Life-threatening drug interactions: what the physician needs to know

Transcription

1 CLINICAL PERSPECTIVES Life-threatening drug interactions: what the physician needs to know Richard O. Day, 1,2,3 Leone Snowden 4 and Andrew J. McLachlan 5 1 Department of Clinical Pharmacology and Toxicology, St Vincent s Hospital, 2 School of Medical Sciences, Medicine, and 3 St Vincent s Clinical School, Medicine, University of New South Wales, 4 New South Wales Medicines Information Centre, and 5 Faculty of Pharmacy, University of Sydney and Centre for Education and Research on Ageing, Concord Hospital, Sydney, New South Wales, Australia Key words drug drug interactions, adverse drug reactions, adverse drug events, pharmacokinetic drug interactions, pharmacodynamic drug interactions, cytochrome P 450 metabolism. Correspondence Richard O. Day, Clinical Pharmacology and Toxicology, Therapeutic Centre, St Vincent s Hospital and UNSW, St Vincent s Hospital, Victoria Street, Darlinghurst, Sydney, NSW 2010, Australia. r.day@unsw.edu.au Abstract Adverse drug drug interactions are a significant cause of adverse events and outcomes. Their incidence is rising, with more patients taking more drugs, and newer, more precise but often more hazardous drugs becoming available. Despite considerable information, including computerised alerts about potential adverse drug drug interactions, prescribers increasingly override alerts, possibly symptomatic of the immense problem of evaluating the risk of an interaction in a particular patient. Many reports emanate from small studies often of normal and young volunteers, entirely different from the real world where, more often, older patients with multiple health conditions are receiving many more than the two drugs identified in the drug interaction report. Focusing on those drug drug interactions that are clinically relevant is necessary, and increasingly, tools and reliable sources of this information are easily accessible. Received 16 July 2016; accepted 11 November doi: /imj Introduction Adverse drug events and reactions have a significant impact on patients and healthcare systems, accounting for a considerable proportion of healthcare resources and costs. Adverse drug reactions (ADR) are a substantial cause of hospital admissions, in the order of 5%, and are a major cause of mortality. 1,2 It has been estimated that an ADR will occur during 6 15% of hospital admissions, and these increase the length of stay, morbidity and death rate. Rates are higher in patients who have longer stays in hospital and are older, female and taking more concurrent medications. 3 A recent Swiss study of people referred to a community nursing service for medication management revealed that 41% had medication errors, Funding: R. O. Day s research work is supported by the National Health and Medical Research Council Program Grant APP and Australian Research Council Linkage Grant LP A. J. McLachlan is the Program Director of the National Health and Medical Research Council of Australia Centre for Research Excellence in Medicines and Ageing (CREMA). Conflict of interest: None. 13% required at least one hospitalisation or a medical review as a result, and over 60% were preventable. 3 In an Australian study, up to 21% of hospital admissions related to adverse drug events were caused by drug interactions, and it is widely recognised that adverse drug interactions make up a significant proportion of adverse drug events and reactions. 4 A literature review found that 0.6 5% of hospital admissions were due to drug interactions, including loss of important therapeutic effect such as analgesia. 5 A more recent systematic review confirmed that drug drug interactions accounted for 1.1% of hospital admissions alone, which was 22% of the admissions for ADR in this study. 6 Furthermore, it is estimated that 1 in 200 hospitalised patients will experience 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 systems warning prescribers and pharmacists of potential interactions. Drug drug interactions are a major contributor to avoidable morbidity and mortality in modern healthcare. Some have linked this increasing problem of adverse drug events in part at least to a declining number of clinical pharmacologists. Clinical pharmacologists specialise 2017 Royal Australasian College of Physicians 501

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

