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GHENT UNIVERSITY

FACULTY OF PHARMACEUTICAL SCIENCES

Department of Bioanalysis

Pharmaceutical Care Unit

Academic year 2014-2015

QT-PROLONGING AND ANTICHOLINERGIC MEDICATION IN OLDER BELGIAN POLYPHARMACY PATIENTS

Eline CHRISTIAEN

1ST master pharmaceutical care

Promoter:

Prof. dr. K.Boussery

Commissioners:

Prof. dr. J.Van Bocxlaer

Prof. dr. A.Somers

GHENT UNIVERSITY

FACULTY OF PHARMACEUTICAL SCIENCES

Department of Bioanalysis

Pharmaceutical Care Unit

Academic year 2014-2015

QT-PROLONGING AND ANTICHOLINERGIC MEDICATION IN OLDER BELGIAN POLYPHARMACY PATIENTS

Eline CHRISTIAEN

1ST master pharmaceutical care

Promoter:

Prof. dr. K.Boussery

Commissioners:

Prof. dr. J.Van Bocxlaer

Prof. dr. A.Somers

“The author and the promoters give the authorization to consult and to copy parts of this thesis for personal use only. Any other use is limited by the laws of copyright, especially concerning the obligation to refer to the source whenever results from this thesis are cited.”

June 2, 2015

Promoter author

Prof. dr. K. Boussery Eline Christiaen

SUMMARY

Polypathology and polypharmacy are a growing problem in our aging society. Consequently, older adults are at greater risk of ADEs due to physiological, pharmacokinetic and pharmacodynamic changes. ADEs are potentially dangerous and can lead to hospitalization and even death. In this study we focus on two types of ADEs; QT-prolongation and anticholinergic (side-)effects. QT-prolongation in itself is not a large problem but can possibly lead to fatal TdP. Anticholinergic (side-) effects on the other hand can include for example (further) deterioration of the aging brain, dry mouth and gastrointestinal problems. Recently there has been increasing research on both of these topics.

In this thesis, the general drug use of 1016 community-dwelling and 400 institutionalized older adults in Belgium was evaluated. Besides that, a literature search was conducted for existing evidence- based risk scales to determine the risk of QT-prolongation and anticholinergic (side-) effects. Consequently the use of QT-prolonging drugs and drugs with anticholinergic properties was evaluated for both subpopulations and a comparison between the subpopulations was made.

There is only one risk scale for QT-prolongation and TdP useful for estimating an individual community-dwelling or institutionalized patient’s risk of TdP available in literature, the one described on the credible meds website. This risk scale was used to evaluate the use of QT-prolonging drugs for the 1016 community-dwelling and 400 institutionalized older Belgian polypharmacy patients.

Anticholinergic risk scales on the other hand exist in abundance but the risk scale described by Duran et al. was chosen because it is the most evidence-based risk scale in the literature. The use of drugs with anticholinergic properties was also evaluated with the risk scale described by Rudolph et al. because it is the most commonly used anticholinergic risk scale.

Generally, the community-dwelling older adults in this study take an average of 11 ± 4 drugs (mean ± SD), while the institutionalized older adults take an average of 12 ± 5 drugs (mean ± SD).

In this study, 63.4% of the community-dwelling older adults and 85.8% of the institutionalized older adults used one or more QT-prolonging drugs. The top 10 most commonly used drugs are largely comparable, but institutionalized older adults relatively use these drugs more.

Besides that, 42.0% of the community-dwelling older adults and 72.9% of the institutionalized older adults used a drug with anticholinergic properties according to Duran et al. while this is 24.6% and 60.0% respectively according to Rudolph et al. The top 10 most commonly used drugs according to Duran et al. and Rudolph et al. were largely comparable but some drugs included by Duran et al. were not included by Rudolph et al. Here as well the percentages in the top 10 were considerably higher for the population of institutionalized older adults.

SAMENVATTING

Polypathologie en polyfarmacie zijn een groeiend probleem in onze verouderende maatschappij. Daarnaast hebben ouderen een groter risico op bijwerkingen door fysiologische, farmacokinetische en farmacodynamische veranderingen. Bijwerkingen kunnen gevaarlijk zijn en leiden tot hospitalisatie en mogelijks zelfs tot de dood. In deze studie werden QT-verlenging en anticholinerge (bij-)werkingen bestudeerd. QT-verlenging op zich is geen groot probleem, maar het kan leiden tot het mogelijks dodelijke TdP. Anticholinerge (bij-)werkingen daarentegen kan leiden tot de (verdere) achteruitgang van de verouderende hersenen, droge mond en gastro-intestinale problemen. De laatste tijd wordt er meer onderzoek verricht naar deze onderwerpen.

In deze thesis werd het algemeen medicatiegebruik van 1016 thuiswonende en 400 geïnstitutionaliseerde oudere polyfarmacie patiënten in België geëvalueerd. Daarnaast werd in de literatuur gezocht naar risicoschalen voor QT-verlenging en anticholinerge (bij-) werkingen. Het gebruik van deze medicatie werd ook geëvalueerd.

Er was slechts één risicoschaal voor QT-verlenging en TdP bruikbaar voor de individuele patiënt, degene beschreven door AZCERT. Deze risicoschaal werd gebruikt om het gebruik van QT- verlengende medicatie in de subpopulaties te evalueren.

Er bestaan meerdere anticholinerge risicoschalen, maar de risicoschaal beschreven door Duran et al. werd gebruikt omdat deze de hoogste graad van evidentie heeft. Daarnaast evalueerden we het gebruik van geneesmiddelen met anticholinerge eigenschappen ook a.d.h.v. de risicoschaal beschreven door Rudolph et al. omdat deze in de literatuur het meest gebruikt wordt.

In het algemeen nemen de thuiswonende ouderen in deze studie een gemiddelde van 11 ± 4 geneesmiddelen (gemiddelde ± SD), terwijl dit 12 ± 5 geneesmiddelen (gemiddelde ± SD) was bij de geïnstitutionaliseerde patiënten.

In deze studie gebruikte 63.4% van de thuiswonende ouderen en 85.8% van de geïnstitutionaliseerde ouderen een of meerdere QT-verlengend geneesmiddelen. De top 10 meest gebruikte geneesmiddelen was grotendeels hetzelfde, maar deze geneesmiddelen werden meer gebruikt door de geïnstitutionaliseerde ouderen.

Daarnaast gebruikte 42.0% van de thuiswonende ouderen en 72.9% van de geïnstitutionaliseerde ouderen een of meerdere geneesmiddelen met anticholinerge eigenschappen volgens Duran et al. Dit was respectievelijk 24.6% and 60.0% volgens Rudolph et al. De top 10 meest voorkomende geneesmiddelen met anticholinerge eigenschappen waren voor beide subpopulaties grotendeels gelijk maar het procentueel voorkomen was hoger voor de geïnstitutionaliseerde ouderen.

ACKNOWLEDGMENTS

I would like to thank the following people for helping me realize this thesis.

First of all I Prof.dr. Boussery for this very interesting study and the advice he gave when I was stuck.

Eline Tommelein for her inspiring ideas, correcting this thesis, her patience... I really couldn’t have wished for a better mentor.

Simon Capiau for helping me order the database of community-dwelling older adults.

And finally, An Mestach for reading and correcting this thesis.

TABLE OF CONTENTS PART 1: INTRODUCTION ...... 1

1.1 PHYSIOLOGICAL CHANGES AND ADVERSE DRUG EVENTS (ADEs) IN OLDER ADULTS ...... 1

1.2 QT-PROLONGATION AND TORSADES DE POINTES (TdP) ...... 3

1.2.1 Physiology ...... 3

1.2.2 Types of QT-prolongation ...... 7

1.2.2.1 Congenital Long QT Syndrome (cLQTS) ...... 7

1.2.2.2 Drug-induced Long QT Syndrome (diLQTS) ...... 8

1.2.3 Risk factors for QT-prolongation and TdP ...... 9

1.2.4 Prevention ...... 10

1.2.5 Treatment ...... 11

1.3 DRUGS WITH ANTICHOLINERGIC (SIDE-) EFFECTS ...... 12

1.3.2 Pharmacology ...... 12

1.3.3 Anticholinergic (side-) effects in older patients ...... 13

PART 2: OBJECTIVES ...... 14

PART 3: REVIEW OF QT-PROLONGING RISK SCALES IN OLDER ADULTS ...... 15

3.1 METHODS ...... 15

3.2 RESULTS ...... 15

PART 4: REVIEW OF ANTICHOLINERGIC RISK SCALES IN OLDER ADULTS ...... 17

4.1 METHODS ...... 17

4.2 RESULTS ...... 17

PART 5: DRUG USE OF BELGIAN OLDER POLYPHARMACY PATIENTS ...... 19

5.1 METHODS ...... 19

5.1.1 Study design, setting and participants ...... 19

5.1.2 Data-analysis ...... 19

5.1.3 Evaluation of use of QT-prolonging drugs in our populations ...... 20

5.1.4 Evaluation of use of drugs with anticholinergic properties in our populations ...... 20

5.2 RESULTS ...... 21

5.2.1 Basic characteristics ...... 21

5.2.2 General drug use of the included population ...... 22

5.2.3 Evaluation of the individual use of QT-prolonging drugs and drugs with anticholinergic properties ...... 23

PART 6: DISCUSSION ...... 33

6.1 RISK SCALES ...... 33

6.1.1 QT-prolonging risk scales in older adults ...... 33

6.1.2 Anticholinergic risk scales in older adults ...... 34

6.2 GENERAL DRUG USE OF THE INCLUDED POPULATIONS ...... 36

6.3 EVALUATION OF THE INDIVIDUAL USE OF QT-PROLONGING DRUGS ...... 37

6.4 EVALUATION OF THE INDIVIDUAL USE OF DRUGS WITH ANTICHOLINERGIC PROPERTIES .. 39

6.5 STRENGHTS AND LIMITATIONS ...... 41

PART 7: CONCLUSION ...... 42

LIST OF USED ABBREVIATIONS

ADE: Adverse Drug Event

ADECA: Adverse Drug Event Causality Analysis

ADR: Adverse Drug Reaction

ADS: Anticholinergic Drug Scale

ARS: Anticholinergic Risk Scale

ATC: Anatomical Therapeutic Chemical

AZCERT: Arizona Center for Education and Research on Therapeutics cLQTS: congenital Long QT Syndrome

CNK: Code National(e) Kodenummer diLQTS: drug-induced Long QT Syndrome

ECG: electrocardiogram

ICD: Implantable Cardioverter-Defibrillator

LQTS: Long QT Syndrome

QoL: quality of life

Pts: patients

QTc: heart rate corrected QT-interval

SA: sino-atrial

TdP: Torsades de Pointes

WHO: World Health Organization

PART 1: INTRODUCTION

1.1 PHYSIOLOGICAL CHANGES AND ADVERSE DRUG EVENTS (ADEs) IN OLDER ADULTS

The World Health Organization (WHO) defines adverse drug reactions (ADR) as “a response to a drug that is noxious and unintended and occurs at doses normally used in men for the prophylaxis, diagnosis or therapy of disease, or for modification of physiological function”.1 Because this is an old and rather vague definition, many people have attempted to formulate a different definition of ADR. An example of such a definition was formulated by Edwards et al.2 and states that an ADR is “an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention of specific treatment, or alteration of the dosage regimen, or withdrawal of the product”. This means that contaminants or inactive excipients can cause ADRs as well as active components and are thus not always inherent to the drug’s pharmacology. Besides that, the terms ‘adverse drug reaction’ and ‘adverse drug effect’ are more or less interchangeable but they don’t necessarily imply the same thing as ‘adverse drug events’ (ADE). ADEs also include those adverse outcomes for which no causality of drug-use has been found. 2

Older adults are more at risk for ADEs due to changes in their physiology, pharmacokinetics and pharmacodynamics. For example, the kidney and liver functions in older adults may be reduced, possibly deteriorated by heart failure. Because of that, the first-pass clearance in the liver and the renal elimination are reduced which means dosage of medication should be adapted accordingly. Besides, drug distribution may change as well because older adults have a different ratio of body weight to body fat. 3

Furthermore, older people may concomitantly use several different chronic medications. This is called polypharmacy. In this thesis we defined polypharmacy as the concomitant use of 5 or more different chronic medications. When drugs are combined, they can influence each other’s pharmacokinetics and/or pharmacodynamics leading to higher or lower clearance of a drug, causing either less or toxic effects. The toxic effect of some drugs may however be synergistic. In other words, due to chronic comorbid conditions and the use of multiple medications, the risk of adverse events increases. This is a growing problem in our aging society. 4, 5, 6

For some medical conditions, there is an association between ADE rate and increasing age. The bigger part of the ADEs that cause hospital admission can however be prevented. Yet, ADEs are a great cost to health care and one of the largest causes of death in older people worldwide. Studies showed that in American hospitals, serious ADEs occurred with an incidence of 6.7% and were fatal in 0.32% of the patients. 6-8

