C L I N I C A L P E R S P E CT I V E S

Life-threatening drug interactions: what the physician needs

to know
Richard O. Day ,1,2,3 Leone Snowden4 and Andrew J. McLachlan5
1
Department of Clinical Pharmacology and Toxicology, St Vincent’s Hospital, 2School of Medical Sciences, Medicine, and 3St Vincent’s Clinical School,
Medicine, University of New South Wales, 4New South Wales Medicines Information Centre, and 5Faculty of Pharmacy, University of Sydney and
Centre for Education and Research on Ageing, Concord Hospital, Sydney, New South Wales, Australia

Key words Abstract

drug–drug interactions, adverse drug reactions,
adverse drug events, pharmacokinetic drug Adverse drug–drug interactions are a significant cause of adverse events and outcomes.
interactions, pharmacodynamic drug Their incidence is rising, with more patients taking more drugs, and newer, more pre-
interactions, cytochrome P 450 metabolism. cise but often more hazardous drugs becoming available. Despite considerable informa-
tion, including computerised alerts about potential adverse drug–drug interactions,
Correspondence prescribers increasingly override alerts, possibly symptomatic of the immense problem
Richard O. Day, Clinical Pharmacology and of evaluating the risk of an interaction in a particular patient. Many reports emanate
Toxicology, Therapeutic Centre, St Vincent’s from small studies often of normal and young volunteers, entirely different from the
Hospital and UNSW, St Vincent’s Hospital, real world where, more often, older patients with multiple health conditions are receiv-
Victoria Street, Darlinghurst, Sydney, NSW ing many more than the two drugs identified in the drug interaction report. Focusing
2010, Australia. on those drug–drug interactions that are clinically relevant is necessary, and increas-
Email: r.day@unsw.edu.au ingly, tools and reliable sources of this information are easily accessible.

Received 16 July 2016; accepted

11 November 2016.

doi:10.1111/imj.13404

Introduction 13% required at least one hospitalisation or a medical

review as a result, and over 60% were preventable.3
Adverse drug events and reactions have a significant
In an Australian study, up to 21% of hospital admis-
impact on patients and healthcare systems, accounting
sions related to adverse drug events were caused by drug
for a considerable proportion of healthcare resources
interactions, and it is widely recognised that adverse
and costs. Adverse drug reactions (ADR) are a substantial
drug interactions make up a significant proportion of
cause of hospital admissions, in the order of 5%, and are
adverse drug events and reactions.4 A literature review
a major cause of mortality.1,2 It has been estimated that
found that 0.6–5% of hospital admissions were due to
an ADR will occur during 6–15% of hospital admissions,
drug interactions, including loss of important therapeutic
and these increase the length of stay, morbidity and
effect such as analgesia.5 A more recent systematic
death rate. Rates are higher in patients who have longer
review confirmed that drug–drug interactions accounted
stays in hospital and are older, female and taking more
for 1.1% of hospital admissions alone, which was 22%
concurrent medications.3 A recent Swiss study of people
of the admissions for ADR in this study.6 Furthermore, it
referred to a community nursing service for medication
is estimated that 1 in 200 hospitalised patients will expe-
management revealed that 41% had medication errors,
rience a serious ADR caused by a drug interaction.7 Drug
interactions occur, and their incidence continues to rise
despite electronic alerts in prescribing and dispensing
Funding: R. O. Day’s research work is supported by the National systems warning prescribers and pharmacists of potential
Health and Medical Research Council Program Grant APP interactions. Drug–drug interactions are a major contrib-
1054146 and Australian Research Council Linkage Grant utor to avoidable morbidity and mortality in modern
LP0990670. A. J. McLachlan is the Program Director of the healthcare.
National Health and Medical Research Council of Australia
Centre for Research Excellence in Medicines and Ageing
Some have linked this increasing problem of adverse
(CREMA). drug events in part at least to a declining number of clin-
Conflict of interest: None. ical pharmacologists. Clinical pharmacologists specialise

© 2017 Royal Australasian College of Physicians 501

Day et al.