3 Life-threatening drug interactions likely seen with the index condition, the therapies recommended and their risk of serious interactions with those of the index condition. 14 For example, statin therapy in older patients may be indicated by cardiovascular guidelines, but around 10% of older patients prescribed statins and admitted to a teaching hospital were discovered to have potentially clinically significant drug interactions with these ubiquitous medicines. 16 An extension of this problem of polypharmacy is that, too commonly, prescribers simply do not know what medicines a person is actually taking, highlighting the importance of a comprehensive and current medication history with reconciliation during transitions of care. The increasing reality of multiple prescribers for a single patient without effective communication between prescribers is a significant contributor to inappropriate polypharmacy. The over-the-counter (OTC) and complementary medicines self-prescribed by our patients also can contribute to polypharmacy and lifethreatening interactions. Metabolism and transporters Cytochrome P450 enzymes (CYP) The cytochrome P450 enzymes (CYP P450) family of enzymes is responsible for most of the oxidative metabolism of medicines that occurs in the liver and, to some extent, in the gut wall. P-glycoprotein (P-gp) is an exporter protein that transports medicines into the gut lumen with a significant cross-over in substrate selectivity for medicines also metabolised by CYP 3A4. It is well established that there are significant, potentially very serious adverse drug events that are due to drug drug interactions related to induction or inhibition of CYP450 enzymes by one of a pair of the interacting drugs, the other being subject to the induction or inhibition. Highly significant are those drug drug interactions involving CYPP450 3A4/5 (Table 1). Less well appreciated but increasingly recognised is that polymorphisms of these key drug-metabolising enzymes contribute to the risk of life-threatening drug interactions. For example, an individual taking the opioid analgesic tramadol is reliant on CYP2D6 to metabolise the drug in the liver and thus detoxify it. Should either fluoxetine or paroxetine, the serotonin reuptake inhibitor antidepressants, be commenced both strong inhibitors of CYP2D6 there is a risk of excessive sedation from increased concentrations of tramadol. There is an additional important risk related to pharmacodynamic effects, namely, the serotonin syndrome, as tramadol also has serotonin reuptake properties. The risk of the serotonin syndrome with this combination of SSRI antidepressants and tramadol increases with the dose of 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 consideration in reducing and avoiding such risks. Even without a genetic polymorphism, variations in the amount of CYP between individuals can change risks significantly. Thus, if our patient taking tramadol has relatively low amounts of functional CYP2D6 enzyme per se without polymorphisms, they would be more prone to the serotonin syndrome if fluoxetine were commenced as, relatively, they already have high concentrations of tramadol. On the other hand, if our patient had relatively large amounts of functional CYP2D6, she or he would be more prone to significant inhibition by fluoxetine and thus a more dramatic increase in tramadol concentrations 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, tacrolimus, everolimus Anticonvulsants Carbamazepine, phenytoin, barbiturates Azole anti-fungals Itraconazole, ketoconazole, posaconazole, voriconazole Anti-arrhythmics: amiodarone Antibiotics Rifampicin Macrolide antibiotics Clarithromycin, erythromycin Statins: simvastatin, atorvastatin, fluvastatin St John s wort Incidental drugs: colchicine, irinotecan, zolpidem Enzalutamide Protease inhibitor antivirals Ritonavir, indinavir, saquinavir, telapravir, bocepravir Antihypertensives: diltiazem, lercanidipine Grapefruit juice Psychotropics: mirtazapine, quetiapine Calcium channel Diltiazem, verapamil blockers Cancer drugs: 21,66 for example, kinase inhibitors cobimetinib, dabrafenib, imatinib, vermurafenib Modafinil, efavirenz Bocepravir, cobicistat Any inducer or inhibitor can operate on any substrate with a potentially serious drug drug interaction result. Selected substrates, inducers and inhibitors more likely to be involved in serious drug drug interactions Royal Australasian College of Physicians 503