Recently more research has been done considering two types of ADEs: QT-prolongation and anticholinergic (side-) effects. This thesis focuses on the use of QT-prolonging and anticholinergic drugs in institutionalized and community dwelling older adults. 6

1.2 QT-PROLONGATION AND TORSADES DE POINTES (TdP)

1.2.1 Physiology

A person’s heart cycle can be subdivided in 3 phases. During the first phase, the depolarization, voltage-gated fast Na+ channels open which allows extracellular Na+ to enter the cardiac muscle cells. Because of a positive feedback cycle, many Na+ channels open causing a reversal of the membrane potential. This phase is followed by a plateau phase (second phase) during which Ca2+ flows in the cell through slow Ca2+ channels. This keeps the cell depolarized because there are few K+ channels open. The third phase is called the repolarization. During this phase the Ca2+ channels are inactivated and the K+ channels are open, allowing K+ to flow out of the cells. Because of this, the membrane potential returns to its resting voltage. 9

This electrical activity spreads from the sino-atrial node (SA node) in the right atrium past the left atrium to the ventricles and can be graphically represented by an electrocardiogram (ECG). On a normal ECG there are 3 waves which are called the P-wave, the QRS-complex and the T-wave. Each of these zones depicts a certain event in either the atria or the ventricles (Figure 1.2.1a). The P-wave depicts the atrial depolarization initiated by the SA node. The QRS complex depicts the ventricular depolarization which begins at the apex of the heart. The atrial repolarization occurs at the same moment but this is obscured by the ventricular depolarization and thus not visible on an ECG. Because the current direction of depolarization through the ventricles changes continuously, the QRS-complex has a complicated shape. Finally, the T-wave depicts ventricular repolarization, which begins at the apex of the heart as well. The ventricular repolarization is slower than the ventricular depolarization. This means that the T-wave has a lower amplitude and spreads out more than the QRS-complex. 9

Figure 1.2.1a: Normal ECG: adopted from: 10

Usually, the size, duration and timing of the waves are consistent and so are the various intervals. This means that changes in the timing or pattern of the ECG may lead to the discovery of a problem with the heart’s conduction system. Here, we will discuss QT-prolongation. The QT-interval depicts the period from the beginning of ventricular depolarization to ventricular repolarization and is usually quite constant in a certain moment. 9

QT-prolongation occurs when the repolarization of the cardiac ventricular cells is reduced. This is most commonly caused by an insufficient outflow of potassium and on an ECG a prolongation of the QT-interval can be seen. As shown in Figure 1.2.1b, the time between the start of the Q-wave and the end of the T-wave is longer compared to Figure 1.2.1a. 11

Figure 1.2.1b: ECG with prolonged QT-interval: adopted from: 10

There are some factors that influence the QT-interval and the interpretation thereof such as diurnal effects, processing of ECG recording and intra- of inter-observer variability. The main factor however is the patient’s heart rate. Because the time needed for repolarization depends on the heart rate, the QT-interval must be corrected accordingly (corrected QT = QTc). If not, patients’ QT-intervals are not comparable and it is hard to find out whether there is QT-prolongation or not. There are several formulas available to correct the QT-interval for heart rate. However, there is a lot of criticism because these formulas are only useful within a narrow interval of resting heart rates. There is no formula that can calculate the QTc for every heart rate. The most commonly used formula is Bazett’s formula. 12, 13, 14

푄푇 푖푛푡푒푟푣푎푙 퐵푎푧푒푡푡′푠 푓표푟푚푢푙푎: 푄푇푐 = √푅 − 푅 푖푛푡푒푟푣푎푙

Additionally, there is no consensus on what QT- interval is regarded as safe. The normal value for a QTc is <450 ms for adult women and <430 ms for men. Usually a QTc of over 500 ms or an increase of 60 ms or more compared to what is normal in that same person, is considered a higher risk of developing of a specific arrhythmia, called Torsades de Pointes (TdP). Yet, there is no limit to what is regarded as safe. 15

Table 1.2.1: QTc values for normal and prolonged QT interval by age and sex in ms: adopted from 11 1-15 years (ms) Adult males (ms) Adult females (ms) Normal <440 <430 <450 Borderline 440-460 430-450 450-470 Prolonged (top 1%) >460 >450 >470

QT-prolongation in itself is not a large problem. Nevertheless, in some cases it can lead to a polymorphic ventricular tachycardia also known as TdP, which literally means “twisting of points”. TdP is rarely recorded on an ECG since it mostly lasts only a few seconds. However, it does show some very characteristic features (Figure 1.2.1c). TdP usually begins with a short-long-short sequence of the R-R cycles. This induces TdP by creating heterogeneity of repolarization. This is followed by changes in the morphology and amplitude of the QRS complexes which is also known as the “twisting of points”. Besides that, the rate of the first couple of beats of ventricular tachycardia varies between 160 and 240 beats per minute which is slower than that of ventricular fibrillation. This is called the “warm-up phenomenon”. Finally, the heart rate can spontaneously return to sinus rhythm. As opposed to ventricular fibrillation, defibrillation is not always necessary.10, 16

Figure 1.2.1c: ECG strip in a patient with drug induced TdP: adopted from 11

If the TdP only lasts a couple of seconds, the heart rhythm can spontaneously return to sinus rhythm without loss of consciousness. The patient may then experience dizziness, lightheadedness, shortness of breath or he may have palpitations. If the arrhythmia however continues, the patient can collapse after a few seconds due to an ineffective cardiac output, possibly associated with tonic- clonic seizures because of brain hypoxia. If this does not stop within about two minutes, it can lead to ventricular fibrillation and sudden death. Return to sinus rhythm leads however to repair of consciousness quite quickly. 11, 12

There are nevertheless some practical issues that need consideration. Due to its rareness, TdP is difficult to notice in study populations or to detect in post-marketing surveillance. Prevalence in use of certain drugs that block potassium or sodium channels may be as high as 1 to 10%. Examples of such drugs are sotalol and quinidine. Besides, there are drugs, proarrhythmics, that cause an arrhythmia similar to that of TdP but without a QT-prolongation. This is not called TdP by definition which means TdP is always accompanied by QT-prolongation but not vice versa. 12,16

1.2.2 Types of QT-prolongation

QT-prolongation can be subdivided in two main categories. The QT-prolongation is either caused by a genetic defect, in which case we consider it a congenital Long QT syndrome (cLQTS), or either by the use of certain drugs, in which case we call it drug-induced LQTS (diLQTS). 12

1.2.2.1 Congenital Long QT Syndrome (cLQTS)

The cLQTS can be caused by mutations in 13 different genes and may lead to unusual electrical activity in the heart. These 13 genes can be divided in 2 main categories.

 Six genes code for a pore-forming protein, functioning as a voltage-gated ion channel. Specific ions such as potassium pass across the cardiac cell membrane through these channels.  The remaining 7 genes encode proteins that modulate ion channel function.

All of these channel dysfunctions are known as “channelopathies”. 12

Because the action potentials and the QT interval depend on the ion current, a defect in ionic flow of potassium, sodium or calcium ions can cause major arrhythmias possibly leading to sudden death. In less dramatic cases it can lead to loss of consciousness. 12

There are three major ion currents that need consideration: IKs, IKr and INa (Figure 1.2.2.1). Ikr symbolizes the rapid component of the potassium outflow and IKs the slow component. The potassium components are responsible for repolarization while activation of the inward INa induces longer depolarization and thus QT-prolongation. cLQTS can be caused by the blockage of any of these three ion channels. There are subdivisions depending on the cause of the cLQTS such as the ion channel malfunctions. They are numbered LQT1, LQT2, LQT3... The cLQTS can be diagnosed with an ECG. 12

Figure 1.2.2.1: The ion channels in a cardiac cell: adopted from 17

1.2.2.2 Drug-induced Long QT Syndrome (diLQTS)

In diLQTS, the QT-prolongation is caused by the use of certain drugs. Here, QT-prolongation is associated with the development of TdP as well. This however is just an association because not all drugs that cause QT-prolongation lead to TdP. For example: amiodarone can cause QT-prolongation but hardly ever induces TdP. Of course there are many drugs that cause both, such as disopyramide. 12

Where cLQTS can be caused by either one of three deficiencies in ion flow (IKr, IKs or INa), diLQTS is almost always caused by blockage of IKr. There are many different classes of drugs that may block these channels including antibiotics, antipsychotics, antihistamines and antiarrhythmics. Some of those, such as diuretics and antidepressants, are often prescribed for older patients. The other two types of ion channels are far less prone to medication. This ability of drugs blocking ion channels and thus possibly leading to certain arrhythmias has had an important effect on the development of new medicines. During the clinical stages of drug development new drugs are now screened for QT- prolongation. 12, 18

1.2.3 Risk factors for QT-prolongation and TdP

Blockage of merely Ikr is often not sufficient to create QT-prolongation. In an analogous manner, QT- prolongation is not always followed by TdP. The presence of other risk factors is necessary in both cases. The most common risk factors for both QT-prolongation and TdP are hypokalemia, atrioventricular block or other bradyarrhythmias (Table 1.2.3). Female sex and hypokalemia increase the risk of arrhythmias in both the congenital and the drug-induced variants of LQTS. Hypokalemia can be caused by many factors such as diarrhea and is a risk in malnutrition and chronic alcohol abuse. There are however some risk factors specific for diLQTS such as pharmacokinetic and pharmacodynamic effects. There are studies examining the genetic predisposition to risk as well. 11, 12

Table 1.2.3: Risk factors for QT-prolongation and TdP: adopted from 12 Risk factor Mechanism of increased risk Female sex Sex hormonal regulation of repolarization especially by testosterone Bradycardia Pause-dependent QT-prolongation with typical short-long-short cycle Electrolyte disturbances Hypokalemia Decreases IKr by enhanced inactivation or exaggerated competitive block of sodium potentiation of drug blockade of residual IKr Hypomagnesemia Modulation of L-type calcium channel Recent conversion from atrial fibrillation especially with Reduced heart rate after conversion to sinus QT remodeling QT-prolonging drugs in AF High drug concentrations and rapid infusion of QT- Dose- or concentration- dependent QT-prolongation (except prolonging drugs quinidine) Digitalis Intracellular calcium overload with delayed afterdepolarizations and inhibition of KCNH2 trafficking Subclinical (congenital) LQTS QT prolonging upon exposure to Ikr -blocking drugs Ion channel polymorphisms Minor effects at baseline but compounded with QT-prolonging drug leading to TdP

Additional risk factors for TdP are old age, various cardiovascular diseases such as bundle branch block and ischemia, and a family history of LQTS. 19

1.2.4 Prevention

There are a number of measures that can be taken into account to prevent QT-prolongation and TdP.

First of all, QT-prolonging medication should be avoided in both patients with cLQTS or diLQTS. There is no consensus on whether these medicines should not be used. Different sources suggest different QTc-values as a limit for risk of QT-prolongation as depicted in the table below. However, all researchers agree that use of QT-prolongating drugs should be precluded in case of a QTc-interval above 500 ms or a rise of over 60 ms. 20

Table 1.2.4: When to avoid QT-prolonging drugs Men QTc Women QTc When to avoid? Al-Khatib et al. (2003) 14 >450 ms >460 ms In the absence of intraventricular conduction defects Li et al. (2010) 19 >460 ms >460 ms In the absence of identifiable risk factors AZCERT 21 >420 ms >440 ms If possible

The patient’s risk factors should be considered as well as the risk-benefit of the drug in that specific patient. Certain combinations of drugs, such as the combination of two QT-prolonging drugs are to be avoided. Besides that, some antiarrhythmics, especially those belonging to class IA (disopyramide, quinidine), are to be avoided in case of QT-prolongation or a high risk thereof. If such a drug does need to be used, it is better to start in a hospital environment under constant cardiac monitoring. Finally, all patients treated with QT-prolonging medication must be warned about symptoms associated with arrhythmia including dizziness, palpitations and syncope. In case one of these symptoms occurs, it is the physician’s responsibility to stop the use of the QT-prolonging drug at once. In this case the ECG should be checked and other factors should be corrected. 20

1.2.5 Treatment

In most cases, QT-prolongation or TdP disappears within 1 to 5 minutes after administrating 2g

MgSO4 intravenously (IV). Standard antiarrhythmics, except most beta-blockers, cannot be used. Beta-blockers inhibit the occurrence of extrasystoles but may lead to bradycardia. If treatment with

MgSO4 is inadequate, isoproterenol, dobutamine or atropine IV can be considered. Potassium is also an option in case of low serum K+ but this should only be considered in a clinical environment after careful consideration of additional risk factors such as renal failure. Alternatively, lidocaine and phenytoin can be used. In case of ventricular fibrillation, cardiac pacing or shocking may be necessary. 20, 22-23

Re-use of the drug molecule leading to QT-prolongation or TdP must be avoided at all cost and

+ 2+ - 24 normal K , Mg and HCO 3 serum values must be maintained.

