with the
H1-antihistamine chlorphenamine or nausea with the opioid
analgesic oxycodone.
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Page 2 of 9
PRACTICE
Adverse drug reactions can affect any part of the body
(fig 2). Even rare reactions can be characteristic (see
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table 1), so adverse drug reactions enter the
differential diagnosis of unusual conditions.
Some conditions—Stevens-Johnson syndrome/toxic
epidermal necrolysis, bone marrow aplasia, and acute
dystonia—are commonly due to adverse drug reactions,
so you should suspect a drug cause for these.
Are there any diagnostic clues?
In taking the patient’s history, ascertain the dose (Do) of the
drug, the time course (T) of the observed clinical event, and the
potential susceptibility (S) of the patient (DoTS).56 Remember
that, occasionally, it is an excipient that causes the adverse drug
reaction, not the active drug;57 and that “herbal” remedies
sometimes contain undeclared potent drugs.58
Dose-response
Toxic reactions, such as liver failure from paracetamol,
usually occur only with high doses (or blood concentrations)
in patients whose susceptibility is normal. If patients are
hypersusceptible, only slight exposure to the drug (below
therapeutic concentration) can cause adverse drug reactions,
as happens when primaquine causes haemolysis in patients
with glucose-6-phosphate dehydrogenase deficiency or
penicillin causes anaphylaxis.
Time course
Some adverse drug reactions, typically anaphylaxis to
intravenous drugs, occur within minutes of administration.
Others, such as the serious dermatological reaction toxic
epidermal necrolysis, are due to delayed-type hypersensitivity
and occur after days or weeks. Cytokine release syndrome
following chimeric antigen receptor (CAR)-T cell therapies can
appear several weeks after treatment.
The risk of atypical femoral fractures from bisphosphonates
increases with the duration of therapy, the odds increasing by
about 1.3 per 100 days of treatment.59
Delayed reactions that become manifest months or years after
exposure to the causative agent are especially hard to diagnose.
It took nearly three decades to establish that diethylstilbesterol
could cause a rare vaginal cancer in young women whose
mothers had taken the drug in pregnancy.60 Chemotherapy with
alkylating agents for childhood lymphoma was introduced in the
1960s and dramatically improved survival, but it also increased
the risk of second malignancies61: after 35 years, nearly half of
those treated will develop a second malignancy.62 It is still too
early to define the long term effects of gene modification and
other advanced therapies.
Potential susceptibility
A patient’s age, concurrent treatments, and pre-existing illnesses
all affect susceptibility to adverse drug reactions. Renal
impairment, hepatic impairment, and obesity63 can increase
exposure to drugs and make adverse drug reactions more likely.
Genetics, including genetic heritage, can be important: patients
described as “black” are three times more likely than
“non-black” patients to develop angioedema with angiotensin
converting enzyme (ACE) inhibitors.64 Some reactions, such as
cough with ACE inhibitors, affect women more often than men. 65
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BMJ 2018;363:k4051 doi: 10.1136/bmj.k4051 (Published 6 November 2018)
How do you prevent or mitigate
adverse drug reactions?
Prudent prescribing
When prescribing a drug, consider whether the potential
benefits outweigh likely adverse drug reactions and whether
the patient might be especially susceptible. Gradual up-
titration of the dose of a drug, if possible, will increase the
chances of reaching an adequate therapeutic dose before
collateral or toxic adverse drug reactions become apparent,
but it will not prevent hypersusceptibility reactions.
Co-prescription can mitigate some adverse drug reactions: folic
acid will reduce the risk of bone marrow failure with
methotrexate, mesna will make cyclophosphamide-induced
cystitis less likely, and senna can prevent constipation with
opioids. Unnecessary polypharmacy, however, makes harm