4 Day et al. Another example of the influence of the amount of CYP enzyme an individual has on the potential for toxicity and drug drug interactions relates to the important CYP 3A4/5 group (Table 1). These enzymes are critical for the metabolism of many important medicines, such as the calcineurin inhibitors cyclosporin and tacrolimus and some statin hypolipidaemic drugs, including simvastatin, fluvastatin and atorvastatin. A drug that inhibits CYP 3A4/5, such as the macrolide antibiotic clarithromycin, will induce a much greater increase in concentration in a drug such as tacrolimus, which is reliant on this enzyme for its metabolism, if the individual patient has above average amounts of CYP 3A4/5 enzyme. 18 Powerful CYP 3A4/5 inducers, like carbamazepine, phenytoin, rifampicin or St John s wort, prescribed in a patient already taking the important antiarrhythmic amiodarone, which is metabolised substantially by CYP3A4, can lead to a major decrease in amiodarone plasma concentrations and a potentially fatal arrhythmia. This effect will be much greater if the individual has relatively less hepatic CYP3A4/5 such that induction will have a significantly greater effect compared to those with inherently more CYP3A4. 19,20 A plethora of oral, small molecule, cancer pharmacotherapeutics, that are revolutionising the treatment of many previously poor prognosis cancers, such as lung cancer and melanoma, has become available since Unfortunately, many are metabolised by the CYP P450 3A4/5 and P-gp enzyme and transporter systems and are therefore subject to multiple drug interactions. 21 For example, cobimetinib, a kinase inhibitor with efficacy in un-resectable metastatic melanoma, is a substrate for CYP 3A4/5 and so is subject to an increased effect with CYP 3A inhibitors and the opposite with inhibitors of CYP 3A. Furthermore, cobimetinib is known to cause myelosuppression, hypertension and myopathy and so is subject to pharmacodynamic drug drug interactions with other medicines associated with myelosuppression (e.g. cytotoxics), hypertension (e.g. NSAID) or myopathy (e.g. statins), especially if there is also a CYP 3A4/5 inhibitor being taken concomitantly (Table 1). 21 Other CYP P450 enzymes are significant in drug drug interactions, including 2D6, 2C9 and 2C19. With new drugs, it is important to consider whether drug drug interactions are a feature. For example, another important CYP 450 enzyme for the metabolism of a limited number of medicines is CYP 1A2. Pomalidomide, a newly available thalidomide analogue and substrate for CYP 1A2 used to treat multiple myeloma, can have its metabolism inhibited significantly by ciprofloxacin or fluvoxamine with increased risk for neutropenia and venous thromboembolus. 21 Such interactions are more easily missed simply because the medicine is recently available and prescribed by a specialist, in this case an oncologist, but the patient s GP is dealing with infections and mental health issues and prescribes an antibiotic or an antidepressant unaware of the potential serious toxicity that may be precipitated. Another hazard that prescribers are increasingly dealing with is concomitant alcohol, tobacco and/or recreational drugs, notably cannabis. The latter is also being used increasingly for medicinal purposes, especially in individuals with cancer and chronic pain. CYP P450 1A2 is induced by both tobacco and marijuana smoke, and the effect is additive so that substrate medicines will potentially be less efficacious, for example, clozapine, duloxetine and erlotinib. Additionally, inducers and inhibitors of cytochrome P450 3A4/5 influence the concentrations and, thus, effects of Δ 9 -tetrahydrocannabinol and cannabidiol derived from vapourised THC/cannabidiol. Much work is needed to unravel the significance of drug interactions involving cannabis derivatives and products. 22 Prescribers can be easily overwhelmed trying to evaluate the risk for CYP P450-based drug interactions in their patients given the numbers of medicines, enzymes and sources of information to consider. Helpfully, a very useful criteria-based analysis of the risk levels for these interactions has been constructed that has concluded that the number of drugs that is proven or likely major perpetrators of pharmacokinetic drug drug interactions is relatively small, which is inconsistent with the high rates of alerting from various sources, including computerised decision support systems. 23 A further increasing problem with metabolic, pharmacokinetic drug drug interactions is the individual patient on multiple medicines that can interact with each other. Multiple interactions are possible, but the likely aggregate effect of these is speculative as there is no reliable guidance available in these situations. For example, people living with HIV infection taking multiple antiretroviral medicines may be prescribed multiple concomitant prophylactic antimicrobial drugs, and these patients increasingly have significant other conditions, such as cardiac disease, diabetes and depression. 24 A new challenge, revealed in an analysis of the risk of potentially clinically significant drug interactions in patients with hepatitis C commenced on an array of new direct acting antiviral agents, has shown that the risk is considerable (see For example, a risk in up to 66% of patients prescribed ombitasvir/paritaprevir/ritonavir dasabuvir is anticipated in one of many possible regimens, with likely interacting medicines including proton pump inhibitors (PPI), thyroid hormones and calcium channel blockers (CCB). 25. In these complex situations, conservative dose rates, increased Royal Australasian College of Physicians