Treatment of TdP depends on the risk of sudden death. High-risk patients are more likely to receive an implantable cardioverter-defibrillator (ICD) or beta-blockers (not sotalol). Usually, these patients already survived a cardiac arrest. 10

Patients who haven’t had a cardiac arrest before are started on beta-blockers too, but are urged to change their lifestyle. If this does not suffice, an ICD is implanted after all. 10

Currently “personalized” pharmacotherapy is being developed because more is known about the pathophysiology of TdP and the various mutations. Genetic testing has improved and has become cheaper. For some variants of cLQTS, specific therapy has been developed. For example potassium supplements are prescribed to patients with LQTS 2 while the therapy of patients with LQTS 3 may include mexiletine. In both LQTS 2 and LQTS 3 patients early ICD placement is considered as well. 10

1.3 DRUGS WITH ANTICHOLINERGIC (SIDE-) EFFECTS

1.3.1 Pharmacology

Acetylcholine is a neurotransmitter in both the central and peripheral nervous system. It mainly binds two types of receptors which are known as nicotinic and muscarinic receptors. There are five subtypes of muscarinic receptors of which M1, M2 and M3 are the most commonly present. Stimulation of these receptors leads to stimulation of the parasympathetic nervous system. There are a lot of drugs that interact with these receptors but drugs that interact with nicotinic receptors are less commonly used due to the extensive occurrence of side effects. There are two main types of medicines that interact with the muscarinic receptors; those that block (parasympatholytic or anticholinergic drug) and those that stimulate these receptors (parasympathomimetics). Because both the sympathetic and the parasympathetic nervous system lead to a wide variety of effects (Appendix 1), these drugs are used for the symptomatic treatment of a wide variety of conditions in older people (Table 1.3.1). 4, 25, 26

Table 1.3.1: The most common symptoms and diseases treated with anticholinergic drugs: 4, 25 Symptoms or diseases Examples of drugs with anticholinergic properties Parkinsonism Bromocriptine, entacapone, procyclidine, trihexyphenidyl Urinary incontinence and urge incontinence Flavoxate, oxybutynin, tolterodine Psychoses Haloperidol, olanzapine, pimozide, quetiapine Depression Amitriptyline, clomipramine, doxepin, imipramine, nortriptyline, pimozide… Allergy Chlorphenamine, fexofenadine, loratadine Obstructive lung diseases Ipratropium, theophylline Peptic ulcer Cimetidine, ranitidine Sleep disorders Paroxetine Cardiac arrhythmias Atropine, disopyramide, Travel sickness Diphenhydramine, meclozine, scopolamine

1.3.2 Anticholinergic (side-) effects in older patients

A patient’s anticholinergic burden can be calculated by adding all the anticholinergic effects of the medication the patient takes. In other words, to calculate a patient’s anticholinergic burden, one must add the scores given to all individual drugs the patient uses. This is possible because anticholinergic effects are additive.4, 27

A higher anticholinergic burden is not always caused by the use of a few drugs with a high anticholinergic activity. This means that how small the contribution of several medicines may be, the patient might still have a heavy anticholinergic burden. Older women may use multiple drugs with a lower anticholinergic activity. Therefore adverse effects are less likely to be attributed to the use of medications with anticholinergic effects.4, 27

The therapeutic indications of anticholinergic drugs, such as sleep disorders and urinary incontinence, are more common in older patients who are more at risk for ADEs. Drugs with anticholinergic (side-) effects can cause both peripheral and central adverse effects. The most common peripheral adverse effects are dry mouth, dry eyes, constipation, blurred vision and tachycardia. The most frequent central adverse effects are dizziness, sedation, confusion, delirium and cognitive impairment.6,28

Many studies show that a higher anticholinergic burden is related to a higher risk of falls, impulsive behavior, loss of independence and delirium. In other words, a higher anticholinergic burden is associated with the loss of functional skills necessary for everyday life such as balance, gait and mobility. 4,29

Older adults with some type of dementia have an additional problem. The use of medication with anticholinergic properties can further deteriorate their memory due to antagonistic effects of anticholinergic medication and acetylcholinesterase-inhibitors. Patients with dementia or Alzheimer’s disease and older people already have a central cholinergic deficiency which is only exacerbated by the use of anticholinergic medication. Even though this may cause complications, studies show that concomitant use of these drugs is common in nursing homes. 30

Although a high anticholinergic burden can cause a lot of adverse effects in older patients, this problem can easily be diminished by a reduction of anticholinergic medications. There are many alternatives available that do not have anticholinergic (side-) effects. For example second-generation antihistamines have fewer anticholinergic side-effects than first-generation antihistamines. Revising a patient’s medication taking into account his or her anticholinergic burden can possibly prevent many complications. 30, 31

PART 2: OBJECTIVES

Polypathology and polypharmacy are a growing problem in our aging society. Consequently, older adults are at greater risk of ADEs due to physiological, pharmacokinetic and pharmacodynamic changes. ADEs are potentially dangerous and can lead to hospitalization and even death. In this study we focus on two types of ADEs; QT-prolongation and anticholinergic (side-) effects. QT-prolongation in itself is not a large problem but can possibly lead to fatal TdP. Anticholinergic (side-) effects on the other hand can include for example (further) deterioration of the aging brain, dry mouth and gastrointestinal problems. Recently there has been increasing research on both of these topics.

The overall goal of this thesis was to get a better insight in the use of QT-prolonging drugs and drugs with anticholinergic properties by older Belgian polypharmacy patients.

To obtain this goal we:

1. Objective 1: reviewed the existing evidence-based risk scales to determine the risk of QT- prolongation. The results of this literature search are described in part 3. 2. Objective 2: reviewed the existing evidence-based risk scales to determine anticholinergic (side-) effects. The results of this literature search are described in part 4. 3. Objective 3: evaluated the drug use of 1016 community-dwelling and 400 institutionalized older adults in Belgium. We evaluated the drug use in general as well as the use of QT-prolonging drugs and drugs with anticholinergic properties. In order to evaluate the use of QT-prolonging drugs, we used one of the methods as described in part 3. For the evaluation of the use of drugs with anticholinergic properties, we used two of the scales as described in part 4. A comparison between both subpopulations was made as well. These evaluations are described in part 5 of this thesis.

PART 3: REVIEW OF QT-PROLONGING RISK SCALES IN OLDER ADULTS

3.1 METHODS

We used the Credible Meds website as a starting point for the literature search on risk scales for QT- prolongation and TdP. We then used the MEDLINE database to search for alternative risk scales using key words such as “QT-prolongation AND older patients”, “TdP AND older patients”, “TdP AND risk scale”, “QT-prolongation AND risk scale”. For TdP, the whole word as well as the abbreviation was used. After reading the most relevant manuscripts, we scanned the reference lists of these manuscripts for other potentially useful manuscripts (“snowballing”). When these manuscripts were not available in Pubmed, we also used Google Scholar and Web of Science. We also used the “related citation” method in Pubmed on the most relevant manuscripts.

3.2 RESULTS

During the literature search approximately 1073 manuscripts were found. A first selection was made based on title and abstract after which the most interesting manuscripts were screened. Eventually one manuscript and the credible meds website was included in this thesis; one by Tisdale et al. and one by the Arizona Center for Education and Research on Therapeutics (AZCERT).

Tisdale et al. researched possible risk factors for TdP in hospitalized patients. They examined the administered medication and the outcome by analyzing patients’ ECGs. Besides, they determined the risk factors with the largest effect on the QT-interval. The factors with the lowest risk were appointed 1 point, medium risk 2 points and factors with the largest risk were appointed 3 points (Table 3.2a). A patient presenting with all risk factors is consequently given a total score of 21. 32

They also determined cut-off points to estimate the severity of the risk. A patient with a risk score of 6 or lower had a low risk of QT-prolongation, patients with a risk score from 7 to 10 a medium risk while patients with a score ranging from 11 to 21 had a high risk for the development of QT- prolongation and TdP. The Tisdale-scale is very useful in hospital settings because all necessary information is available. 21, 32

Table 3.2a: Calculation of Risk Score for QTc-interval prolongation: adopted from 32 Risk factors Points Age > 67 y 1 Female 1 Use of loop diuretic 1 Serum K+ ≤3.5 mEq/L 2 Admission QTc ≥450 ms 2 Acute myocard infarct in the past 2 ≥2 QTc-prolonging drugs 3 Sepsis 3 Heart failure 3 One QTc-prolonging drug 3 Maximum risk score 21

Where the screening method of Tisdale et al. calculates an individual risk per hospitalized patient the people of AZCERT took the drugs themselves as a starting point. They developed a process to divide all drugs with a potential risk of QT-prolongation or TdP into 4 categories (Table 3.2b) which is called the Adverse Drug Event Causality Analysis (ADECA)-process. 21

Table 3.2b: the 4 categories for risk of TdP 21 1 Drugs to avoid for people with cLQTS This list also contains all medication in the other three lists 2 Conditional risk of TdP There is a risk in certain circumstances such as excessive dosage, bradycardia, hypokalemia, cLQTS or other risk factors 3 Possible risk of TdP There is insufficient evidence that these drugs cause TdP, they do however prolong the QT-interval 4 Risk of TdP Drugs that cause TdP under normal conditions

ADECA includes research on the following three sources: cases posted on their website (credible meds), medical literature search and drugs labeled QT-prolonging by the FDA. They categorize drugs according to the Bradford Hill criteria (Figure 3.2, Appendix 4) and based on the expert opinion of the Credible Meds team and an advisory board. 21

Figure 3.2: The Bradford Hill criteria: adopted from 21

PART 4: REVIEW OF ANTICHOLINERGIC RISK SCALES IN OLDER ADULTS

4.1 METHODS

We used the MEDLINE database for the study on anticholinergic risk scales. We used key words such as “anticholinergic AND elderly”, “anticholinergic burden AND older patients”, “anticholinergic risk (scale)”. After reading the most relevant manuscripts, we scanned the reference lists of these manuscripts for other potentially useful manuscripts (“snowballing”). When these manuscripts were not available in Pubmed, we used Google Scholar and Web of Science. We also used the “related citation” method in Pubmed on the most relevant manuscripts.

4.2 RESULTS

During the literature search approximately 5246 manuscripts were found. A first selection was made based on title and abstract after which the most interesting manuscripts were screened. Eventually 10 manuscripts were included in this thesis.

Until now, several scales to evaluate anticholinergic (side-) effects have been developed. These scales measure or calculate the anticholinergic burden of an individual patient. There is a great heterogeneity between the various scales with regard to the examined outcome. Some scales predict peripheral effects such as the Anticholinergic Drug Scale (ADS - Carnahan et al.33), other scales include both peripheral and central effects (ARS - Rudolph et al.31) and/or cognitive performance (Anticholinergic Cognitive Burden Scale - Hilmer et al.34). 27

Most of these scales are based on expert opinion and rank drugs according to their presumed anticholinergic activity. An overview is given in Table 4.2. 27

The majority of the developed scales provided the most commonly prescribed drugs with an anticholinergic activity score from 0 (no anticholinergic activity) to 3 or 4 (strong anticholinergic activity). In 2013 Duran et al. provided a systematic review of seven of these scales and divided these drugs into two categories: drugs with a high anticholinergic potency and drugs with a low anticholinergic potency (Appendix 5). 28, 27

Table 4.2: The nine scales to estimate the anticholinergic burden for an individual patient: adopted from and adapted: 28 Study ID (author, year, Grading system and methodology Outcome studied Other researchers that country) used this method Carnahan 2006 USA Scores: 4-point scale (0 to 3) Serum anticholinergic Kouladijan 2014, (AnticholinergicDrugScale) Basis: Expert opinion activity Kashyap 2014, Number of drugs: 117 Kersten 2014 Ancelin 2006 France Scores: 4-point scale (0 to 3) Cognitive performance Kouladijan 2014, Basis: serum anticholinergic and Kashyap 2014, activity and mild cognitive Kersten 2014 expert opinion impairment Number of drugs: 27

Hilmer 2007 USA34 Scores: 3-point scale Physical and cognitive Kouladijan 2014, Basis: expert opinion performance Kashyap 2014, Number of drugs: not mentioned Tay 2014 Han 2008 USA Scores: 4-point scale (0 to 3) Memory performance Kouladijan 2014, Basis: previous published and Tay 2014, anticholinergic scale and expert executive function Kersten 2014 opinion Number of drugs: 60

Rudolph 2008 USA Scores: 4-point scale (0 to 3) Frequency of Kouladijan 2014, (Anticholinergic Risk Scale Basis: detailed literature review anticholinergic adverse Kashyap 2014, ARS) and expert opinion effects Kersten 2014 Number of drugs: 49 Chew 2008 USA Scores: 4-point scale (0 to 3) Anticholinergic activity Kouladijan 2014, Basis: radioreceptor assay in vitro Kersten 2013, Number of drugs: 22 Cetinel 2013

Boustani 200835 Scores: 3-point scale (1 to 3) Long-term cognitive Campbell 2015, Basis: expert opinion decline Kersten 2013, Number of drugs: 88 Cai 2013

Ehrt 2010 Norway Scores: 5-point scale (0 to 4) Long-term cognitive Kouladijan 2014, Basis: Chew 2008 and expert decline Wojtalik 2012 opinion Number of drugs: 29 Sittironnarit 2011 Australia Scores: 4-point scale (0 to 3) Psychomotor speed Kouladijan 2014, (Anticholinergic Loading Basis: Ancelin 2006, Han 2008, and executive function Puustinen 2012, Scale) Chew 2008, Rudolph 2008 and Thorpe 2012 expert opinion Number of drugs: 49

PART 5: DRUG USE OF BELGIAN OLDER POLYPHARMACY PATIENTS

5.1 METHODS

5.1.1 Study design, setting and participants

From December 2013 until July 2014, an observational study was conducted in 1016 Belgian older adults with polypharmacy (≥70 years and chronic ≥5 drugs). These patients were recruited in 204 community-pharmacies in Belgium (142 in Flanders – 62 in Wallonia). Each pharmacy recruited a maximum of 5 patients. The goal of this observational study was to identify potential drug-related problems in older polypharmacy patients in Belgium. Participating patients were interviewed by a pharmacist-intern through a structured questionnaire. The patient was questioned about his or her demographic data, alcohol consumption, functional status, cognitive status, fall incidents and hospitalizations in the past year, self-scored quality of life and current medication use.