more likely, especially if it represents a “prescribing cascade,”
when successive drugs are given to alleviate symptoms caused
by drugs already prescribed.66 Polypharmacy also increases the
risk of drug-drug interactions.
Identify susceptible patients
Harm is less likely if susceptible patients can be identified
before prescribing. Ask about previous drug reactions. Skin-
prick testing can help detect patients allergic to penicillin and
prevent an anaphylactic reaction.67 Genotyping to detect
polymorphisms that alter drug metabolism or action can
sometimes help to avoid adverse drug reactions. For some
drugs, it is standard practice to establish the patient’s
phenotype or genotype before treatment (table 2).
Discuss harms with the patient
Well informed patients are better able to distinguish between
likely adverse effects and other symptoms. They will need to
know of some rare but potentially serious adverse drug reactions,
such as mouth ulcers with carbimazole or methimazole, which
may indicate neutropenia. Sometimes specific advice on
administration can minimise harm: oesophageal injury with
alendronic acid is less likely if patients take tablets whole, on
rising, with at least 200 mL of water, and on an empty stomach
and then remain upright for at least 30 minutes.69
The recent UK Supreme Court judgment in Montgomery v
Lanarkshire Health Board requires that patients should be
informed of risks, however small, that are important to them: “a
patient should be told whatever they want to know, not what the
doctor thinks they should be told.”70 Brief consultations and a
patient information leaflet (package insert) may no longer
suffice. The internet can be a useful source of information (see
Additional Educational Resources box) but can also carry
alarmist or over-optimistic stories. Physicians, pharmacists, and
other healthcare professionals can provide patients with a more
realistic picture of the benefits and harms of medicines.
How do you treat adverse drug reactions?
In spite of precautions to avoid adverse drug reactions, they
still occur. In the face of a serious adverse drug reaction
such as toxic epidermal necrolysis the crucial first step is to
stop exposure to the causative drug. Some adverse drug
reactions require emergency treatment: for example, the use
of granulocyte-colony stimulating factors for drug induced
neutropenia is common, and idarucizumab is used to reverse
the anticoagulant effects of dabigatran.
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Page 3 of 9
PRACTICE
Many reactions with minor symptoms and no sinister
consequence require no treatment and are accepted as the price
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to be paid for the benefits of therapy. Medicines with unpleasant
adverse effects and minor benefits can be stopped: the patient
should decide whether the benefit outweighs the unpleasantness.
If the drug is important and the suspected reaction is
inconvenient rather than serious, you could rechallenge with the
drug, after discussing the benefits and risks with the patient, to
test whether the suspicion is correct. Rechallenge is not
generally advised if the suspected adverse drug reaction was
serious, because rechallenge is likely to cause serious harm.
Patients’ reports of adverse experiences have proved
valuable, and so we encourage patients to report suspected
adverse drug reactions they have experienced.71 72Figure 3
provides an algorithm for patients on when and how to
report adverse drug reactions, and help to improve drug
safety. Adverse drug reactions are inevitable with effective
medicines. We can help minimise them by prescribing
prudently, giving patients adequate information, taking
adequate drug histories, and considering drugs in the
differential diagnosis of many conditions.
Questions for future research
• How can advances in pharmacogenetics help identify patients who
are more susceptible to adverse drug reactions?
• How best can large databases be used to detect adverse drug
reactions earlier and improve the safety of marketed medicines?
• What rational monitoring schemes can be developed to protect
patients from adverse drug reactions?
• How do we involve patients in making medicines safer?