5 Life-threatening drug interactions monitoring and an educated patient are important protections against unexpected toxicity from drug interactions. P-glycoproteins and other transporter molecules A wide variety of transporter proteins is responsible for the movement of drugs across cell membranes. Most well known is P-gp that pumps medicines out of cells, such as from gut cells back into the gut or the central nervous system at the blood brain barrier back into the systemic circulation. Many of the drugs that are substrates, inducers or inhibitors of CYP 3A4 act in a similar manner on P-gp. Inducers will decrease and inhibitors will increase plasma concentrations of P-gp substrate drugs. Well-known substrates are digoxin, apixiban, dabigatran, cyclosporin, amiodarone, imitanib and irinotecan; well-known inducers include rifampicin, carbamazepine and St John s wort; and well-known inhibitors include clarithromycin, erythromycin, itraconazole, carvedilol, ritonavir, vemurafenib and verapamil. An important P-gp-based interaction involves digoxin. Concentrations of orally administered digoxin increase markedly with the addition of clarithromycin, and this effect is due to the inhibition of the P-gp-mediated transport of digoxin into the gut and renal tubules. 26 Another P-gp interaction affecting digoxin is seen with the coadministration of rifampicin that leads to substantially decreased digoxin concentrations due to the induction of P-gp. 27 Interactions in the gut Medicines that act in the gut can interfere with the absorption of other medicines, and serious consequences may result. For example, the cholesterol-lowering resin cholestyramine will reduce the absorption and concentrations of the active metabolites of mycophenolate by 35 40% 28 and also other medicines critical in transplantation and autoimmune disorders, including leflunomide and its active metabolite. Iron supplements are known to interfere with the absorption of many drugs, notably fluoroquinolones and tetracycline antibiotics through the reduction of bioavailability due to iron medicine complex formation. 29 Antacids not only bind medicines in the gut but also lead to ph changes in the gut and urine that can affect absorption and/or the renal clearance of weak acids and bases. Thus, salicylate concentrations fall because of alkalinisation of urine, 30 while a number of important cancer pharmacotherapeutics, including gefitinib and erlotinib, and many HIV medicines, such as dolutegravir, may have substantial reductions in bioavailability. 31 A general rule is to take medicines 2 h before or 3 6 h after any cholestyramine, oral iron preparations or antacids. PPI and histamine 2 selective inhibitors also reduce gastric ph, and this can influence the absorption of many medicines very substantially. Thus, it is advised that due to the significant drop in concentrations and area under the concentration time curve of the tyrosine kinase inhibitor erlotinib due to concomitant PPI (about 50% decrease), the combination ought to be avoided. The solubility of the erlotinib is reduced greatly in non-acid environments. 32 As PPI have potentially significant effects on the absorption of many drugs, it is imperative that their use, especially in older people, is reviewed as, oftentimes, a convincing rationale is absent. Organ dysfunction Organ impairments contribute to the risk of lifethreatening drug interactions. Impaired renal function is common, especially in older and diabetic patients. Surprisingly, significant renal impairment is often not diagnosed because a mildly elevated plasma creatinine concentration in an older, low-bodyweight individual is not recognised to be indicative of this condition. If one of a pair of interacting drugs is reliant on the kidney for its clearance from the body, then the risk of a lifethreatening interaction can be substantially increased. For example, the active form of morphine, morphine-6- glucuronide, is dependent in part on glomerular filtration for its elimination. 