At the same time, a second dataset, containing all dispensed chronic medication to 400 institutionalized patients, randomly selected from 10 different Flemish nursing homes, was obtained. Analogously, institutionalized patients could only be included if they were 70 years or older and were chronically prescribed 5 or more different drugs.

5.1.2 Data-analysis

All data was entered digitally via an electronic platform by the interns who conducted the study. The results were then extracted into Excel (Microsoft, 2010, Redmond, WA) and double checked using the paper version by Eline Christiaen and Simon Capiau. Chronic and acute medication was listed per patient. Each drug or supplement was linked to an ATC-code as well as the content of pharmaceutical compounded drugs.

The basic characteristics of the population, drug- and alcohol use were mainly statistically described by frequency tables and center sizes. Descriptives were displayed as counts with percentages and means with standard deviations or medians with interquartile ranges as appropriate. To analyze the interactions between drugs and the use of QT-prolonging drugs as well as drugs with anticholinergic properties, cross tables were used. Here, the ATC codes of the drugs used in the elderly population were compared with the ATC codes in the listed risk scales.

All analyses were carried out using Microsoft Excel of SPSS Statistics (IBM Corp, 2013, IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY).

5.1.3 Evaluation of use of QT-prolonging drugs in our populations

Two different risk scales to evaluate the risk for QT-prolongation and TdP were retrieved. Only the one by credible meds is however useful for the purpose of this research as an individual score per drug used was given. The risk score developed by Tisdale et al. is specific for hospitalized patients and laboratory and clinical data are needed that are not available in this research. The ATC codes corresponding to the drugs on the credible meds list were added to a Microsoft Excel table (Appendix 2 and 3) and the patients of both subpopulations were scanned for use of drugs that may cause TdP as described by AZCERT. Consequently, prevalence of use of QT-prolonging drugs in the general population was calculated. A custom table that lists the number of drugs with and without interactions of every patient was created. 17, 21

5.1.4 Evaluation of use of drugs with anticholinergic properties in our populations

There is a wide variety of anticholinergic risk scales. In this research the method described by Duran et al. will be used because it has the highest level of evidence (systematic review, level A). Duran et al. grouped all medication described in the nine scales to estimate the anticholinergic burden for an individual patient (Table 1.3.1) and divided them into two groups: high and low anticholinergic activity. However, the nine anticholinergic scales where it was based on divided them in 4 or 5 groups, assigning them a score from 0 to 3 or 4. Because these scales are more commonly used, we also briefly compared the method described by Duran et al. and the one developed by Rudolph et al. with regard to the outcome as Rudolph’s scale is the most widely used. The ATC codes corresponding to the drugs with anticholinergic properties as described by Duran et al. and Rudolph et al. were added to a Microsoft Excel table (Appendix 5 and 6) and the patients of both subpopulations were scanned for use of drugs with anticholinergic properties. Consequently, prevalence of use of drugs with anticholinergic properties in the general population was calculated. A custom table that lists the number of drugs with and without anticholinergic (side-) effects of every patient was created. 28, 31

5.2 RESULTS

5.2.1 Basic characteristics

As displayed in Table 5.2.1, the institutionalized population is markedly older than the community- dwelling population (mean vs mean) and significantly more women were included.

Table 5.2.1: Basic characteristics Community-dwelling (n=1016) Institutionalized (n=400) Age, Mean (SD) 78.8 5.5 86.2 6.3 Age ≥ 85j, # (%) 162 16 250 63 Gender, # women (%) 592 58 298 75 BMI, Mean (SD) 26.6 4.3 NA NA BMI < 22, # (%) 131 13 NA NA Smoker, # (%) 57 6 NA NA Living situation Alone 434 43 0 0 With partner/family 582 57 0 0 Nursing home 0 0 400 100 Need help to Wash 110 11 NA NA Dress 54 5 NA NA Toileting 19 2 NA NA Go outside the house 117 12 NA NA Eat 38 4 NA NA Clean 382 38 NA NA Minicog Minicog 0 t.e.m. 2 335 33 NA NA (=positive diagnosis) Minicog 3 t.e.m. 5 681 67 NA NA Description health condition, # (%) Excellent 19 2 NA NA Very good 104 10 NA NA Good 497 49 NA NA Average 343 34 NA NA Bad 53 5 NA NA Pts with fall incident in the past year, # (%) 333 33 NA NA Number fall incidents, Med (IQL) 1 1-3 NA NA

5.2.2 General drug use of the included population

The community-dwelling older adults take an average of 11 ± 4 drugs (mean ± SD). The population as a whole (1016 patients) used 635 different molecules and 10705 drugs in total.

The institutionalized older adults taken an average of 12 ± 5 drugs (mean ± SD). The population as a whole (400 patients) uses 486 different molecules and 4647 drugs in total. Table 5.2.2 displays all drug classes that contain more than 2% of the 10705 drugs and the 4647 drugs. We used the short ATC version of the frequency table and gave as example the three most frequently used drugs of this class. The complete list of drugs used by the population of community-dwelling and institutionalized older adults are presented in the appendix (Appendix 7 and 8).

Table 5.2.2: Most frequently used drugs by community-dwelling and institutionalized older adults in Belgium Community-dwelling (n= 1016) Institutionalized (n= 400) ATC code Drug (group) name No. of pts % ATC code Drug (group) name No. of pts % 1 B01A Antithrombotic agents 806 7.5 B01A Antithrombotic agents 295 6.3 B01AC06 Acetylsalicylic acid 500 4.7 B01AC06 Acetylsalicylic acid 158 3.4 B01AA03 Warfarin 65 0.6 B01AB05 Enoxaparin 38 0.8 B01AC04 Clopidogrel 65 0.6 B01AA03 Warfarin 26 0.6 2 C10A Lipid modifying agents, plain 719 6.7 A06A Drugs for constipation 276 5.9 C10AA01 Simvastatin 289 2.7 A06AD65 Macrogol, 153 3.3 C10AA05 Atorvastatin 165 1.5 A06AD11 combinations 54 1.2 C10AA07 Rosuvastatin 133 1.2 A06AG10 Lactulose 24 0.5 Docusate sodium, incl. combinations 3 J07B Viral vaccines 686 6.4 A02B Drugs for peptic ulcer 212 4.6 J07BB02 Influenza, inactivated, split 685 6.4 and gastor- virus or surface antigen oesophageal reflux J07BC01 Hepatitis B, purified antigen 1 0.0 A02BC02 disease (GORD) 118 2.5 A02BC01 Pantoprazole 46 1.0 A02BA02 Omeprazole 36 0.8 Ranitidine 4 C07A Beta blocking agents 586 5.5 N06A Antidepressants 211 4.5 C07AB07 Bisoprolol 317 3.0 N06AX05 Trazodone 55 1.2 C07AB12 Nebivolol 64 0.6 N06AB10 Escitalopram 51 1.1 C07AA07 Sotalol 49 0.5 N06AX11 Mirtazapine 25 0.5 5 A02B Drugs for peptic ulcer and 469 4.4 N02B Other analgesics and 166 3.6 gastor-oesophageal reflux antipyretics disease (GORD) N02BE01 Paracetamol 159 3.4 A02BC02 Pantoprazole 221 2.1 N02BE51 Paracetamol, 5 0.1 A02BC01 Omeprazole 151 1.4 N02BA01 combinations ASA 2 0.0 A02BA02 Ranitidine 42 0.4 6 A10B Blood glucose lowering 431 4.0 C07A Beta blocking agents 163 3.5 drugs, excl. insulins C07AB07 Bisoprolol 112 2.4 A10BA02 Metformin 245 2.3 C07AB02 Metoprolol 10 0.2 A10BB09 Gliclazide 66 0.6 C07AA05 Propranolol 9 0.2 A10BX02 Repaglinide 27 0.3 7 N05B Anxiolytics 330 3.1 C03C High-ceiling diuretics 148 3.2 N05BA06 Lorazepam 121 1.1 C03CA02 Bumetanide 74 1.6 N05BA12 Alprazolam 98 0.9 C03CA01 Furosemide 73 1.6 N05BA08 Bromazepam 44 0.4 8 N02B Other analgesics and 329 3.1 N05C Hypnotics and 144 3.1 antipyretics N05CD06 sedatives 76 1.6 N02BE01 Paracetamol 303 2.8 N05CF02 Lormetazepam 45 1.0

N02BE51 Paracetamol, combinations 16 0.1 N05CD03 Zolpidem 5 0.1 excl. psycholeptics Flunitrazepam N02BA01 Acetylsalicylic acid 6 0.1 9 N05C Hypnotics and sedatives 315 2.9 N05A Antipsychotics 131 2.8 N05CD06 Lormetazepam 122 1.1 N05AH04 Quetiapine 36 0.8 N05CF02 Zolpidem 104 1.0 N05AX08 Risperidone 34 0.7 N05CF01 Zopiclone 23 0.2 N05AD01 Haloperidol 19 0.4 10 N06A Antidepressants 273 2.6 N05B Anxiolytics 121 2.6 N06AX05 Trazodone 49 0.5 N05BA06 Lorazepam 43 0.9 N06AB10 Escitalopram 41 0.4 N05BA12 Alprazolam 35 0.8 N06AA09 Amitriptyline 30 0.3 N05BA08 Bromazepam 16 0.3 11 A11C Vitamin A and D, incl. 253 2.4 N02A Opioids 111 2.4 combinations of the two N02AX02 Tramadol 36 0.8 A11CC05 Colecalciferol 246 2.3 N02AB03 Fentanyl 30 0.6 A11CC03 Alfacalcidol 6 0.1 N02AX52 Tramadol, 22 0.5 A11CC04 Calcitriol 1 0.0 combinations 12 C09A Ace inhibitors, plain 236 2.2 A12A Calcium 106 2.3 C09AA04 Perindopril 105 1.0 A12AX Calcium with vitamin D 95 2.0 C09AA03 Lisinopril 70 0.7 A12AA04 Calcium carbonate 9 0.2 C09AA05 Ramipril 43 0.4 A12AA12 Calcium acetate 3 0.1 anhydrous 13 C08C Selective calcium channel 225 2.1 A10B Blood glucose lowering 98 2.1 blockers with mainly drugs, excl. insulins vascular effects A10BA02 Metformin 57 1.2 C08CA01 Amlodipine 114 1.1 A10BB08 Gliquidone 17 0.4 C08CA13 Lercanidipine 55 0.5 A10BB09 Gliclazide 16 0.3 C08CA12 Barnidipine 33 0.3 14 M01A Antiinflammatory and 225 2.1 R03A Adrenergics, inhalants 96 2.1 antirheumatic products, non- R03AL01 Fenoterol and 28 0.6 steroids ipratropium bromide M01AX05 Glucosamine 56 0.5 R03AK06 Salmeterol and 23 0.5 M01AE01 Ibuprofen 40 0.4 fluticasone M01AB05 Diclofenac 26 0.2 R03AC02 Salbutamol 14 0.3 15 A12A Calcium 213 2.0 C10A Lipid modifying agents, 93 2.0 A12AX Calcium, combinations with 117 1.1 plain vitamin D and/or other drugs C10AA01 Simvastatin 46 1.0 A12AA04 Calcium carbonate 87 0.8 C10AA05 Atorvastatin 26 0.6 A12AA12 Calcium acetate anhydrous 6 0.1 C10AA07 Rosuvastatin 10 0.2

5.2.3 Evaluation of the individual use of QT-prolonging drugs and drugs with anticholinergic properties

We also compared the relative occurrence of the top 10 most commonly used drugs by the community-dwelling and the institutionalized older adults. We used the same colors in the figures below in case the same drug appeared in the top 10 for the community-dwelling older adults as well as for the institutionalized older adults. We used analogue techniques for all tables below.