in enabling safe and effective use of medicines in hypoglycaemia and renal failure. The most prevalent
humans. They have been an important influence and obviously life-threatening drug interactions are still
towards achieving rational prescribing. Thus, Viscount those related to combinations of medicines that do the
Hawton, who was one of a number of speakers in a same thing, such as lower blood pressure, interfere with
recent Short Debate in the House of Lords, United King- the coagulation or clotting systems or lead to excessive
dom, focused on Clinical Pharmacology, bemoaned the central nervous system depression. These can be classi-
shortage of clinical pharmacologists in the UK National fied mechanistically as pharmacodynamic drug interac-
Health Service.a Viscount Hawton noted that ‘Poor pre- tions. Pharmacokinetic mechanisms for drug interactions
scribing is one way in which patients can come to harm. result in potentially critical increases or decreases in the
A lack of knowledge can also make general practitioners concentration of a drug, leading to the risk of harm. This
vulnerable to the persuasions of drug companies that are is most relevant to medicines with a low therapeutic
intent on selling their remedies without regard to their index, that is, the difference in doses or concentrations
efficacy or their dangers. It is difficult to estimate the cost that separate toxic from therapeutic effects. For example,
to our health service of the inappropriate adoption of the safe plasma concentration range for lithium therapy
drugs that have been the subject of hard sales techni- for people with bipolar disorder is narrow, and presenta-
ques, but it must be considerable’ and went on to say, tions to emergency departments with toxicity due to
‘The decline in the number of specialist clinical pharma- excessive concentrations are common in older people
cologists in the health service and the marginalisation of and are serious, often precipitated by the commence-
pharmacology in medical training implies that there will ment of diuretics or angiotensin-converting enzyme
be acute problems in the near future’. This argument (ACE) inhibitors.11 Alternatively, pharmacokinetic inter-
extends to Australia where the number of clinical phar- actions that decrease a drug’s concentration can be life-
macologists in medical schools and teaching hospitals is threatening if that drug is preventing a life-threatening
now approaching extinction, and there are evident pro- event, for example, arrhythmias, venous thromboembo-
blems in prescribing standards leading to drug–drug lism, tumour growth, seizures or suicidal depression.
interactions and other ADR.8–10 Additionally, the
demands on the ‘few’ clinical pharmacologists in our
Factors that increase the risk from
health systems and medical schools for guidance and
‘life-threatening’ drug interactions
involvement in medicines research, regulatory and med-
icines governance matters and research ethics can no
Polypharmacy
longer be sustained or accepted and is therefore detract-
ing from proper attention to the quality of prescribing. The more medicines an individual takes, the greater the
The focus of this communication is on ‘potentially life- risk of drug–drug interactions. Overall, our patients are
threatening drug–drug interactions’, those none of us older, have more comorbid conditions and take more
would like to miss. Some drug combinations should sim- medicines.12,13 An important challenge for the physician
ply be avoided. These are usually designated as ‘contra- is that each of the contemporary guideline recommenda-
indicated’ in interaction resources and approved product tions for the treatment of each particular condition that
information. These interactions either have adverse con- afflicts a patient will result in a very substantial number
sequences for the majority of patients given the combi- of potentially serious drug interactions.14 Thus, for type
nation, or the risk far outweighs any potential benefit, 2 diabetes, there are four medicines recommended as
but these extreme situations are unusual. Other poten- first-line therapies, four medicines for hypertension and
tially hazardous combinations may be used knowingly another four for post-myocardial infarction, so it is not
and appropriately by prescribers with relevant expertise unexpected that there might be serious drug interactions
but with extreme caution, attention to dose selection if a patient had all three conditions, and guidelines were
and increased monitoring, especially in vulnerable being followed, especially if there is no focus on this
patients. potential for serious drug–drug interactions in any of the
The life-threatening harms resulting from drug inter- guidelines. However, the guidelines for the individual
actions involve bleeding, bone marrow suppression, conditions usually do not note or emphasise the risk for
arrhythmias, hypotension, central nervous system serious drug interactions if the patient has other, often
depression, seizures, serotonin toxicity, significant elec- common, comorbidities.15 Dumbreck et al. identifies an
trolyte disturbance (hypo- or hyperkalaemia), important need for guidelines to be redesigned to deal
with this increasing reality of ‘multi-morbidity’ and the
a
https://www.bps.ac.uk/news-events/news/society-news/ likelihood of serious drug interactions. This ‘new’ design
articles/clinical-pharmacology-debate-in-the-house-of-lords needs to deal with the epidemiology of the comorbidities

502 © 2017 Royal Australasian College of Physicians

 Life-threatening drug interactions

likely seen with the index condition, the therapies enzymes by one of a pair of the interacting drugs, the
recommended and their risk of serious interactions with other being ‘subject’ to the induction or inhibition.
those of the index condition.14 For example, statin ther- Highly significant are those drug–drug interactions invol-
apy in older patients may be indicated by cardiovascular ving CYPP450 3A4/5 (Table 1).
guidelines, but around 10% of older patients prescribed Less well appreciated but increasingly recognised is
statins and admitted to a teaching hospital were discov- that polymorphisms of these key drug-metabolising
ered to have potentially clinically significant drug inter- enzymes contribute to the risk of life-threatening drug
actions with these ubiquitous medicines.16 interactions. For example, an individual taking the opi-
An extension of this problem of polypharmacy is that, oid analgesic tramadol is reliant on CYP2D6 to metabo-
too commonly, prescribers simply do not know what lise the drug in the liver and thus detoxify it. Should
medicines a person is actually taking, highlighting the either fluoxetine or paroxetine, the serotonin reuptake
importance of a comprehensive and current medication inhibitor antidepressants, be commenced – both strong
history with reconciliation during transitions of care. The inhibitors of CYP2D6 – there is a risk of excessive seda-
increasing reality of multiple prescribers for a single tion from increased concentrations of tramadol. There is
patient without effective communication between pre- an additional important risk related to pharmacody-
scribers is a significant contributor to inappropriate poly- namic effects, namely, the serotonin syndrome, as tra-
pharmacy. The over-the-counter (OTC) and madol also has serotonin reuptake properties. The risk of
complementary medicines ‘self-prescribed’ by our the serotonin syndrome with this combination of SSRI
patients also can contribute to polypharmacy and life- antidepressants and tramadol increases with the dose of
threatening interactions. tramadol and the age of the patient.17 However, there
are alternative opioid analgesics and SSRI that eliminate
the risk. Thus, medicine selection is an important consid-
Metabolism and transporters eration in reducing and avoiding such risks.
Even without a genetic polymorphism, variations in
Cytochrome P450 enzymes (CYP) the amount of CYP between individuals can change risks
The cytochrome P450 enzymes (CYP P450) family of significantly. Thus, if our patient taking tramadol has rel-
enzymes is responsible for most of the oxidative metabo- atively low amounts of functional CYP2D6 enzyme per se
lism of medicines that occurs in the liver and, to some without polymorphisms, they would be more prone to
extent, in the gut wall. P-glycoprotein (P-gp) is an the serotonin syndrome if fluoxetine were commenced
exporter protein that transports medicines into the gut as, relatively, they already have high concentrations of
lumen with a significant cross-over in substrate selectiv- tramadol. On the other hand, if our patient had rela-
ity for medicines also metabolised by CYP 3A4. It is well tively large amounts of functional CYP2D6, she or he
established that there are significant, potentially very would be more prone to significant inhibition by fluoxe-
serious adverse drug events that are due to drug–drug tine and thus a more dramatic increase in tramadol con-
interactions related to induction or inhibition of CYP450 centrations and opioid-related adverse effects.