33 The addition of a second central nervous system (CNS) depressant will be more hazardous in a renally impaired patient taking morphine. If a patient has significant cirrhosis, then the bioavailability of oral morphine would be dramatically increased as first-pass metabolism is greatly reduced as a result. This is equivalent to a very large dose increase, for example, the equivalent of doubling of a dose is not unusual. Adding another CNS depressant, such as an antipsychotic or hypnotic drug, could tip the patient into severe CNS and thus respiratory depression. Life-threatening harm from drug drug interactions Bleeding and thrombosis Warfarin and the direct-acting oral anticoagulants (dabigatran, rivaroxaban and apixaban) are hazardous in their own right but more so in patients taking other medicines that affect the pharmacokinetics or the pharmacodynamics of these anticoagulants. The hazard is the greatest when stopping or starting other medicines or in patients with organ dysfunction (hepatic or renal). For example, starting or stopping macrolide antibiotics, such as erythromycin or clarithromycin, that inhibit CYP3A Royal Australasian College of Physicians 505

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

7 Life-threatening drug interactions metabolite oxypurinol inhibit the enzyme xanthine oxidase, which is also important in the detoxification of azathioprine. 38 The combination can be used if the dose of azathioprine or its active metabolite 6-mercaptopurine is reduced to about a quarter to a third, and the patient is closely monitored for marrow toxicity. In fact, the combination is being used by gastroenterologists specialising in inflammatory bowel diseases in order to enhance the effectiveness of azathioprine, and safety is being enhanced by regular monitoring of the concentrations of azathioprine metabolites in blood. 39 Illustrating the important intersection of genetic variability between patients contributing to the risk of life-threatening drug interactions, patients with low concentrations of thiopurine methyltransferase enzyme (TPMT) at baseline need to be identified prior to prescribing azathioprine. If moderately low TPMT concentrations are detected, even smaller doses of allopurinol would have to be selected, and therapeutic drug monitoring of the active metabolites of azathioprine undertaken by experienced clinicians is strongly recommended. Extremely low amounts of TPMT would negate the use of the combination with azathioprine completely. Methotrexate This drug is very widely prescribed for chronic inflammatory conditions, notably rheumatoid arthritis, and also as a corticosteroid-sparing agent in conditions where long-term corticosteroid therapy may be needed, such as polymyalgia rheumatica. Methotrexate is a folate antagonist, and a combination with other folate antagonists, such as trimethoprim and combinations of trimethoprim with sulfamethoxasole, may lead to agranulocytosis and thrombocytopenia with the potential for serious infection. 40 This catastrophic outcome is more likely in renally impaired patients (or those receiving drugs that affect renal function) as methotrexate is partially eliminated renally, and as noted, renal impairment is often overlooked or missed in the older patients. Immunosuppression: too much or too little St John s wort, a complementary medicine commonly taken for depression, as noted previously, is a significant inducer of CYP3A4 metabolism (Table 1). This can lower the concentrations of the critical calcineurin inhibitor group of medicines, including cyclosporin, everolimus and tacrolimus, which are essential therapies for inhibiting the rejection of transplanted organs, and certain tyrosine kinase inhibitors, for example, tofacitinib and irinotecan, the cancer chemotherapeutic. 41,42 Viral diseases Interactions involving medications used to treat HIV are numerous and can be serious. An excellent resource has been maintained by the Liverpool HIV Pharmacology Group, University of Liverpool, UK ( hiv-druginteractionslite.org/). Loss of suppression of the virus is the most important hazard. Thus, for example, a major reduction in indinavir concentrations is likely to occur with the prescription of carbamazepine, a CYP 3A4/5 inducer indicated for epilepsy or neuropathic pain (Table 1). The potential for interactions with directacting antiviral agents to treat hepatitis C is discussed above. Arrhythmias Medicines that prolong the QT interval on the ECG or interactions that increase the QT prolongation effect of either drug can cause irreversible torsades des pointes ventricular arrhythmia. Several medicines have been withdrawn from the market, for example, the calcium channel blocker mibefradil (Posicor), because they increase the QTc and have been associated with torsades and sudden death. Patients with inherent, genetically based, long QT syndrome (QT > 450 ms in adult males; >470 in adult females) 43 are more at risk, and patients with a family history of sudden death due to