5.2.3.1 Individual use of QT-prolonging medication disregarding the risk scores

In the population of community-dwelling older adults 634 of the 1016 patients (62.4%) uses one or more drugs with risk for QT-prolongation or TdP. In the population of institutionalized older adults this is 343 out of 400 or 85.8% and thus remarkably higher. The top 10 most commonly used drugs that can lead to QT-prolongation and TdP by older polypharmacy patients in Belgium is listed below (Table 5.2.3.1). The complete tables for community- dwelling older adults and institutionalized older adults are presented in Appendix 9 and 10.

Table 5.2.3.1: Top 10 drugs with risk for QT-prolongation and TdP used by older adults disregarding the risk score Community-dwelling (n=1016) Institutionalized (n=400) Drug name ATC code Risk No. of % Drug name ATC code Risk No. of % score pts score pts 1 Pantoprazole A02BC02 2 221 21.8 Pantoprazole A02BC02 2 118 29.5 2 Furosemide C03CA01 2 76 7.5 Furosemide C03CA01 2 73 18.3 (frusemide) (frusemide) 3 Formoterol R03AK07 1 65 6.4 Trazodone N06AX05 2 55 13.8 4 Salmeterol R03AK06 1 59 5.8 Escitalopram N06AB10 4 51 12.8 5 Sotalol C07AA07 4 49 4.8 Domperidone A03FA03 4 38 9.5 6 Trazodone N06AX05 2 49 4.8 Quetiapine N05AH04 3 36 9.0 7 Amiodarone C01BD01 4 46 4.5 Risperidone N05AX08 3 34 8.5 8 Escitalopram N06AB10 4 41 4.0 Moxifloxacin J01MA14 4 29 7.3 9 Indapamide C03BA11 2 40 3.9 Mirtazapine N06AX11 3 25 6.3 10 Domperidone A03FA03 4 35 3.4 Salmeterol R03AK06 1 23 5.8

Six drugs appear in both the top 10’s but formoterol, sotalol, amiodarone and indapamide only appear in that of the community-dwelling population while quetiapine, risperidone, moxifloxacin and mirtazapine only appear in that of the institutionalized older adults.

Figure 5.2.3.1: Top 10 drugs with risk for QT-prolongation and TdP used by older adults disregarding the risk score Community-dwelling (n=1016) (%) Institutionalized (n=400) (%)

3.4 Pantoprazole 5.8 3.9 Furosemide 6.3 21.8 Formoterol 7.3 4.0 29.5 Salmeterol Sotalol 8.5 4.5 Trazodone Amiodarone Escitalopram 9.0 4.8 Indapamide Domperidone 18.3 Quetiapine 4.8 9.5 Risperidone 7.5 5.8 Moxifloxacin 12.8 13.8 6.4 Mirtazapine

5.2.3.2 Individual use of QT-prolonging medication with high risk of TdP (risk score 4)

In the population of community-dwelling older adults 257 of the 1016 patients (25.3%) uses one or more drugs with risk for QT-prolongation or TdP. In the population of institutionalized older adults this is 206 out of 400 or 51.5% and thus remarkably higher. Remark however that it is possible here that a single patient took two or more drugs with risk score 4. The complete tables for community- dwelling older adults and institutionalized older adults are presented in Appendix 11 and 12.

The top 10 most commonly used drugs with a known risk for QT-prolongation and TdP (risk score 4) by older polypharmacy patients in Belgium is listed below (Table 5.2.3.2).

Table 5.2.3.2: Top 10 drugs with risk for QT-prolongation and TdP used by older adults with risk score 4 Community-dwelling (n=1016) Institutionalized (n=400) Drug name ATC code Risk No. of % Drug name ATC code Risk No. of % score pts score pts 1 Sotalol C07AA07 4 49 4.8 Escitalopram N06AB10 4 51 12.8 2 Amiodarone C01BD01 4 46 4.5 Domperidone A03FA03 4 38 9.5 3 Escitalopram N06AB10 4 41 4.0 Moxifloxacin J01MA14 4 29 7.3 4 Domperidone A03FA03 4 35 3.4 Amiodarone C01BD01 4 19 4.8 5 Flecainide C01BC04 4 29 2.9 Haloperidol N05AD01 4 19 4.8 6 Sulpiride N05AL01 4 23 2.3 Citalopram N06AB04 4 13 3.3 7 Citalopram N06AB04 4 16 1.6 Azithromycin J01FA10 4 10 2.5 8 Azithromycin J01FA10 4 9 0.9 Sotalol C07AA07 4 9 2.3 9 Clarithromycin J01FA09 4 5 0.5 Levofloxacin J01MA12 4 7 1.8 10 Moxifloxacin J01MA14 4 3 0.3 Sulpiride N05AL01 4 7 1.8

Eight drugs appear in both the top 10’s but flecaïnide and clarithromycin only appear in that of the community-dwelling population while haloperidol and levofloxacin only appear in that of the institutionalized older adults.

Figure 5.2.3.2: Top 10 drugs with risk score 4 for QT-prolongation and TdP Community-dwelling (n=1016) (%) Institutionalized (n=400) (%) 0.5 0.3 Sotalol 0.9 1.8 1.8 Amiodarone 1.6 4.8 2.3 Escitalopram 2.5 12.8 2.3 Domperidone Flecainide 3.3 Sulpiride 2.9 Citalopram 4.5 4.8 Azithromycin Clarithromycin Moxifloxacin 4.8 9.5 3.4 Haloperidol 4.0 Levofloxacin 7.3

5.2.3.3 Number of QT-prolonging drugs per patient

In the population of community-dwelling older adults the number of QT-prolonging drugs per patient varies between 0 and 6 with a median (IQR) of 1 ± 2 drugs. In the population of institutionalized older adults on the other hand the number of QT-prolonging drugs per patient varies between 0 and 8 with a median (IQR) of 2 ± 2 drugs.

We compared the distribution of the number of QT-prolonging drugs per patient of the community- dwelling older adults and the institutionalized older adults. This is presented in Figure 5.2.3.3. The y- axis depicts the number of QT-prolonging drugs a patient might take and the X-axis depicts the number of patients in per cent.

Figure 5.2.3.3: Comparison of the number of QT-prolonging drugs per patient between community-dwelling older adults and institutionalized older adults in percentage of patients

Community-dwelling (n=1016) Institutionalized older adults (n=400)

8 0.0 8 0.2 7 0.0 7 0.2 6 0.2 6 0.5 5 0.3 5 3.8

prolonging drugs 4

1.5 prolonging drugs 4 8.2

- - 3 5.9 3 16.8 2 18.1 2 26.2

1 36.4 1 29.8 NumberQT of 0 37.6 NumberQT of 0 14.2

0 10 20 30 40 0 10 20 30 40 Percentage of patients (n=1016) (%) Percentage of patients (n=400) (%)

5.2.3.4 Individual use of drugs with anticholinergic properties according to Duran et al., disregarding the risk scores

In the population of community-dwelling older adults 427 of the 1016 of the patients (42.0%) uses one or more drugs with anticholinergic properties. In the population of institutionalized older adults this is 291 out of 400 patients or 72.9% and thus remarkably higher.

The top 10 drugs most commonly used drugs with anticholinergic properties drugs according to Duran et al. by older polypharmacy patients in Belgium is listed below (Table 5.2.3.4). The complete tables are presented in Appendix 13 and 14.

Table 5.2.3.4: Top 10 drugs with anticholinergic properties according to Duran et al. used by older adults, disregarding the risk scores Community-dwelling (n=1016) Institutionalized (n=400) Drug name ATC code Risk No. of % Drug name ATC code Risk No. of % score pts score pts 1 Tramadol N02AX02 L 91 9.0 Ipratropium* R03AL01 H 56 14.0 2 Trazodone N06AX05 L 49 4.8 Trazodone N06AX05 L 55 13.8 3 Ipratropium* R03AL01 H 47 4.6 Domperidone A03FA03 L 38 9.5 4 Ranitidine A02BA02 L 42 4.1 Quetiapine N05AH04 L 36 9.0 5 Combinations N02AX52 L 36 3.5 Ranitidine A02BA02 L 36 9.0 with tramadol or methadone 6 Domperidone A03FA03 L 35 3.4 Tramadol N02AX02 L 36 9.0 7 Amitriptyline N06AA09 H 30 3.0 Risperidone N05AX08 L 34 8.5 8 Fentanyl N02AB03 L 29 2.9 Fentanyl N02AB03 L 30 7.5 9 Paroxetine N06AB05 L 27 2.7 Mirtazapine N06AX11 L 25 6.3 10 Loperamide A07DA03 L 26 2.6 Combinations N02AX52 L 22 5.5 with Tramadol or methadone

Figure 5.2.3.4: Top 10 drugs with anticholinergic (side-) effects according to Duran et al. disregarding the risk score Community-dwelling (n=1016) (%) Institutionalized (n=400) (%) Tramadol 2.6 Trazodone 5.5 5.2 6.3 14.0 2.7 Ipratropium Ranitidine 7.5 2.8 Domperidone 4.7 Comb. with tramadol or methadone 13.8 Amitriptyline 8.5 3.0 Fentanyl Paroxetine 4.6 Loperamide 3.4 9.0 9.5 Quetiapine (fumarate) 3.4 4.1 Risperidone 9.0 9.0 Mirtazapine

*: Ipratropium is usually not considered for the calculation of the anticholinergic burden because it works locally after inhalation and is barely absorbed systemically. 36

5.2.3.5 Individual use of drug with a high anticholinergic activity according to Duran et al.

In the population of community-dwelling older adults 117 of the 1016 of the patients (11.5%) uses a drug with a high anticholinergic activity. In the population of institutionalized older adults this is 117 out of 400 patients or 29.3% and thus remarkably higher. Remark however that here it is possible that a single patient took 2 or more drugs with a high anticholinergic activity.

The top 10 most commonly used drugs with a high anticholinergic activity according to Duran et al. by older polypharmacy patients in Belgium is listed below (Table 5.2.3.5). The complete tables are presented in Appendix 15 and 16.

Table 5.2.3.5: Top 10 drugs with anticholinergic properties according to Duran et al. used by older adults with high anticholinergic activity Community-dwelling (n=1016) Institutionalized (n=400) Drug name ATC code Risk No. of % Drug name ATC code Risk No. of % score pts score pts 1 Ipratropium* R03AL01 H 47 4.6 Ipratropium* R03AL01 H 56 14.0 2 Amitriptyline N06AA09 H 30 3.0 Oxybutynin G04BD04 H 19 4.8 3 Oxybutynin G04BD04 H 17 1.7 Amitriptyline N06AA09 H 14 3.5 4 Hydroxyzine N05BB01 H 7 0.7 Clozapine N05AH02 H 6 1.5 5 Meclozine R06AE05 H 3 0.3 Hydroxyzine N05BB01 H 5 1.3 6 Diphenhydramine R06AA02 H 2 0.2 Trihexyphenidyl N04AA01 H 3 0.8 7 Doxepin N06AA12 H 2 0.2 Promethazine R06AD02 H 3 0.8 8 Nortriptyline N06AA10 H 2 0.2 Levomepromazine N05AA02 H 2 0.5 9 Tolterodine G04BD07 H 2 0.2 Nortriptyline N06AA10 H 2 0.5 10 Belladona A03BA04 H 1 0.1 Diphenhydramine D04AA32 H 2 0.5 alkaloids Scopolamine N05CM05 H 2 0.5

Figure 5.2.3.5: Top 10 drugs with high anticholinergic activity according to Duran et al. Community-dwelling (n=1016) (%) Institutionalized (n=400) (%)

0.2 0.2 Ipratropium* 0.5 0.5 0.1 0.5 0.5 0.2 0,2 Amitriptyline 0.3 Oxybutynin 0.8 0.8 0.7 4.6 Hydroxyzine 1.3 Meclozine Diphenhydramine 1.5 1.7 Doxepin Nortriptyline 14.0 Tolterodine Belladona alkaloids 3.5 Clozapine Trihexyphenidyl Promethazine Levomepromazine 4.8 3.0 Scopolamine (hyoscine)

*: Ipratropium is usually not considered for the calculation of the anticholinergic burden because it works locally after inhalation and is barely absorbed systemically. 36

5.2.3.6 Number of drugs with anticholinergic properties according to Duran et al. per patient

In the population of community-dwelling older adults the number of drugs with anticholinergic properties according to Duran et al. varies between 0 and 6 with a median (IQR) of 0 ± 1 drug. In this population of institutionalized older adults on the other hand the number of drugs with anticholinergic properties according to Duran et al. varies between 0 and 6 with a median (IQR) of 1 ± 2 drugs.