Table 1 Selected substrates, inducers and inhibitors of CYP 450 3A4/5 enzymes, significant contributors to life-threatening drug–drug interactions

Inducers of CYP 3A4/5†‡ Inhibitors of CYP 3A4/5†‡

Substrates for metabolism by CYP 3A4/5†‡ Class Drugs Class Drugs

Calcineurin inhibitors: cyclosporin, Anticonvulsants Carbamazepine, phenytoin, Azole anti-fungals Itraconazole, ketoconazole,
tacrolimus, everolimus barbiturates posaconazole, voriconazole
Anti-arrhythmics: amiodarone Antibiotics Rifampicin Macrolide antibiotics Clarithromycin, erythromycin
Statins: simvastatin, atorvastatin, fluvastatin St John’s wort
Incidental drugs: colchicine, irinotecan, Enzalutamide Protease inhibitor Ritonavir, indinavir, saquinavir,
zolpidem antivirals telapravir, bocepravir
Antihypertensives: diltiazem, lercanidipine Grapefruit juice
Psychotropics: mirtazapine, quetiapine Calcium channel Diltiazem, verapamil
blockers
Cancer drugs:21,66 for example, kinase Modafinil, efavirenz Bocepravir, cobicistat
inhibitors cobimetinib, dabrafenib,
imatinib, vermurafenib

†Any inducer or inhibitor can operate on any substrate with a potentially serious drug–drug interaction result. ‡Selected substrates, inducers and inhi-
bitors more likely to be involved in serious drug–drug interactions.

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Day et al.

Another example of the influence of the amount of available and prescribed by a specialist, in this case an
CYP enzyme an individual has on the potential for toxic- oncologist, but the patient’s GP is dealing with infections
ity and drug–drug interactions relates to the important and mental health issues and prescribes an antibiotic or
CYP 3A4/5 group (Table 1). These enzymes are critical an antidepressant unaware of the potential serious toxic-
for the metabolism of many important medicines, such ity that may be precipitated.
as the calcineurin inhibitors cyclosporin and tacrolimus Another hazard that prescribers are increasingly deal-
and some statin hypolipidaemic drugs, including simvas- ing with is concomitant alcohol, tobacco and/or recrea-
tatin, fluvastatin and atorvastatin. tional drugs, notably cannabis. The latter is also being
A drug that inhibits CYP 3A4/5, such as the macrolide used increasingly for medicinal purposes, especially in
antibiotic clarithromycin, will induce a much greater individuals with cancer and chronic pain. CYP P450 1A2
increase in concentration in a drug such as tacrolimus, is induced by both tobacco and marijuana smoke, and
which is reliant on this enzyme for its metabolism, if the the effect is additive so that substrate medicines will
individual patient has above average amounts of CYP potentially be less efficacious, for example, clozapine,
3A4/5 enzyme.18 Powerful CYP 3A4/5 inducers, like car- duloxetine and erlotinib. Additionally, inducers and
bamazepine, phenytoin, rifampicin or St John’s wort, inhibitors of cytochrome P450 3A4/5 influence the con-
prescribed in a patient already taking the important anti- centrations and, thus, effects of Δ9-tetrahydrocannabinol
arrhythmic amiodarone, which is metabolised substan- and cannabidiol derived from vapourised THC/cannabi-
tially by CYP3A4, can lead to a major decrease in amio- diol. Much work is needed to unravel the significance of
darone plasma concentrations and a potentially fatal drug interactions involving cannabis derivatives and
arrhythmia. This effect will be much greater if the indi- products.22
vidual has relatively less hepatic CYP3A4/5 such that Prescribers can be easily overwhelmed trying to evalu-
induction will have a significantly greater effect com- ate the risk for CYP P450-based drug interactions in their
pared to those with inherently more CYP3A4.19,20 patients given the numbers of medicines, enzymes and
A plethora of oral, small molecule, cancer pharma- sources of information to consider. Helpfully, a very use-
cotherapeutics, that are revolutionising the treatment of ful ‘criteria-based’ analysis of the risk levels for these
many previously poor prognosis cancers, such as lung interactions has been constructed that has concluded
cancer and melanoma, has become available since 2010. that the number of drugs that is ‘proven or likely major
Unfortunately, many are metabolised by the CYP P450 perpetrators of pharmacokinetic drug–drug interactions
3A4/5 and P-gp enzyme and transporter systems and are is relatively small’, which is inconsistent with the high
therefore subject to multiple drug interactions.21 For rates of alerting from various sources, including compu-
example, cobimetinib, a kinase inhibitor with efficacy in terised decision support systems.23
un-resectable metastatic melanoma, is a substrate for A further increasing problem with metabolic, pharma-
CYP 3A4/5 and so is subject to an increased effect with cokinetic drug–drug interactions is the individual patient
CYP 3A inhibitors and the opposite with inhibitors of on multiple medicines that can interact with each other.
CYP 3A. Furthermore, cobimetinib is known to cause Multiple interactions are possible, but the likely aggre-
myelosuppression, hypertension and myopathy and so is gate effect of these is speculative as there is no reliable
subject to pharmacodynamic drug–drug interactions guidance available in these situations. For example, peo-
with other medicines associated with myelosuppression ple living with HIV infection taking multiple antiretrovi-
(e.g. cytotoxics), hypertension (e.g. NSAID) or myopathy ral medicines may be prescribed multiple concomitant
(e.g. statins), especially if there is also a CYP 3A4/5 prophylactic antimicrobial drugs, and these patients
inhibitor being taken concomitantly (Table 1).21 increasingly have significant other conditions, such as
Other CYP P450 enzymes are significant in drug–drug cardiac disease, diabetes and depression.24 A new chal-
interactions, including 2D6, 2C9 and 2C19. With new lenge, revealed in an analysis of the risk of potentially
drugs, it is important to consider whether drug–drug clinically significant drug interactions in patients with
interactions are a feature. For example, another impor- hepatitis C commenced on an array of new direct acting
tant CYP 450 enzyme for the metabolism of a limited antiviral agents, has shown that the risk is considerable
number of medicines is CYP 1A2. Pomalidomide, a (see www.hep-druginteractions.org). For example, a risk
newly available thalidomide analogue and substrate for in up to 66% of patients prescribed ombitasvir/paritapre-
CYP 1A2 used to treat multiple myeloma, can have its vir/ritonavir  dasabuvir is anticipated in one of many
metabolism inhibited significantly by ciprofloxacin or possible regimens, with likely interacting medicines
fluvoxamine with increased risk for neutropenia and including proton pump inhibitors (PPI), thyroid hor-
venous thromboembolus.21 Such interactions are more mones and calcium channel blockers (CCB).25. In these
easily ‘missed’ simply because the medicine is recently complex situations, conservative dose rates, increased