this problem need to be aware of medicines that can cause torsades des pointes ( everyone/). Risk increases with female gender, increased age, electrolyte abnormalities and a range of cardiac conditions, such as heart failure. Psychotropic medications have been identified as a particular risk group citalopram, an SSRI; thioridazine, a typical antipsychotic and ziprasidone, an atypical antipsychotic as manifesting the most risk for QTc prolongation. Many non-psychiatric medications are also associated with prolonged QTc, for example, sotalol, macrolide and quinolone antibiotics, anti-fungals, such as ketoconazole, and anti-malarials. Combinations of drugs that each prolong the QTc increase the risk of torsades (e.g. citalopram and thioridazine). A pharmacokinetic interaction can also be problematic where the concentration of the QTc-prolonging drug increases due to inhibition of its metabolism, for example, ritonavir or grapefruit juice increasing the concentration of ziprasidone or quetiapine Digoxin toxicity remains a hazard in older and renally impaired patients. Concurrent diuretic-induced hypokalaemia in these patients is a risk for serious, potentially fatal arrhythmias. Monitoring plasma potassium and digoxin concentrations more often in these patients, 2017 Royal Australasian College of Physicians 507

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

9 Life-threatening drug interactions Seizures People with epilepsy are at significant risk of drug drug interactions. These occur between medicines taken for their epilepsy, especially as these medicines are susceptible to interactions. However, some epilepsy medicines, such as phenytoin, carbamazepine and phenobarbitone, are known to be strong inducers of metabolism of other anti-epilepsy drugs, such as lamotrogine, and also other medicines, including warfarin and oral contraceptives. 59 Phenytoin toxicity with cerebellar function effects (midline ataxia, nystagmus, slurred speech and incoordination) occurs easily with the inhibition of its metabolism because the latter is saturable in the tight therapeutic concentration range for this drug. CYP-2C9 is responsible for most of the metabolism of phenytoin, and therefore, this can be inhibited by, for example, amiodarone or fluconazole. Carbamazepine is metabolised by CYP 3A4/5 and therefore susceptible to the inhibitors and inducers of this enzyme system. Thus, commencing a macrolide antibiotic could precipitate carbamazepine toxicity, with a decreased level of consciousness or drowsiness. Serotonin syndrome People with common chronic disorders, such as diabetes and heart failure, are also more likely to suffer with depression and to be prescribed antidepressants. Commonly prescribed serotonin reuptake inhibitors (SSRI), such as fluoxetine, sertraline and escitalopram, are prone to causing the serotonin syndrome, which is a distressing and potentially very serious neurological disorder characterised by hyperthermia, confusion, tachycardia and labile blood pressure, hyper-reflexia and clonus. 60 Other medicines that inhibit serotonin reuptake taken concomitantly can precipitate the syndrome for example, tramadol and fentanyl opioid analgesics, St John s wort, amphetamine and derivatives used recreationally and the antibiotic linezolid. This syndrome is important to be aware of and to consider in patients on multiple drugs with the advent of some of the suite of symptoms noted, although many cases will have other explanations. 61 Electrolyte disturbance (hypo- or hyperkalaemia) Hypokalaemia commonly results from thiazide diuretic use and can lead to serious cardiac rhythm disturbances, notably in patients taking digoxin. Glucocorticosteroids can also contribute to hypokalaemia. Hyperkalaemia with the risk of cardiac arrest commonly results from combinations of ACE inhibitors or angiotensin II blockers with potassium or potassium-sparing diuretics, such as amiloride or spironolactone. A common drug drug interaction is potassium salts given with a potassiusparing diuretic, such as amiloride. 37 Hypoglycaemia Any diabetic patient may present with hypoglycaemia. The combination of insulin and/or a sulfonylurea drug (gliblenclamide, glimepiride) with a DPP-4 inhibitor (sitagliptin, alogliptin, saxagliptin, vildagliptin) or SGLT2 inhibitor (canagliflozin, dapaglifozin, empagliflozin) can induce serious hypoglycaemia. Older age, renal impairment and concomitant infections are recognised risk factors for drug drug-induced hypoglycaemia. 