We compared the distribution of the number of drugs with anticholinergic properties per patient of the community-dwelling older adults and the institutionalized older adults. This is presented in Figure 5.2.3.6. The y-axis depicts the number of drugs with anticholinergic properties a patient might take and the X-axis depicts the number of patients in per cent.

Figure 5.2.3.6: Comparison of the number of drugs with anticholinergic properties according to Duran et al. per patient between community-dwelling older adults and institutionalized older adults in per cent

Community-dwelling (n=1016) Institutionalized older adults (n=400)

6 0.1 6 0.2 5 0.2 5 2.8 4 1.1 4 3.8 3 2.5 3 12,5 2 8.4 2 21.2

1 29.7 1 32.2 Numberdrugs of with

Numberdrugs of with 0 58.0 0 27.3

anticholinergic properties anticholinergic properties 0 20 40 60 80 0 10 20 30 40 Percentage of patients (n=1016) (%) Percentage of patients (n=400) (%)

5.2.3.7 Individual use of drugs with anticholinergic properties according to Rudolph et al., disregarding the risk scores

In the population of community-dwelling older adults 250 of the 1016 patients (24.6%) uses one or more drugs with anticholinergic properties. In the population of institutionalized older adults this is 240 (60.0%) out of the patients or 60.0% and thus remarkably higher.

The top 10 most commonly used drugs with anticholinergic properties according to Rudolph et al. by older polypharmacy patients in Belgium is listed below (Table 5.2.3.7). The complete tables are presented in Appendix 17 and 18.

Table 5.2.3.7: Top 10 drugs with anticholinergic properties according to Rudolph et al. used by older adults disregarding the risk score Community-dwelling (n=1016) Institutionalized (n=400) Drug name ATC code Risk No. % Drug name ATC code Risk No. of % score of pts score pts 1 Trazodone N06AX05 1 49 4.8 Trazodone N06AX05 1 55 13.8 2 Ranitidine A02BA02 1 42 4.1 Carbidopa- N04BA02 1 44 11.0 levodopa 3 Carbidopa- N04BA02 1 31 3.1 Quetiapine N05AH04 1 36 9.0 levodopa 4 Amitryptyline N06AA09 3 30 3.0 Ranitidine A02BA02 1 36 9.0 5 Paroxetine N06AB05 1 27 2.7 Risperidone N05AX08 1 34 8.5 6 Loperamide A07DA03 2 26 2.6 Mirtazapine N06AX11 1 25 6.3 7 Cetirizine R06AE07 2 25 2.5 Cetirizine R06AE07 2 21 5.3 8 Oxybutynin G04BD04 3 17 1.7 Loperamide A07DA03 2 20 5.0 9 Mirtazapine N06AX11 1 15 1.5 Oxybutynin G04BD04 3 19 4.8 10 Metoclopramide A03FA01 1 9 0.9 Haloperidol N05AD01 1 19 4.8

Seven drugs appear in both the top 10’s but amitriptyline, paroxetine and metoclopramide only appear in that of the community-dwelling population while quetiapine, risperidone and haloperidol only appear in that of the institutionalized older adults.

Figure 5.2.3.7: Top 10 drugs with anticholinergic properties according to Rudolph et al. disregarding the risk score Community-dwelling (n=1016) (%) Institutionalized (n=400) (%) Trazodone 0.9 1.5 4.8 4.8 Ranitidine 4.8 13.8 1.7 Carbidopa-levodopa Amitryptyline 5.0 2.5 Paroxetine Loperamide 5.3 Cetirizine 2.6 Oxybutynin 11.0 4.1 6.3 Mirtazapine Metoclopramide 2.7 9.0 3.1 Quetiapine 8.5 3.0 Risperidone 9.0 Haloperidol

5.2.3.8 Individual use of drugs with risk score 3 for anticholinergic (side-) effects according to Rudolph et al.

In the population of community-dwelling older adults 59 of the 1016 patients (5.8%) uses one or more drugs with anticholinergic properties. In the population of institutionalized older adults this is 43 out of 400 patients or 10.8% and thus remarkably higher. Remark however that here it is possible that a single patient took 2 or more drugs with risk score 3.

There are only 5 drugs with anticholinergic properties according to Rudolph et al. taken by older polypharmacy patients in Belgium. This is listed in Table 5.2.3.8.

Table 5.2.3.8: Top 10 drugs with risk score 3 for anticholinergic (side-) effects used by older adults according to Rudolph et al. Community-dwelling (n=1016) Institutionalized (n = 400) Drug name ATC code Risk No. of % Drug name ATC code Risk No. of % score pts score pts 1 Amitryptyline N06AA09 3 30 3.0 Oxybutynin G04BD04 3 19 4.8 2 Oxybutynin G04BD04 3 17 1.7 Amitryptyline N06AA09 3 14 3.5 3 Hydroxyzine N05BB01 3 7 0.7 Hydroxyzine N05BB01 3 5 1.3 4 Meclozine R06AE05 3 3 0.3 Promethazine R06AD02 3 3 0.8 5 Diphenhydra R06AA02 3 2 0.2 Diphenhydrami D04AA32 3 2 0.5 mine ne

Four of the drugs appear in both the top 5’s but meclozine only appears in that of the community- dwelling population while promethazine only appears in that of the institutionalized older adults.

Figure 5.2.3.8: Top 10 drugs with risk score 3 for anticholinergic (side-) effects according to Rudolph et al. Community-dwelling (n=1016) (%) Institutionalized (n=400) (%)

0.3 0.2 0.5 0.8 3.0 Amitryptyline 0.7 1.3 Oxybutynin

Hydroxyzine 4.8

Meclozine

Diphenhydramine 1.7 Promethazine 3.5

5.2.3.9 Number of drugs with anticholinergic properties according to Rudolph et al. per patient

In the population of community-dwelling older adults the number of drugs with anticholinergic properties according to Rudolph et al. varies between 0 and 4 per patient with a median (IQR) of 0 ± 0 drugs. In the population of institutionalized older adults on the other hand the number of drugs with anticholinergic properties varies between 0 and 6 with a median (IQR) of 1 ± 2 drugs.

We compared the distribution of the number of drugs with anticholinergic properties per patient of the community-dwelling older adults and the institutionalized older adults. This is presented in Figure 5.2.3.9. The y-axis depicts the number of drugs with anticholinergic properties a patient might take and the X-axis depicts the number of patients in per cent.

Figure 5.2.3.9: Comparison of the number of drugs with anticholinergic properties according to Rudolph et al. per patient between community-dwelling older adults and institutionalized older adults in per cent

Community-dwelling (n=1016) Institutionalized (n=400)

6 0.0 6 0,5

5 0.0 5 0.2 4 0.1 4 1.3

3 1.2 3 4.2

2 3.2 2 22.0

1 20.1 1 31.8

Numberdrugs of with Numberdrugs of with anticholinergic properties anticholinergic properties 0 75.4 0 40.0

0 20 40 60 80 0 20 40 60 Percentage of patients (n= 1016) (%) Percentage of patients (n=400) (%)

PART 6: DISCUSSION

6.1 RISK SCALES

6.1.1 QT-prolonging risk scales in older adults

Drug induced QT-prolongation and TdP is currently a topic receiving a lot of attention by researchers37 as well as the media38, 39. However, during the literature search we only found two existing risk scales for QT-prolongation and TdP and only one of them includes a list of drugs with a risk for TdP.21, 32 A possible explanation for this lack of risk scales is that the occurrence of TdP is very hard to measure because it usually only lasts a couple of seconds.12 The credible meds list is however updated monthly and currently remains the largest available database of QT-research.21 It is likely that this new interest by researchers and the media will lead to new and improved scales to predict QT-prolongation and TdP.

The credible meds lists in itself are quite clear but a log-in must be made for the website.21 In the community-pharmacy, however, these lists are not practical because the pharmacist would have to scan the lists for every drug the patient uses which is a time-consuming activity. Here the top 10 most commonly used QT-prolonging drugs as found in this research might be useful because then the physician or pharmacist would only have to look for the 10 most commonly used drugs. Further research could also focus on what pharmacists might find useful in every day practice.

6.1.2 Anticholinergic risk scales in older adults

Scales to predict the anticholinergic burden of an individual patient exist in abundance.28 There are many scales that predict more or less the same, so we made an evidence-based decision on what scales would be used in this thesis.28 The results of the evaluation of the drugs with anticholinergic properties according to Duran et al. and Rudolph et al. were largely the same because the list by Duran et al. includes some drugs that Rudolph et al. did not include, even the top 10 most commonly used drugs by both subpopulations varies. It is reasonable to conclude that the other anticholinergic risk scales would have led to even other outcomes.

An Australian study evaluated the use of drugs with anticholinergic properties in a community- dwelling population of older men using four different anticholinergic risk scales (Table 6.1.2).40

Table 6.1.2: Use of drugs with anticholinergic properties, an Australian study: adopted from 40 Anticholinergic risk scale % of patients with at least one drug with anticholinergic properties ARS 13.0 ADS 39.0 ACB 39.0 DBI-Ach 18.0

Pont et al. concluded that there is little agreement between the four anticholinergic risk scales included in their study and conclusions regarding anticholinergic risk should be made with great care due to the great variations between the existing scales.40

Besides that, even though the anticholinergic risk scale designed by Duran et al. includes all medication included by earlier scales as well as Martindale, it is a lot harder for pharmacists to calculate a patient’s anticholinergic burden because the drugs are not graded.28 It also contains drugs such as ipratropium which, when used properly, are barely absorbed in the blood stream and do not lead to systemic ADE’s.36

The list composed by Rudolph et al. on the other hand does not include some of the most commonly used drugs with anticholinergic properties by either of the subpopulations in this thesis.31 Because the drugs are graded, as in most existing anticholinergic risk scales, it is possible for the pharmacist to calculate the anticholinergic burden for the individual patient.28, 31

However, there is no consensus on the grades given to these drugs so further research is necessary.28 Besides that, the score of the anticholinergic burden leading to ADE’s such as deterioration of the aging brain, falls etc. was not found, possibly because here there is no consensus either.4, 28, 29 This means that a pharmacist can calculate a patient’s anticholinergic burden taking into account the fact that there are many possibilities depending on what scale was used. However, it is impossible for the pharmacist to then predict the actual risk of ADE’s for that patient. This is especially important because the risk of ADE’s depends on the anticholinergic burden and anticholinergic effects are additive.4, 27

Hopefully further research will lead to an unambiguous anticholinergic risk scale that includes all drugs with anticholinergic properties that may lead to ADE’s and that is useful for calculating a patient’s risk of ADE’s by physicians or pharmacists.

6.2 GENERAL DRUG USE OF THE INCLUDED POPULATIONS

Generally, the expected result was that institutionalized older adults use more medication than community-dwelling older adults. This turned out to be right, but the average difference was smaller than expected. A possible explanation for this small difference might for example be that the drugs of the community-dwelling older adults included flu vaccines and all sorts of supplements where that was not included for the institutionalized population.

The average number of drugs used by the Belgian older population was then compared to that of foreign older populations. However, the general drug use in older polypharmacy patients has not been described before. The general drug use of institutionalized older adults has only been described a few times and not in polypharmacy patients. This means that the results as described in Table 6.2 are not comparable to those in this study because they also or mainly included non-polypharmacy patients. Generally, the number of drugs used by the older adults in other countries are more or less comparable but can vary depending on for example age and the relative number of polypharmacy patients. The drug use as described by Felton et al. (United-States) is considerably lower, but they only included prescription drugs.41

Table 6.2: General use of medication in various countries Community-dwelling Institutionalized Belgium (this study) 11 ± 4 12 ± 5 France 8.3 ± 4.2 42 Spain 4.6 ± 2.9 43 6.5 ± 2.9 44 Cognitive impaired: 5.2 ± 3.2 43 Not cognitive impaired: 4.0 ± 2.7 43 United-States 1.7 ± 1.9 (prescription drugs) 41

6.3 EVALUATION OF THE INDIVIDUAL USE OF QT-PROLONGING DRUGS

As expected, a large difference between community-dwelling and institutionalized older adults was found regarding the percentage of patients taking one or more QT-prolonging drugs as well as the number of QT-prolonging drugs per patient. This is possibly because institutionalized older adults have more comorbidities and generally are in a worse medical condition than community-dwelling older adults. Especially the institutionalized older adults in general use a lot of QT-prolonging drugs with known risk of TdP (risk score 4). Because two of the risk factors for TdP are old age and female sex and this is a population with a lot of female older adults (75%), many of them are possibly at risk for TdP.12

We compared this use of QT-prolonging drugs with other studies. Four interesting studies regarding QT-prolonging drugs were found but none of them included older polypharmacy patients. This is the first research for older polypharmacy patients.