Additional educational resources
• EudraVigilance—European database of suspected adverse drug
reaction reports. www.adrreports.eu/en/
• European Medicines Agency. European public assessment
reports: Medicines. www.ema.europa.eu/en/medicines/
– Drugs assessed by the European Medicines Agency, categorised
by therapeutic area, type, and outcome of assessment
• European Medicines Agency. Human regulatory: Medicines under
additional monitoring. www.ema.europa.eu/human-regulatory/post-
authorisation/pharmacovigilance/medicines-under-additional-monitoring
• US Food and Drug Administration. Medwatch Safety Alert
Archive, 2018.
– FDA’s safety alerts for human medical products
• ScienceDirect. Meyler’s Side Effects of Drugs. 16th Edition 2016. www.
sciencedirect.com/referencework/9780444537164/meylers-side-
effects-of-drugs
– International encyclopaedia of adverse drug reactions and interactions
• Medicines and Healthcare products Regulatory Agency (MHRA).
YellowCard: Interactive Drug Analysis Profiles.
https://yellowcard.mhra. gov.uk/iDAP/
– All suspected adverse drug reactions reported via the Yellow Card
scheme from healthcare professionals and members of the public
• Uppsala Monitoring Centre. www.who-umc.org/
– The WHO Collaborating Centre for International Drug Monitoring
• Choosing Wisely. Choosing Wisely: Promoting conversations
between patients and clinicians. www.choosingwisely.org/
– An initiative of the ABIM (American Board of Internal Medicine)
Foundation to encourage avoidance of unnecessary medical
tests, treatments, and procedures
• University of Cambridge. Winton Centre for Risk and Evidence
Communication. https://wintoncentre.maths.cam.ac.uk/what-we-do
– Undertakes research into how people understand information
to ensure evidence is communicated clearly
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BMJ 2018;363:k4051 doi: 10.1136/bmj.k4051 (Published 6 November 2018)
Information resources for patients
• eMC (electronic Medicines Compendium). www.medicines.org.uk/emc
– Provides patient information leaflets and summaries of
product characteristics for medicines licensed in the UK
• Eudravigilance. How to report a side effect.
www.adrreports.eu/en/ report_side_effect.html
– European Medicines Agency. Information on why, how and what
to report. www.adrreports.eu/docs/ADR_reporting_FINAL_EN.pdf
• Medicines and Healthcare products Regulatory Agency (MHRA).
Yellow Card. https://yellowcard.mhra.gov.uk/
– Provides information on how patients can report suspected
adverse drug reactions in the UK
• US National Library of Medicine. Dailymed.
https://dailymed.nlm.nih. gov/dailymed/
– Provides labels (product information) for US medicines
Education into practice
• How will you ascertain if a patient’s symptoms are due to an
adverse drug reaction?
• How will you report a suspected adverse drug reaction in the area
where you practise?
• How will you discuss known adverse effects of a drug with your
patient? What resources do you typically use?
How patients were involved in the creation of this article
We asked several patients representatives on UK and European bodies for
their views, and took into account the views of patient reviewers. They gave
us advice on wording, made helpful suggestions on the flow chart,
discussed information sources used by patients, and reminded us of the
importance of registries.
We thank the patients who read and advised on the content of this article,
particularly Giulio Maria Corbelli of the European Community Advisory Board,
François Houÿez of the European Organisation for Rare Diseases, and Phil
Willan, patient representative on the Pharmacovigilance Expert Advisory Group of
the Medicines and Healthcare products Regulatory Agency.
Contributors: REF and PMcG contributed equally to the planning and
refinement of the manuscript; REF wrote the first draft.
Competing interests: We have read and understood the BMJ Group policy on
declaration of interests and declare the following interests: REF has provided
medico-legal reports on adverse drug reactions.
Provenance and peer review: Commissioned; externally peer reviewed.
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Tables