62 In patients taking oral anti-hyperglycaemic drugs, changes in drug therapy ought to lead to the consideration of effects on blood sugar and heightened surveillance. Renal failure A combination of an ACE inhibitor or angiotensin II inhibitor with a thiazide diuretic and an NSAID places the patient at great risk of precipitating renal failure renal impairment/failure (a.k.a. the triple whammy ). This is even more likely in older patients and those with a reduced glomerular filtration rate. A common scenario is an elderly individual whose hypertension and/or heart failure is well controlled with an ACE inhibitor and thiazide diuretic who complains of increasing pain in the knees, hips or back. An NSAID or COX II inhibitor is prescribed or obtained OTC. The patient becomes unwell due to increasing renal impairment and ultimately failure if not recognised. Hyperkalaemia is also a hazard. 63 As noted previously, St John s wort, the herbal medicine taken for depression, is a significant inducer of cytochrome P450 3A4 metabolism. This can lower the concentrations of the calcineurin inhibitor group of cyclosporin, everolimus and tacrolimus, essential therapies for inhibiting the rejection of transplanted organs, including the kidneys. On the other hand, the inhibition of metabolism of these drugs can lead to renal toxicity. Where to look for help? Software prescribing packages automatically check for drug interactions, but prescribers need to take note of these. MIMS, Micromedex and UpToDate all also provide good interaction checkers, useful for day-to-day use. If more detailed and rigorously selected information on drug drug interactions and options for their management is needed, then Stockley s Drug Interactions and Hansten and Horn s Drug Interaction Analysis and Management 2017 Royal Australasian College of Physicians 509

10 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 pharmacodynamic (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 clinically significant as noted is difficult, a problem of seeing the wood for the trees. Contributing to this is the large number of reports examining interactions in normal volunteers, often vastly different to the reality of our patients, especially the elderly, who are exposed to multiple potentially interacting drugs. In part, this might explain the common practice of overriding alerts in electronic prescribing systems. 65 The Australian Medicines Handbook has usefully evaluated potential drug interactions and only include clinically significant interactions ( Minimising the risk of life-threatening drug interactions It is impossible to list all potentially life-threatening interactions; however, the drugs and drug classes listed in Table 3 have a high risk of serious interactions. Consider potential interactions carefully before prescribing or dispensing any of them or when adding or stopping other drugs in a patient previously stabilised on one of the listed drugs. Clinical monitoring for the known harmful effects of a medicine (e.g. hypotension, increased risk of bleeding) is essential. If therapeutic drug-monitoring services are available for the medicine of concern in a potential drug drug interaction, then concentrations can be monitored, optimally prior to the addition of the second drug in a potential interacting drug pair. 20,66 When considering the potential for severe interactions, check all the patient s medications, including nonprescription and complementary and alternative medicines. It may be possible to substitute a drug that does not interact or that interacts to a lesser extent or to manage 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 medicines, that accompanies them in all their interactions with all health services, optimally overseen by the patient or their carers and their pharmacists and GP, is the elusive gold standard to which we all aspire and need to continue to strive towards. Additionally, we need to enquire about all of the substances that a person may be ingesting, including alcohol, tobacco and recreational drug intake such as cannabis, 22 to understand the risk of drug drug interactions. References 1 Beijer HJ, de Blaey CJ. Hospitalisations caused by adverse drug reactions (ADR): a meta-analysis of observational studies. Pharm World Sci 2002; 24: Kongkaew C, Noyce PR, Ashcroft DM. Hospital admissions associated with adverse drug reactions: a systematic review of prospective observational studies. Ann Pharmacother 2008; 42: Elliott RA, Lee CY, Beanland C, Vakil K, Goeman D. Medicines management, medication errors and adverse medication events in older people referred to a community nursing service: a retrospective observational study. Drugs Real World Outcomes 2016; 3: Roughead EE, Kalisch LM, Barratt JD, Gilbert AL. Prevalence of potentially hazardous drug interactions amongst Australian veterans. Br J Clin Pharmacol 2010; 70: Royal Australasian College of Physicians