Vandael et al. studied the use of QT-prolonging drugs in Belgian psychiatry. However, they focused on drug interactions including a QT-prolonging drug. Vandael et al. used the credible meds lists as well but only included antipsychotics and antidepressants, probably because these are the only relevant classes in psychiatry. The drug use of 43 patients (7.3%) contains one or more interactions with a severe or very severe risk for QT-prolongation. Remark however that they did not include the use of QT-prolonging drugs of other classes, the use of QT-prolonging drugs without interactions or QT-prolonging drugs with a small or medium risk for QT-prolongation. Besides that, the psychiatric patients are considerably younger than the community-dwelling and institutionalized patients and the population also includes non-polypharmacy patients. This might explain the big difference in the use of QT-prolonging drugs between the psychiatric patients and the patients in this study (Table 6.3a). 45

Table 6.3a: The use of QT-prolonging drugs in Belgium: a comparison between the use in psychiatric, community- dwelling and institutionalized patients Adopted from 45 This study Population Psychiatric Community-dwelling Institutionalized No. of pts 592 1016 400 % female 46 58 75 Age (mean ± SD) in years 52.4 ± 17.3 78.8 ± 5.5 86.2 ± 6.3 1 QTPD or more (%) 7.3 62.4 85.8

Vandael et al. also listed the most commonly used antipsychotics and antidepressants by Belgian psychiatry patients. We compared this to the Belgian community-dwelling and institutionalized older adults (Table 6.3b) and found that the use of antipsychotics was considerably lower in community- dwelling older adults but considerably higher in institutionalized older adults. The use of antidepressants in community-dwelling as well as institutionalized older adults was lower than in

37 psychiatric patients except for Amitriptyline. This might be explained by comments as described for Table 6.3a.45

Table 6.3b: Most commonly used antipsychotics and antidepressants in Belgian psychiatry: a comparison with Belgian community-dwelling and institutionalized older adults Adopted from 45 This study Psychiatric (n=592) Community-dwelling (n=1016) Institutionalized (n=400) No. of pts % No. of pts % No. of pts % Antipsychotics Risperidone 15 2.5 1 0.1 34 8.5 Olanzapine 14 2.4 1 0.1 13 3.3 Quetiapine 14 2.4 5 0.5 36 9.0

Antidepressants Venlafaxine 15 2.5 20 2.0 7 1.8 Dosulepine 11 1.9 16 1.6 0 0.0 Amitriptyline 11 1.9 30 3.0 14 3.5

The three remaining studies researched the use of QT-prolonging drugs or interactions involving QT- prolonging drugs (Table 6.3c). First of all, the difference in use of QT-prolonging drugs might be explained by the fact that Baptista et al., Curtis et al. and Allen LaPointe et al. also included non- polypharmacy patients. Further, Curtis et al. recruited a considerably younger population, while this is not known for the research by Allen La Pointe et al. Besides that, Allen LaPointe et al. only searched for interactions including QT-prolonging drugs and Baptista et al. only screened for 19 different QT-prolonging drugs. This might explain the big difference in the use of QT-prolonging drugs between the populations in these studies and ours.46-48

Table 6.3c: Evaluation of the individual use of QT-prolonging drugs: a comparation with other studies This study Baptista et al. 46 Curtis et al. 47 Allen LaPointe et al. 48 Country Belgium Portugal United-States United-States Population Community- Institutionalized Hospitalized Community- Community-dwelling dwelling dwelling No. of pts 1016 400 108,045 4,825,345 2,000,000 Age (Mean ± SD) in 78.8 ± 5.5 86.2 ± 6.3 74.2 ± 12.5 49.0 ± 16 - years No. of drugs 175 175 19 76 - researched 1 QTPD or more (%) 62.4 85.8 17.5 22.8 11.4 (high-risk use) 2 QTPD 18.1 26.2 2.6 % 8.7 4.6 3 QTPD 5.9 16.8 0.3 % 0.7 (3 or more) 4 QTPD 1.5 8.2 0.025 % 5 QTPD 0.3 3.8 0.009 %

There are many patients in both subpopulations who take one or more QT-prolonging drugs and physicians and pharmacists should consider the risks of these drugs when prescribing or delivering them in daily practice. The problem and a possible solution are described in 6.1.1.

Besides that, further research could focus on the effect of reduced use of QT-prolonging drugs on the patient’s quality of life (QoL). When exactly a patient is at risk for drug-induced TdP, is being researched.49

6.4 EVALUATION OF THE INDIVIDUAL USE OF DRUGS WITH ANTICHOLINERGIC PROPERTIES

The expected differences between community-dwelling older adults and institutionalized older adults were found as well as a slight difference between the use of drugs with anticholinergic properties as described by Duran et al. and Rudolph et al.28, 31

The literature was searched for comparable researches. The two most interesting studies are discussed below.

An American study by Felton et al. compared the use of drugs with anticholinergic properties between black and white older Americans spread over 10 years. They started with a population of 1266 black (41.4%) and 1789 white (58.6%) community-dwelling Americans aged 70 to 79 years in year one and researched the evolution of the use of drugs with anticholinergic properties over 10 years. The manuscript does not state how many of them became institutionalized over the years.41

The use of drugs with anticholinergic properties in year 1, year 5 and year 10 are presented in Table 6.4a. The general use of drugs with anticholinergic properties is much lower in both American subpopulations than in either of our subpopulations this might be explained by the fact that Felton et al. also included non-polypharmacy patients.41

Table 6.4a: American anticholinergic use by type and race over time: adopted from 41 Anticholinergic Year 1 Year 5 Year 10 use Blacks Whites Blacks Whites Blacks (n=537) Whites (n=1266) (%) (n=1789) (%) (n=1035) (%) (n=1610) (%) (%) (n=1001) (%) Prescription 8.8 11.4 11.4 11.9 5.0 7.0 Non-prescription 5.4 6.9 2.7 4.9 3.4 6.1 Any 13.4 17.8 13.9 16.3 8.0 12.5

Felton et al. also created a top 10 most commonly used drugs with anticholinergic properties for these subpopulations but they used the 2012 American Geriatrics Society Beers Criteria (Table

41 6.4b).

Table 6.4b: Top 10 most commonly used anticholinergic drugs by white older adults in the United-States: adopted from41 Year 1 (n=1789) Year 5 (n=1610) Year 10 (n=1001) Drug name No. of % Drug name No. of % Drug name No. of % pts pts pts Diphenhydramine 82 4.6 Diphenhydramine 51 3.2 Meclozine 13 1.3 Chlorpheniramine 41 2.3 Tolterodine 40 2.5 Oxybutynin 12 1.2 Amitriptyline 32 1.8 Paroxetine 32 2.0 Tolterodine 9 0.9 Meclozine 28 1.6 Meclozine 29 1.8 Paroxetine 6 0.6 Paroxetine 19 1.1 Oxybutynin 26 1.6 Diphenhydramine 3 0.3 Hydroxyzine 15 0.8 Amitriptyline 22 1.4 Nortriptyline 3 0.3 Hyoscyamine 14 0.8 Hydroxyzine 10 0.6 Atropine 3 0.3 Clemastine 12 0.7 Chlorpheniramine 10 0.6 Dicyclomine 2 0.2 Atropine 11 0.6 Olanzapine 7 0.4 Hyoscyamine 2 0.2 Nortriptyline 10 0.6 Dicyclomine 7 0.4 Solifenacin 2 0.2

Compared to the top 10 most commonly used drugs with anticholinergic properties found in the American study, some drugs do not appear in our top 10 such as dicyclomine and clemastine because they are not available in Belgium. Solifenacin does not appear in either of the lists we used. Compared to year 1 and 10, 6 drugs appear in both the American study as in our top 10 for drugs with a high anticholinergic activity according to Duran et al. 41

A British study by Fox et al. researched the use of drugs with anticholinergic properties in a population of community-dwelling as well as institutionalized older adults living in England and Wales (Table 6.4c). However, Fox et al. also included non-polypharmacy patients and 21% of the older adults did not use any drug. We excluded the older adults who did not take any drug and estimated the use of drugs with anticholinergic properties. Fox et al. their population included both community-dwelling and institutionalized older adults and the use of anticholinergic drugs lays somewhere between that of the community-dwelling and the institutionalized older adults in this study. This means it is reasonable to say that the use of drugs with anticholinergic properties in Fox et al. their study and ours is very comparable.50

Table 6.4c: Evaluation of the use of drugs with anticholinergic properties in a British population of community-dwelling and institutionalized older adults adopted from 50 This study Community-dwelling Community- Institutionalized + institutionalized dwelling No. of pts 13,004 1016 400 Age (mean ± SD) in years 75.2 ± 6.8 78.8 ± 5.5 86.2 ± 6.3 pts taking any drug (%) 9,850 (79) pts using one or more drug(s) with anticholinergic 6010 (48) properties (%) % of pts using one or more drug(s) with 61 42.0 72.8 anticholinergic properties when excluding those who don’t use any drug

Analogue to the research on QT-prolongation, physicians and pharmacists should consider avoiding the use of drugs with anticholinergic properties where possible. They should also take a patient’s cognitive status into account because drugs with anticholinergic properties can (further) deteriorate the aging brain.30 However, as described in 6.1.2 the lists of drugs with anticholinergic (side-) effects are not readily usable in daily practice. Besides that, drugs with anticholinergic properties have some large adverse effects such as (further) deterioration of the aging brain, falls and decreasing abilities to live independently. So further research could focus on the effects on patients’ QoL with and without reduced use of drugs with anticholinergic properties and on the absolute risk of ADE’s with anticholinergic drugs in order to be able to estimate the individual patient’s risk of large anticholinergic ADE’s and therefor his QoL.6

6.5 STRENGHTS AND LIMITATIONS

This study includes a large group of patients and focuses on community-dwelling older adults as well as institutionalized older adults. In this study, the general drug use as well as the use of QT- prolonging drugs and drugs with anticholinergic properties were evaluated. This means that multiple aspects of drug use in Belgian older polypharmacy patients were evaluated for community-dwelling older adults as well as institutionalized older adults. A comparable study for the use of QT-prolonging drugs and drugs with anticholinergic properties has never been conducted for older polypharmacy patients. Because the same methods were used for both subpopulations, the results could easily be compared. Besides that, the Strengthening the Reporting of Observational studies in Epidemiology (STROBE)-guidelines were followed for this observational study.51

Because of the choice of population, the information obtained in this study may not apply to similar but slightly different populations such as hospitalized older adults or foreign older patients. Besides that, this is a retrospective observational study so it doesn’t have the highest level of evidence. Consequently, only associations can be made following the results found in this thesis and no causality. We didn’t evaluate the severity of the drug use. For QT-prolongation we didn’t take the risk factors as described in Table 1.2.3 into account.

PART 7: CONCLUSION

Generally, community-dwelling older adults in this study take an average of 11 ± 4 drugs (mean ± SD), while institutionalized older adults take an average of 12 ± 5 drugs (mean ± SD).

Firstly, there is only one risk scale to estimate an individual patient’s risk of TdP available in the literature; the one described by AZCERT. This risk scale was used to evaluate the use of QT- prolonging drugs for the 1016 community-dwelling and 400 institutionalized older Belgian polypharmacy patients. In this first part of our research, we found that 63.4% of the community- dwelling older adults and 85.8% of the institutionalized older adults used one or more QT-prolonging drugs. There is a considerable difference between community-dwelling older adults and institutionalized older adults in the number of QT-prolonging drugs per patient as well. The top 10 most commonly used drugs are largely comparable, but institutionalized older adults use these drugs more. Finally, further research is necessary to estimate the individual risk of TdP for these patients and to estimate the increase in QoL in case the use of QT-prolonging drugs is reduced.

Subsequently the existence of anticholinergic risk scales was researched and these seemed to exist in abundance. The risk scale described by Duran et al. was chosen because it is the most evidence- based risk scale in the literature. The use of drugs with anticholinergic properties was also evaluated with the risk scale described by Rudolph et al. because it is the most commonly used anticholinergic risk scale. In the population of community-dwelling older adults 42.0% of the patients used a drug with anticholinergic properties according to Duran et al. while this is 72.9% in the population of institutionalized older adults. Here as well there is a considerable difference between community- dwelling older adults and institutionalized older adults regarding the number of drugs with anticholinergic properties per patient as well. The results for the evaluation using Rudolph et al. were comparable to those using Duran et al. However, the percentage of patients using one or more drugs with anticholinergic properties was much lower: 24.6% of the community-dwelling older adults and 60.0% of the institutionalized older adults. This is because Duran et al. included all drugs considered to have anticholinergic properties while Rudolph et al. did not. The top 10 most commonly used drugs according to Duran et al. and Rudolph et al. were largely comparable. Here as well the percentages in the top 10 were considerably higher for the population of institutionalized older adults. These numbers were lower in other studies but they also included non-polypharmacy patients. Finally, further research is necessary to create an unambiguous risk scale for estimating the individual risk of ADE’s and to estimate the increase in QoL in case the use of drugs with anticholinergic properties is reduced.