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 Life-threatening drug interactions

monitoring and an educated patient are important pro- 2 selective inhibitors also reduce gastric pH, and this can
tections against unexpected toxicity from drug influence the absorption of many medicines very sub-
interactions. stantially. Thus, it is advised that due to the significant
drop in concentrations and area under the concentration
P-glycoproteins and other transporter molecules
time curve of the tyrosine kinase inhibitor erlotinib due
A wide variety of ‘transporter’ proteins is responsible for to concomitant PPI (about 50% decrease), the combina-
the movement of drugs across cell membranes. Most tion ought to be avoided. The solubility of the erlotinib is
well known is P-gp that pumps medicines out of cells, reduced greatly in non-acid environments.32 As PPI have
such as from gut cells back into the gut or the central potentially significant effects on the absorption of many
nervous system at the blood–brain barrier back into the drugs, it is imperative that their use, especially in older
systemic circulation. Many of the drugs that are sub- people, is reviewed as, oftentimes, a convincing rationale
strates, inducers or inhibitors of CYP 3A4 act in a similar is absent.
manner on P-gp. Inducers will decrease and inhibitors
will increase plasma concentrations of P-gp substrate
Organ dysfunction
drugs. Well-known substrates are digoxin, apixiban,
dabigatran, cyclosporin, amiodarone, imitanib and irino- Organ impairments contribute to the risk of life-
tecan; well-known inducers include rifampicin, carba- threatening drug interactions. Impaired renal function is
mazepine and St John’s wort; and well-known inhibitors common, especially in older and diabetic patients. Sur-
include clarithromycin, erythromycin, itraconazole, car- prisingly, significant renal impairment is often not diag-
vedilol, ritonavir, vemurafenib and verapamil. An nosed because a mildly elevated plasma creatinine
important P-gp-based interaction involves digoxin. Con- concentration in an older, low-bodyweight individual is
centrations of orally administered digoxin increase not recognised to be indicative of this condition. If one of
markedly with the addition of clarithromycin, and this a pair of interacting drugs is reliant on the kidney for its
effect is due to the inhibition of the P-gp-mediated trans- clearance from the body, then the risk of a life-
port of digoxin into the gut and renal tubules.26 Another threatening interaction can be substantially increased.
P-gp interaction affecting digoxin is seen with the co- For example, the active form of morphine, morphine-6-
administration of rifampicin that leads to substantially glucuronide, is dependent in part on glomerular filtra-
decreased digoxin concentrations due to the induction of tion for its elimination.33 The addition of a second central
P-gp.27 nervous system (CNS) depressant will be more hazard-
ous in a renally impaired patient taking morphine.
Interactions in the gut
If a patient has significant cirrhosis, then the bioavaila-
Medicines that act in the gut can interfere with the bility of oral morphine would be dramatically increased
absorption of other medicines, and serious consequences as first-pass metabolism is greatly reduced as a result.
may result. For example, the cholesterol-lowering resin This is equivalent to a very large dose increase, for exam-
cholestyramine will reduce the absorption and concen- ple, the equivalent of doubling of a dose is not unusual.
trations of the active metabolites of mycophenolate by Adding another CNS depressant, such as an antipsy-
35–40%28 and also other medicines critical in transplan- chotic or hypnotic drug, could tip the patient into severe
tation and autoimmune disorders, including leflunomide CNS and thus respiratory depression.
and its active metabolite. Iron supplements are known to
interfere with the absorption of many drugs, notably
Life-threatening harm from drug–drug
fluoroquinolones and tetracycline antibiotics through
interactions
the reduction of bioavailability due to iron–medicine
complex formation.29 Antacids not only bind medicines
Bleeding and thrombosis
in the gut but also lead to pH changes in the gut and
urine that can affect absorption and/or the renal clear- Warfarin and the direct-acting oral anticoagulants (dabi-
ance of weak acids and bases. Thus, salicylate concentra- gatran, rivaroxaban and apixaban) are hazardous in
tions fall because of alkalinisation of urine,30 while a their own right but more so in patients taking other
number of important cancer pharmacotherapeutics, medicines that affect the pharmacokinetics or the phar-
including gefitinib and erlotinib, and many HIV medi- macodynamics of these anticoagulants. The hazard is the
cines, such as dolutegravir, may have substantial reduc- greatest when stopping or starting other medicines or in
tions in bioavailability.31 A general rule is to take patients with organ dysfunction (hepatic or renal). For
medicines 2 h before or 3–6 h after any cholestyramine, example, starting or stopping macrolide antibiotics, such
oral iron preparations or antacids. PPI and histamine as erythromycin or clarithromycin, that inhibit CYP3A4

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Day et al.