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Table 1| Recently recognised or unusual adverse drug reactions

Drug Adverse reaction Comments

Acid suppressant medicines (H2
antagonists and proton pump inhibitors)
Antiparkinsonian drugs (especially
pramipexole, ropinirole)
Bisphosphonates, denosumab, strontium Osteonecrosis: destruction of the tissue
ranelate (no longer marketed) with exposure of necrotic bone 36
Bisphosphonates, denosumab
Checkpoint inhibitors (antibodies against
cytotoxic T-lymphocyte associated protein
4 (CTLA-4) and programmed death 1
(PD-1)) such as ipilimumab, nivolumab,
pembrolizumab
Clozapine
Dopamine agonists (including
apomorphine, levodopa, pramipexole,
rotigotine)
Finasteride
Gadolinium contrast media for magnetic Nephrogenic systemic fibrosis: diffuse,
resonance imaging indurated woody plaques in skin and
Nicorandil
Oestrogen implants
SGLT2 inhibitors (canagliflozin,
dapagliflozin, empagliflozin)
SGLT2 inhibitors
Sildenafil and other PDE5 inhibitors
Sildenafil and other PDE5 inhibitors
Statins (such as atorvastatin, pravastatin,
rosuvastatin, simvastatin)
Sumatriptan
Trastuzumab
Treatments for multiple sclerosis
(dimethyl fumarate, fingolimod,
natalizumab)
Bacterial gastroenteritis 34
Sleep attacks: sudden onset of sleep
without preceding drowsiness35
Atypical femoral fractures: low trauma
stress fractures 37 38
Immune related adverse events 39 40
Fatal bowel obstruction 41
Impulse control disorders42 43
Finasteride withdrawal syndrome
(post-finasteride syndrome) 44
internal organs45
Oral, anal, and perineal ulceration46
Migration to the pulmonary vasculature 47
Diabetic keto-acidosis in patients with
type 2 diabetes48
Lower limb amputations49
Blue vision (cyanopsia) 50
Sudden loss of hearing in one or both
ears51
Diabetes52
Dark green blood53
Cardiac dysfunction 54
Progressive multifocal
leukoencephalopathy: a relentless and
fatal viral infection of the brain55
A cohort study showed that the risk of bacterial infection (with Clostridium difficile,
Campylobacter, Salmonella, or Escherichia coli O157) was doubled in patients
taking acid suppressant medication
Sleep attacks can occur some time after treatment has begun, and can have
serious consequences (such as when driving a vehicle). More likely when
ropinirole is used for Parkinson’s disease than for “restless legs”
Osteonecrosis of the jaw is associated mainly with sites of infection or dental
treatment (extraction, implantation) and is more likely in patients with cancer or
those treated with corticosteroids. Good dental care before start of treatment
can reduce the incidence.
More recently, and much more rarely, patients have presented with apparent
chronic ear infection caused by osteonecrosis of the external auditory canal
These fractures occur after some years of treatment for osteoporosis and are
typically transverse fractures across the proximal third of the femoral shaft
Inhibiting regulatory T cells permits cytotoxic T cells to act unchecked and greatly
increases the risk of new autoimmune disease or reactivation of old disease.
Conditions associated with checkpoint inhibitor treatment include adrenalitis,
bone marrow failure, enterocolitis, hepatitis, hypophysitis, myocarditis,
pancreatitis, pneumonitis, thyroid disorders, and uveitis
Clozapine is anticholinergic and commonly causes constipation. There are reports
of fatal faecal impaction. In rare cases, paralytic ileus causing pseudo-obstruction
can develop rapidly
These may include punding: stereotyped repetitive, obsessional behaviour, such
as sorting objects or tidying up. Binge eating and binge shopping are recorded.
More sinister behaviours include pathological gambling and hypersexuality
Patients who have taken the 5α-reductase inhibitor finasteride and then stop
can experience loss of libido, erectile dysfunction, and other sexual dysfunction,
together with loss of muscle bulk, gynaecomastia, depression, and other
symptoms
Fibrosis occurs 2-4 weeks after exposure; is more likely in patients with renal
impairment; and mainly seen with linear contrast agents such as gadodiamide
which release free gadolinium
Nicorandil impairs wound healing because of its action on ion channels. It is
associated with painful ulcers in the mouth, at or around the anus, and elsewhere;
the ulcers usually heal when the drug is stopped. Patients have undergone
extensive surgery when the diagnosis has not been made
Rare cases have required thoracotomy
Risk factors for keto-acidosis with SGLT2 inhibitors include conditions that
increase the need for insulin (such as infection, major surgery, serious illness)
An increased risk of amputation has been noted in observational studies of
canagliflozin. It is not explained, and it is uncertain whether the association is
causal or, if so, whether it is a class effect
PDE5 inhibitors can also affect retinal PDE6, an enzyme in the phototransduction
pathway
Sudden hearing loss is rare; these drugs increase the risk substantially in an
observational study
The adjusted risk of incident diabetes is increased by ≥10%
A case report described a man undergoing surgery for compartment syndrome
whose blood was green due to the formation of sulfhaemoglobin
Left ventricular dysfunction can affect up to 1 in 5 women treated with
trastuzumab.
The risk is greatly increased by the presence of anti-JC virus antibodies in serum,
especially if there has been previous immunosuppressant therapy or treatment
with natalizumab for >2 years

SGLT2=sodium–glucose transporter 2. PDE5=phosphodiesterase 5. JC virus=John Cunningham virus.

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Table 2| Examples of drugs where some patients have genetic, metabolic, or other factors that increase the risk of adverse drug reactions or