in a patient on warfarin or direct-acting oral anticoagu- Table 2 Selected drug interactions with warfarin
lants risks bleeding when starting these antibiotics or Increased risk of Increased risk of
thrombosis when stopping them. The commonly pre- Interacting drug bleeding thrombosis
scribed anti-arrhythmic amiodarone increases the effect
Amiodarone √ Raised INR
of warfarin markedly on the risk of bleeding by inhibit-
Fluconazole, voriconazole √ Raised INR
ing the metabolism of warfarin. Commencing or ceasing Erythromycin, roxithromycin, √ Raised INR
inducers of CYP enzymes, especially CYP2C9, can have clarithromycin
catastrophic effects in a patient previously stable on war- Ritonavir, efavirenz √ Raised INR
farin. The anticonvulsants, carbamazepine and pheny- Teniposide √ Raised INR
toin and the antibiotic rifampicin are well-known Fluoxetine, fluvoxamine √ Raised INR
Rifampicin √ Lowered INR
inducers of the metabolism of warfarin through this
St Johns wort √ Lowered INR
mechanism, rendering the anti-thrombotic effects of
Dabrafenib √ Lowered INR
warfarin ineffective unless there is a substantial increase Aspirin, NSAID Platelet inhibition
in its dose. Often overlooked is the potent effect of some Clopidogrel Platelet inhibition
complementary medicines on CYP450-catalysed reac- SSRI antidepressants Platelet inhibition
tions.34 For example, the widely used St John’s wort
induces the metabolism of both S and R enantiomers of
HIV protease inhibitor ritonavir, are being prescribed
warfarin, with significant decreases in the INR and
(Table 1). Moderate CYP 3A4 and/or P-gp inhibitors can
increased risk of thrombosis.35
still be a risk of bleeding in patients with moderate renal
Practically, it is important to check the INR in patients
impairment on usual doses of rivaroxaban.
taking warfarin more often after stopping and starting
Similarly, apixaban, another factor Xa inhibitor, is also
possibly interacting drugs. These interactions are so
subject to metabolism by CYP 3A4 and transported by P-
important that in patients taking warfarin chronically,
gp, and concomitant treatment with strong inhibitors
whenever another drug is prescribed or discontinued,
(anti-fungals and HIV protease inhibitors) is listed as a
the possibility of either increased or decreased effect of
contraindication, and care should be taken in renal
warfarin needs to be considered. Additionally, it is sound
impairment with moderate inhibitors. Strong inducers of
practice to increase the frequency of INR monitoring
CYP 3A4 and P-gp, such as carbamazepine, rifampicin
until there is confidence that the INR is stable. The more
and St John’s wort, will reduce concentrations of apixa-
active form, namely S-warfarin, is metabolised by the
ban, and there is a risk of loss of sufficient anti-
hepatic enzyme CYP2C9, and many medicines are either
thrombotic effect.
inducers or inhibitors of CYP2C9, thereby altering the
Dabigatran, the direct thrombin inhibitor, is elimi-
amount of warfarin’s effect (Table 2). A helpful analysis
nated in part renally and is subject to interactions with
of the risk of major bleeding in older patients admitted
P-gp inducers and inhibitors similarly.
to hospital who were taking warfarin with various co-
A combination of any of the direct-acting oral anticoa-
medications revealed significant, adjusted relative risk
gulants with other anticoagulants, namely heparin or
rates for bleeding, with the risk rate of low-dose aspirin
warfarin, is generally contraindicated. Care needs to be
being 1.44, clopidogrel 2.23, clopidogrel with aspirin
taken with the co-prescription of anti-platelet drugs,
3.44, amiodarone 3.33 and ‘antibiotics’ 2.34.36
namely aspirin, NSAID, clopidogrel and prasugrel, but
A very common combination with a high risk of
they are not necessarily contraindicated (see What are
bleeding is warfarin with aspirin or NSAID that can also
the risks of using anti-platelet agents in combination
be accessed OTC (‘over the counter’).37
with the novel oral anticoagulants in patients with atrial
All the ‘direct-acting oral anticoagulants’ are subject to
fibrillation, and how should the potential risks be mana-
important pharmacokinetic, metabolic drug–drug inter-
ged? From the UK Medicines Information service of the
actions with risks of bleeding or thrombosis. Rivaroxa-
National Health Service http://www.medicinesresources.
ban is an orally active, highly selective factor Xa
nhs.uk/getdocument.aspx?pageid=802641).
inhibitor indicated as an anti-thrombotic agent. It is
metabolised in part by CYP 3A4, transported in part by
the efflux protein P-gp and excreted in part unchanged
Bone marrow toxicity
in the urine, necessitating a reduction in dose when cre-
atinine clearance falls below 30 mL/min. The drug is The combination of allopurinol for gout and azathioprine
contraindicated if concomitant strong inhibitors of CYP for immunological conditions, such as systemic lupus
3A4 and P-gp, such as the azole anti-fungals (itracona- erythematosus (SLE) or Crohn disease (inflammatory
zole, ketoconazole, voriconazole, posaconazole) and the bowel disease), can be lethal as allopurinol and its

506 © 2017 Royal Australasian College of Physicians

 Life-threatening drug interactions

metabolite oxypurinol inhibit the enzyme xanthine oxi- Viral diseases

dase, which is also important in the detoxification of
Interactions involving medications used to treat HIV are
azathioprine.38 The combination can be used if the dose
numerous and can be serious. An excellent resource has
of azathioprine or its active metabolite 6-mercaptopurine
been maintained by the Liverpool HIV Pharmacology
is reduced to about a quarter to a third, and the patient
Group, University of Liverpool, UK (http://www.
is closely monitored for marrow toxicity. In fact, the
hiv-druginteractionslite.org/). Loss of suppression of the
combination is being used by gastroenterologists specia-
virus is the most important hazard. Thus, for example, a
lising in inflammatory bowel diseases in order to
major reduction in indinavir concentrations is likely to
enhance the effectiveness of azathioprine, and safety is
occur with the prescription of carbamazepine, a CYP
being enhanced by regular monitoring of the concentra-
3A4/5 inducer indicated for epilepsy or neuropathic pain
tions of azathioprine metabolites in blood.39
(Table 1). The potential for interactions with direct-
Illustrating the important intersection of genetic
acting antiviral agents to treat hepatitis C is discussed
variability between patients contributing to the risk of
above.
life-threatening drug interactions, patients with low con-
centrations of thiopurine methyltransferase enzyme
(TPMT) at baseline need to be identified prior to pre-
Arrhythmias
scribing azathioprine. If moderately low TPMT concen-
trations are detected, even smaller doses of allopurinol Medicines that prolong the QT interval on the ECG or
would have to be selected, and therapeutic drug moni- interactions that increase the QT prolongation effect of
toring of the active metabolites of azathioprine under- either drug can cause irreversible ‘torsades des pointes’
taken by experienced clinicians is strongly ventricular arrhythmia. Several medicines have been
recommended. Extremely low amounts of TPMT would withdrawn from the market, for example, the calcium
negate the use of the combination with azathioprine channel blocker mibefradil (Posicor), because they
completely. increase the QTc and have been associated with tor-
sades and sudden death. Patients with inherent, genet-
Methotrexate ically based, long QT syndrome (QT > 450 ms in adult
males; >470 in adult females)43 are more at risk, and
This drug is very widely prescribed for chronic inflam-
patients with a family history of sudden death due to
matory conditions, notably rheumatoid arthritis, and
this problem need to be aware of medicines that can
also as a corticosteroid-sparing agent in conditions where
cause torsades des pointes (https://crediblemeds.org/
long-term corticosteroid therapy may be needed, such as
everyone/). Risk increases with female gender,
polymyalgia rheumatica. Methotrexate is a folate antag-
increased age, electrolyte abnormalities and a range of
onist, and a combination with other folate antagonists,
cardiac conditions, such as heart failure. Psychotropic
such as trimethoprim and combinations of trimethoprim
medications have been identified as a particular risk
with sulfamethoxasole, may lead to agranulocytosis and
group – citalopram, an SSRI; thioridazine, a ‘typical’
thrombocytopenia with the potential for serious infec-
antipsychotic and ziprasidone, an atypical antipsychotic
tion.40 This catastrophic outcome is more likely in renally
– as manifesting the most risk for QTc prolongation.
impaired patients (or those receiving drugs that affect
Many non-psychiatric medications are also associated
renal function) as methotrexate is partially eliminated
with prolonged QTc, for example, sotalol, macrolide
renally, and as noted, renal impairment is often over-
and quinolone antibiotics, anti-fungals, such as ketoco-
looked or missed in the older patients.
nazole, and anti-malarials. Combinations of drugs that
each prolong the QTc increase the risk of torsades
(e.g. citalopram and thioridazine). A pharmacokinetic
Immunosuppression: too much or too little
interaction can also be problematic where the concen-
St John’s wort, a complementary medicine commonly tration of the QTc-prolonging drug increases due to
taken for depression, as noted previously, is a significant inhibition of its metabolism, for example, ritonavir or
inducer of CYP3A4 metabolism (Table 1). This can lower grapefruit juice increasing the concentration of ziprasi-
the concentrations of the critical calcineurin inhibitor done or quetiapine.44–46
group of medicines, including cyclosporin, everolimus Digoxin toxicity remains a hazard in older and renally
and tacrolimus, which are essential therapies for inhibit- impaired patients. Concurrent diuretic-induced hypoka-
ing the rejection of transplanted organs, and certain laemia in these patients is a risk for serious, potentially
tyrosine kinase inhibitors, for example, tofacitinib and fatal arrhythmias. Monitoring plasma potassium and dig-
irinotecan, the cancer chemotherapeutic.41,42 oxin concentrations more often in these patients,

© 2017 Royal Australasian College of Physicians 507

Day et al.