reduce the efficacy

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Drug (main indication) Adverse drug reaction susceptibility
Abacavir (HIV infection) HLA-B*5701 is associated with SJS/TEN from abacavir. Patients with HLA-B*5701 must not be treated, so
testing before treatment is mandatory†
Allopurinol (gout) HLA-B*5801 allele—common in people of Han Chinese, Thai, and Korean origin—is associated hypersensitivity
syndrome and SJS/TEN from allopurinol.† It is good practice to screen before starting treatment in patients
where the allele is common
Azathioprine, mercaptopurine (immunosuppression) Toxicity is increased in patients with reduced thiopurine methyl transferase (TPMT) activity, as the enzyme is
responsible for the breakdown of mercaptopurine and the active metabolites of azathioprine.† Testing before
treatment is advisable
Capecitabine, fluocytosine, fluorouracil Capecitabine is a pro-drug of 5-fluorouracil, which is metabolised to the less toxic 5,6-dihydro compound by
(gastrointestinal and breast cancers) the enzyme dihydropyrimidine dehydrogenase (DPD). Rare patients deficient in DPD are at high risk of life
threatening toxicity‡
Carbamazepine, oxcarbazepine, eslicarbazepine HLA-B*1502 allele is associated with SJS/TEN from carbamazepine and related drugs in Han Chinese, Thai,
(epilepsy) and other Asian populations, who should be screened for the allele before treatment†
Clopidogrel (antiplatelet therapy) Clopidogrel is less effective in CYP2C19-poor metabolisers, as the enzyme is required to make the active
metabolite†
Codeine (analgesia) The risk of toxicity is increased in ultra-rapid metabolisers with duplications of the CPY2D6 gene who convert
codeine (methyl-morphine) into morphine more rapidly than others‡
Flucloxacillin (infection) HLA-B*5701 allele increases risk of liver injury, but the reaction is rare (<1:500) even in carriers, and routine
screening is unnecessary† 68
Glyceryl trinitrate (cardiac disease) Glyceryl trinitrate is metabolised to active nitric oxide by aldehyde dehydrogenase; its efficacy is reduced in
patients with ALDH2*2 genotype, who are poor metabolisers
Idursulfase (mucopolysaccharidosis II (Hunter Paediatric patients with the complete deletion or large rearrangement genotype are likely to develop antibodies
syndrome)) to idursulfase†
Irinotecan (colon cancer) Irinotecan is a pro-drug whose active metabolite is detoxified by uridine diphosphate-glucuronosyl transferase
1A1 (UGT1A1); the risk of severe neutropenia is very low in patients homozygous for the wild type gene, 12.5%
in patients heterozygous for the UGT1A1*28 allele, and 50% in patients homozygous for UGT1A1*28‡
Lapatinib (breast cancer) The risk of liver damage with lapatinib is about 10% in patients with HLA DQA1*02:01 or DRB1*07:01 genotype,
and 0.5% in those without†
Metoclopramide (nausea) Patients with NADH-cytochrome b5 reductase deficiency are at an increased risk of developing
methaemoglobinaemia‡
Pegloticase (gout) It can cause haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, and those at risk of
deficiency (such as patients of African or Mediterranean ancestry) should be tested before treatment‡
Primaquine (malaria) It can cause haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, a test for G6PD
deficiency is required before treatment‡
Rasburicase (hyperuricaemia from tumour lysis) It can cause haemolysis in patients with glucose-6-phosphate dehydrogenase deficiency, and those at higher
risk of deficiency (such as patients of African or Mediterranean ancestry) should be tested before treatment‡
Simvastatin (hypercholesterolaemia) Patients who carry the SLC01B1 gene allele (c.521T >C) coding for a less active organic acid transporter
protein 1B1 are at increased risk of myopathy with high dose simvastatin: about 50 times greater in those
homozygous for the genotype than in those with the wild type gene. Testing may be worthwhile in patients
who are proposed for high dose simvastatin†
Strontium ranelate (osteoporosis – no longer HLA-A*33:03 and HLA-B*58:01 alleles increase risk of SJS/TEN related to strontium ranelate in Han Chinese
marketed) patients, who merit testing before treatment†
Tramadol (analgesia) Risk of toxicity is increased in ultra-rapid metabolisers with duplications of the CPY2D6 gene who convert drug
into active metabolite O-desmethyltramadol more rapidly and completely than others‡

SJS/TEN = Stevens-Johnson syndrome/toxic epidermal necrolysis.

† Data from the Summary of Product Characteristics (SmPC) Section 4.4 of the electronic Medicines Compendium at https://www.medicines.org.uk/emc.
‡ Data from US Food and Drugs Administration (FDA).

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Figures

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Fig 1 The standard European nomenclature for the frequency of adverse drug reactions, with examples

Fig 2 Examples of possible adverse drug reactions

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Fig 3 Algorithm for patients on when and how to report adverse drug reactions

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