especially during intercurrent illnesses such as infections, of myotoxicity from statins.50 Those patients with genetic
is recommended. As noted previously, there is an susceptibility to statin-induced rhabdomyolysis are at
increased risk for digoxin toxicity when clarithromycin is increased risk, although routine identification pre-
co-prescribed, but the risk is much greater in older therapy is not yet standard.51 It is important that patients
patients because of the contribution of reduced renal understand that new muscle pains following the pre-
function.46,47 Similarly, the combination of digoxin with scription of statins, or additional medicines if already sta-
spironolactone in patients with renal impairment can bilised on statins, needs to be attended to by their
lead to dangerously increased concentrations of GP/specialist. People of Aboriginal and Torres Strait
digoxin.48 Islander ancestry may be at an increased risk of serious
muscle weakness, rhabdomyolysis and death from statin
exposure and interactions.52
Hypotension
A common problem observed is using potent statins,
Combinations of antihypertensive drugs, some of which such as rosuvastatin, at too high a dose, especially in
may also be prescribed for cardiac failure or renoprotec- older people. There are two problems here. First, the
tion in type II diabetes (e.g. ACE inhibitors or angioten- dose–response relationship, and the ED50,b for statins
sin II receptor inhibitors), increase the risk of postural shifts to the left as patients become older, that is the
hypotension with the attendant risk of injury from falls. same dose in an older person has more effect. Second,
Diltiazem, a CCB, indicated for hypertension can the dose selected is often far too many multiples of the
retard the heart rate and exacerbate heart failure as well ED50, for example, a dose of rosuvastatin of 40 mg when
as contribute to postural hypotension when co- the ED50 is around 1 mg in an older person.53 Under
prescribed with other antihypertensives. It is unfortu- these circumstances, there is an increased risk of muscle
nately common to see patients prescribed this CCB with pain and possible rhabdomyolysis. This may be exacer-
a beta-blocker, risking serious bradycardia as well as bated by a drug interaction that increases the effect of
hypotension. 37 While this combination is often used to the statin.54 On the other hand, use of statins in second-
good effect in cardiology with careful monitoring, older ary prevention in the elderly at an appropriate dose is
patients, especially those with a degree of organ dysfunc- often overlooked. Again, the case for promoting more
tion and polypharmacy, appear to be most at risk of the rational therapeutics based on an individual patient’s
harmful effects of this combination. Diltiazem also is a needs evaluated in the context in which the patient
CYP 3A4/5 inhibitor and a commonly selected antihy- exists can be illustrated by statin prescription or a lack of
pertensive in cardiac transplant patients prescribed calci- it in older people.55
nerin inhibitors, such as cyclosporin, the dose of the
latter being significantly lower in the presence of
diltiazem.49
Central nervous system depression
The media provides an almost daily reminder of the seri-
Rhabdomyolysis ous consequences of combinations of CNS depressants –
Simvastatin, the hypocholesterolaemic medicine, can opioids, antipsychotics, antidepressants, hypno-sedatives
cause muscle damage and pain and, potentially, renal and sedating anti-histaminics, namely, death or serious
failure because of the release of creatine phosphokinase, injury from hypoxia or accident. The risk is compounded
more so with higher doses. Concomitant medicines that by OTC opioid- and anti-histaminic-containing formula-
inhibit CYP P450 3A4/5 and or P-gp, important in the tions and alcohol. For example, alcohol (56%), benzo-
metabolism and transport of simvastatin, can lead to diazepines (17%) and antidepressants (17%) were
very high concentrations of simvastatin.50 Macrolide detected in drivers from 229 fatal motor vehicle acci-
antibiotics, such as erythromycin and clarithromycin, the dents in Ontario, Canada, over 1 year.56 Co-ingestion of
calcium channel blocker diltiazem and the anti-fungal alcohol with prescription medicines known to interact
itraconazole, are recognised antagonists, and alternatives with alcohol is common in adolescents and middle-aged
to these medicines are recommended. Fluvastatin, pra- and older adults with a range of proven adverse effects,
vastatin and rosuvastatin are less subject to these meta- including critical failure to adhere to HIV antiretroviral
bolic interactions. Cyclosporin and gemfibrozil, medications.57,58
commonly co-prescribed with a ‘statin’ in transplanta-
tion patients, also inhibit CYP 3A4/5 (cyclosporin) and b
The dose at which half-maximal effect is achieved. This will
transporters P-gp (cyclosporin) and OATP1B1 (cyclos- be lower in a potent member of a class of drugs, such as the
porin and gemfibrozil), substantially increasing the risk statins, the most potent being rosuvastatin.

508 © 2017 Royal Australasian College of Physicians

 Life-threatening drug interactions

Seizures with potassium or potassium-sparing diuretics, such as

amiloride or spironolactone. A common drug–drug
People with epilepsy are at significant risk of drug–drug
interaction is potassium salts given with a potassiu-
interactions. These occur between medicines taken for
sparing diuretic, such as amiloride.37
their epilepsy, especially as these medicines are suscepti-
ble to interactions. However, some epilepsy medicines,
such as phenytoin, carbamazepine and phenobarbitone, Hypoglycaemia
are known to be strong inducers of metabolism of other
Any diabetic patient may present with hypoglycaemia.
anti-epilepsy drugs, such as lamotrogine, and also other
The combination of insulin and/or a sulfonylurea drug
medicines, including warfarin and oral contraceptives.59
(gliblenclamide, glimepiride) with a DPP-4 inhibitor
Phenytoin toxicity with cerebellar function effects (mid-
(sitagliptin, alogliptin, saxagliptin, vildagliptin) or SGLT2
line ataxia, nystagmus, slurred speech and incoordina-
inhibitor (canagliflozin, dapaglifozin, empagliflozin) can
tion) occurs easily with the inhibition of its metabolism
induce serious hypoglycaemia. Older age, renal impair-
because the latter is saturable in the ‘tight’ therapeutic
ment and concomitant infections are recognised risk fac-
concentration range for this drug. CYP-2C9 is responsible
tors for drug–drug-induced hypoglycaemia.62 In patients
for most of the metabolism of phenytoin, and therefore,
taking oral anti-hyperglycaemic drugs, changes in drug
this can be inhibited by, for example, amiodarone or flu-
therapy ought to lead to the consideration of effects on
conazole. Carbamazepine is metabolised by CYP 3A4/5
blood sugar and heightened surveillance.
and therefore susceptible to the inhibitors and inducers
of this enzyme system. Thus, commencing a macrolide
antibiotic could precipitate carbamazepine toxicity, with Renal failure
a decreased level of consciousness or drowsiness.
A combination of an ACE inhibitor or angiotensin II
inhibitor with a thiazide diuretic and an NSAID places
Serotonin syndrome the patient at great risk of precipitating renal failure –
renal impairment/failure (a.k.a. the ‘triple whammy’).
People with common chronic disorders, such as diabetes This is even more likely in older patients and those with
and heart failure, are also more likely to suffer with a reduced glomerular filtration rate. A common scenario
depression and to be prescribed antidepressants. Com- is an elderly individual whose hypertension and/or heart
monly prescribed serotonin reuptake inhibitors (SSRI), failure is well controlled with an ACE inhibitor and thia-
such as fluoxetine, sertraline and escitalopram, are prone zide diuretic who complains of increasing pain in the
to causing the ‘serotonin syndrome’, which is a distress- knees, hips or back. An NSAID or COX II inhibitor is pre-
ing and potentially very serious neurological disorder scribed or obtained OTC. The patient becomes unwell
characterised by hyperthermia, confusion, tachycardia due to increasing renal impairment and ultimately fail-
and labile blood pressure, hyper-reflexia and clonus.60 ure if not recognised. Hyperkalaemia is also a hazard.63
Other medicines that inhibit serotonin reuptake taken As noted previously, St John’s wort, the herbal medi-
concomitantly can precipitate the syndrome – for exam- cine taken for depression, is a significant inducer of cyto-
ple, tramadol and fentanyl opioid analgesics, St John’s chrome P450 3A4 metabolism. This can lower the
wort, amphetamine and derivatives used recreationally concentrations of the calcineurin inhibitor group of
and the antibiotic linezolid. This syndrome is important cyclosporin, everolimus and tacrolimus, essential thera-
to be aware of and to consider in patients on multiple pies for inhibiting the rejection of transplanted organs,
drugs with the advent of some of the suite of symptoms including the kidneys. On the other hand, the inhibition
noted, although many cases will have other of metabolism of these drugs can lead to renal toxicity.
explanations.61

Where to look for help?

Electrolyte disturbance (hypo- or
Software prescribing packages automatically check for
hyperkalaemia)
drug interactions, but prescribers need to take note of
Hypokalaemia commonly results from thiazide diuretic these. MIMS, Micromedex and UpToDate all also pro-
use and can lead to serious cardiac rhythm disturbances, vide good interaction checkers, useful for ‘day-to-day’
notably in patients taking digoxin. Glucocorticosteroids use. If more detailed and rigorously selected information
can also contribute to hypokalaemia. Hyperkalaemia on drug–drug interactions and options for their manage-
with the risk of cardiac arrest commonly results from ment is needed, then Stockley’s Drug Interactions and Han-
combinations of ACE inhibitors or angiotensin II blockers sten and Horn’s Drug Interaction Analysis and Management

© 2017 Royal Australasian College of Physicians 509

Day et al.

Table 3 Drugs and drug classes with a high risk of involvement in serious drug–drug interactions based on pharmacokinetic (PK) and pharmacody-
namic (PD) mechanisms

Classes Mechanism: PK, PD or PK and PD Individual drugs

Anti-arrhythmics PK and PD Amiodarone, digoxin†

Anticoagulants PK and PD Warfarin, DOAC
Antibiotics PK Ciprofloxacin, erythromycin, rifampicin
Platelet inhibitors PD Clopidogrel, aspirin
Potassium agents PD Spironolactone, amiloride
Anti-seizure agents PK and PD Barbiturates, carbamazepine, phenytoin
Azole anti-fungals PK Fluconazole, itraconazole, ketaconazole, voriconazole
Calcium channel blockers PK Diltiazem, verapamil
Cytotoxics PK and PD Azathioprine, methotrexate
Hypolipidaemics PK and PD Gemfibrozil
Immunosuppressants (calcineurin inhibitors) PK Cyclosporin, everolimus, sirolimus, tacrolimus
Macrolide antibiotics PK Clarithromycin, erythromycin
MAO inhibitors‡,§ PD Phenelzine, tranylcypromine, moclobemide
Protease inhibitors PK Ritonavir
Psychotropics (SSRI, antipsychotics) PK and PD Fluoxetine, lithium, paroxetine
Others PK Allopurinol, St John’s wort, colchicine, theophylline

†Drugs in bold represent drugs most frequently occurring in ‘clinically relevant interactions’ that should be avoided if an alternative is available to pair
with the otherwise interacting drug.23,37 ‡Risk of interaction also exists with selective MAO inhibitors at a high dose. §Linezolid and methylene blue
are mild MAO inhibitors but may also interact. DOAC, direct-acting oral anticoagulants.

are recommended.64 Sorting which interactions are clini- effects of a medicine (e.g. hypotension, increased risk of
cally significant as noted is difficult, a problem of ‘seeing bleeding) is essential. If therapeutic drug-monitoring ser-
the wood for the trees’. Contributing to this is the large vices are available for the medicine of concern in a
number of reports examining interactions in normal potential drug–drug interaction, then concentrations can
volunteers, often vastly different to the reality of our be monitored, optimally prior to the addition of the sec-
patients, especially the elderly, who are exposed to mul- ond drug in a potential interacting drug pair.20,66
tiple potentially interacting drugs. In part, this might When considering the potential for severe interac-
explain the common practice of overriding alerts in elec- tions, check all the patient’s medications, including non-
tronic prescribing systems.65 The Australian Medicines prescription and complementary and alternative medi-
Handbook has usefully evaluated potential drug interac- cines. It may be possible to substitute a drug that does
tions and only include clinically significant interactions not interact or that interacts to a lesser extent or to man-
(https://amhonline.amh.net.au/). age an interaction by increased monitoring or reducing
the dose. A complete and up-to-date list of a patient’s
medications, including OTC and complementary medi-
Minimising the risk of life-threatening
cines, that accompanies them in all their interactions
drug interactions
with all health services, optimally overseen by the
It is impossible to list all potentially life-threatening inter- patient or their carers and their pharmacists and GP, is
actions; however, the drugs and drug classes listed in the ‘elusive’ gold standard to which we all aspire and
Table 3 have a high risk of serious interactions. Consider need to continue to strive towards. Additionally, we
potential interactions carefully before prescribing or dis- need to enquire about all of the substances that a person
pensing any of them or when adding or stopping other may be ingesting, including alcohol, tobacco and recrea-
drugs in a patient previously stabilised on one of the tional drug intake such as cannabis,22 to understand the
listed drugs. Clinical monitoring for the known harmful risk of drug–drug interactions.

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512 © 2017 Royal Australasian College of Physicians