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Appendix

Appendix 1: Sympathic and parasympathic effect on various organs: adopted from52 Organ Sympatic stimulation Parasympathic stimulation Eye - Iris - Stimulates radial fibers (dilates - Stimulates circular fibers pupil) (constricts pupil) - Ciliary muscle - Inhibits (flattens lens- weak action) - Stimulates (bulges lens) Salivary glands (parotid, sublingual, Vasoconstriction may diminish Stimulates copious secretion high in submaxillary) secretion enzym content Lacrimal glands Stimulates secretion Sweat glands Copious sweating (cholinergic) Heart - SA node - Increased rate - Decreased rate - Muscle - Increased force of contraction Lungs - Bronchi - Dilatation - Constriction Stomach - Wall - Decreased motility and tone - Increased motility and tone - Glands - Stimulates secretion of alkaline juice - Stimulates secretion of acid juice with with low enzym activity high enzym activity Intestine - Wall - Decreased motility and tone - Increased motility and tone - Anal sphincter - Contraction - Inhibition Pancreas Vasoconstriction may diminish Stimulates secretion of pancreatic secretion enzymes Suprarenal gland - Medulla - Secretion of epinephrine Urinary bladder - Wall - Inhibition - Excitation - Sphincter - Excitation - Inhibition Penis Ejaculation Erection (vasodilatation) Arrector pili muscles of hair follicles Contraction Arterioles - Splanchnic region and skin skeletal - Constriction muscles - Baro- and chemoreceptor response - Constriction - Response to exercise and alarm - Dilatation

Appendix 2: Alphabetical list of QT-prolonging ATC code Drug name ATC Risk medication: adopted from and adapted 21 combination score ATC code Drug name ATC Risk A03FA03 Domperidone 4 combination score N06AA12 Doxepin 2 R03AC12 Albuterol R03CC02 1 (salbutamol) R03AL02 N05AD08 Droperidol 4 R03AK04 C01CA26 Ephedrine A08AA56 1 G04CA01 Alfuzosin G04CA51 3 R01AA03 Ephedrine 1 C01BD01 Amiodarone 4 R01AB05 Ephedrine 1 N05AL05 Amisulpride 2 R03CA02 Ephedrine 1 N06AA09 Amitriptyline N06CA01 2 S01FB02 Ephedrine 1 L01XX35 Anagrelide 4 A01AD01 Epinephrine R03AK01 1 G04BE07 Apomorphine 3 (adrenaline) S01EA51 N04BC07 Apomorphine 3 B02BC09 Epinephrine 1 N05AX12 Aripiprazole 3 C01CA24 Epinephrine 1 L01XX27 Arsenic trioxide 4 R01AA14 Epinephrine 1 J05AE08 Atazanavir 3 R03AA01 Epinephrine 1 N06BA09 Atomoxetine 1 S01EA01 Epinephrine 1 J01FA10 Azithromycin J01RA07 4 L01XX41 Eribulin 3 S01AA26 Azithromycin 4 D10AF02 Erythromycin D10AF52 4 J04AK05 Bedaquiline 3 J01FA01 Erythromycin 4 L01XX32 Bortezomib 3 S01AA17 Erythromycin 4 L01XE14 Bosutinib 3 N06AB10 Escitalopram 4 N05CC01 Chloral hydrate 2 N03AX10 Felbamate 3 P01BA01 Chloroquine 4 L04AA27 Fingolimod 3 S01AE03 Ciprofloxacin J01RA10 2 C01BC04 Flecainide 4 J01RA12 J02AC01 Fluconazole J01RA07 2 J01RA11 D01AC15 Fluconazole 2 S03AA07 Ciprofloxacin 2 N06AB03 Fluoxetine N06CA03 2 S02AA15 Ciprofloxacin 2 R03AC13 Formoterol R03AL05 1 J01MA02 Ciprofloxacin 2 R03AK08 N06AB04 Citalopram 4 R03AK07 J01FA09 Clarithromycin A02BD06 4 R03AK11 A02BD07 R03AK09 A02BD09 J05AD01 Foscarnet 3 A02BD05 C03CA01 Furosemide C03CB01 2 A02BD04 (frusemide) C03EB01 N06AA04 Clomipramine 2 N06DA04 Galantamine 2 N05AH02 Clozapine 3 A04AA02 Granisetron 3 L01XE16 Crizotinib 3 N05AD01 Haloperidol 4 L01XE23 Dabrafenib 3 C03AA03 Hydrochlorothiazide C09XA52 2 L01XE06 Dasatinib 3 C09XA54 C03AB03 N05CM18 Dexmedetomidine 3 C03EA01 P01BF05 Dihydroartemisinin 3 C03AX01 + piperaquine C09DX03 D04AA32 Diphenhydramine D04AA33 2 C09DX01 R06AA52 P01BA02 Hydroxychloroquine 2 R06AA02 Diphenhydramine 2 N05BB01 Hydroxyzine N05BB51 2 C01BA03 Disopyramide 4 N06AA02 Imipramine N06AA03 2 C01CA07 Dobutamine 1 (melipramine)

ATC code Drug name ATC Risk ATC code Drug name ATC Risk combination score combination score C03BA11 Indapamide C09BX01 2 H01BB02 Oxytocin G02AC01 3 C01CA02 Isoproterenol R03AK02 1 N05AX13 Paliperidone 3 (isoprenaline) R03CB51 A02BC02 Pantoprazole A02BD04 2 R03AB02 Isoproterenol 1 N06AB05 Paroxetine 2 R03CB01 Isoproterenol 1 L01XE11 Pazopanib 3 C08CA03 Isradipine 3 P01CX01 Pentamidine 4 J02AC02 Itraconazole 2 C01EB17 Ivabradine 2 V08DA04 Perflutren lipid 3 D01AC08 Ketoconazole 2 microspheres C01CA06 Phenylephrine R01BA53 1 G01AF11 Ketoconazole 2 S01GA55 J02AB02 Ketoconazole 2 R01AA04 Phenylephrine 1 L01XE07 Lapatinib 3 R01AB01 Phenylephrine 1 J01MA12 Levofloxacin A02BD10 4 R01BA03 Phenylephrine 1 J01RA05 S01FB01 Phenylephrine 1 S01AE05 Levofloxacin 4 S01GA05 Phenylephrine 1 N07BC02 Methadone N02AC52 4 N05AG02 Pimozide 4 N06BA04 Methylphenidate 1 N05AD05 Pipamperone 3 A03FA01 Metoclopramide 2 J02AC04 Posaconazole 2 A01AB17 Metronidazole A02BD08 2 J01RA03 D04AA10 Promethazine V03AB05 3 J01RA10 R06AD52 A02BD03 R06AD02 Promethazine 3 A02BD02 R01BA02 Pseudoephedrine R01BA52 1 P01AB51 A02BD01 N05AH04 Quetiapine 3 J01RA04 J05AG05 Rilpevirine 3 D06BX01 Metronidazole 2 N05AX08 Risperidone 3 G01AF01 Metronidazole 2 J05AE03 Ritonavir J05AR10 2 J01XD01 Metronidazole 2 J01FA06 Roxithromycin 3 P01AB01 Metronidazole 2 R03AC12 Salmeterol R03AK06 1 G03XB01 Mifepristone G03XB51 3 J05AE01 Saquinavir 3 G04BD12 Mirabegron 3 N05AE03 Sertindole 3 N06AX11 Mirtazapine 3 N06AB06 Sertraline 2 C09AA13 Moexipril/HCTZ C09BA13 3 N01AB08 Sevoflurane 4 J01MA14 Moxifloxacin 4 G04BD08 Solifenacin G04CA53 2 S01AE07 Moxifloxacin 4 L01XE05 Sorafenib 3 C08CA04 Nicardipine 3 C07AA07 Sotalol C07BA07 4 L01XE08 Nilotinib 3 C07AA57 C01CA03 Norepinephrine 1 N05AL01 Sulpiride 4 (noradrenaline) L01XE04 Sunitinib 3 J01MA06 Norfloxacin J01RA13 3 L02BA01 Tamoxifen 3 S01AE02 Norfloxacin 3 J05AE11 Telaprevir 2 N06AA10 Nortriptyline 2 J01FA15 Telithromycin 3 J01MA01 Ofloxacin J01RA09 3 N07XX06 Tetrabenazine 3 S01AE01 Ofloxacin 3 M03BX02 Tizanidine 3 S02AA16 Ofloxacin 3 G04BD07 Tolterodine 3 N05AH03 Olanzapine 3 N06AX05 Trazodone 2 A04AA01 Ondansetron 4

ATC code Drug name ATC Risk ATC code Drug name ATC Risk combination score combination score L01XE12 Vandetanib 4 N06AX16 Venlafaxine 3 G04BE09 Vardenafil 3 J02AC03 Voriconazole 2 L01XE15 Vemurafenib 3

N05CC01 Chloral hydrate 2 S01AE03 Ciprofloxacin J01RA10 2 Appendix 3: Categorical list of QT-prolonging medication: 20 J01RA12 adopted from and adapted J01RA11 ATC Drug name ATC Risk S03AA07 Ciprofloxacin 2 combination score R03AC12 Albuterol R03CC02 1 S02AA15 Ciprofloxacin 2 (salbutamol) R03AL02 J01MA02 Ciprofloxacin 2 R03AK04 N06BA09 Atomoxetine 1 N06AA04 Clomipramine 2 C01CA07 Dobutamine 1 D04AA32 Diphenhydramine D04AA33 2 R06AA52 C01CA26 Ephedrine A08AA56 1 R06AA02 Diphenhydramine 2 R01AA03 Ephedrine 1 N06AA12 Doxepin 2 R01AB05 Ephedrine 1 J02AC01 Fluconazole J01RA07 2 R03CA02 Ephedrine 1 D01AC15 Fluconazole 2 S01FB02 Ephedrine 1 N06AB03 Fluoxetine N06CA03 2 A01AD01 Epinephrine R03AK01 1 C03CA01 Furosemide C03CB01 2 (adrenaline) S01EA51 (frusemide) C03EB01 B02BC09 Epinephrine 1 N06DA04 Galantamine 2 C01CA24 Epinephrine 1 C03AA03 Hydrochlorothiazide C09XA52 2 R01AA14 Epinephrine 1 C09XA54 C03AB03 R03AA01 Epinephrine 1 C03EA01 S01EA01 Epinephrine 1 C03AX01 R03AC13 Formoterol R03AL05 1 C09DX03 R03AK08 C09DX01 R03AK07 P01BA02 Hydroxychloroquine 2 R03AK11 N05BB01 Hydroxyzine N05BB51 2 R03AK09 N06AA02 Imipramine N06AA03 2 C01CA02 Isoproterenol R03AK02 1 (melipramine) (isoprenaline) R03CB51 C03BA11 Indapamide C09BX01 2 R03AB02 Isoproterenol 1 J02AC02 Itraconazole 2 R03CB01 Isoproterenol 1 C01EB17 Ivabradine 2 N06BA04 Methylphenidate 1 D01AC08 Ketoconazole 2 C01CA03 Norepinephrine 1 (noradrenaline) G01AF11 Ketoconazole 2 C01CA06 Phenylephrine R01BA53 1 J02AB02 Ketoconazole 2 S01GA55 R01AA04 Phenylephrine 1 A03FA01 Metoclopramide 2 R01AB01 Phenylephrine 1 A01AB17 Metronidazole A02BD08 2 J01RA03 R01BA03 Phenylephrine 1 J01RA10 S01FB01 Phenylephrine 1 A02BD03 A02BD02 S01GA05 Phenylephrine 1 P01AB51 R01BA02 Pseudoephedrine R01BA52 1 A02BD01 R03AC12 Salmeterol R03AK06 1 J01RA04 D06BX01 Metronidazole 2 N05AL05 Amisulpride 2 G01AF01 Metronidazole 2 N06AA09 Amitriptyline N06CA01 2

J01XD01 Metronidazole 2 H01BB02 Oxytocin G02AC01 3 P01AB01 Metronidazole 2 N05AX13 Paliperidone 3 N06AA10 Nortriptyline 2 L01XE11 Pazopanib 3 A02BC02 Pantoprazole A02BD04 2 V08DA04 Perflutren lipid 3 N06AB05 Paroxetine 2 microspheres N05AD05 Pipamperone 3 J02AC04 Posaconazole 2 D04AA10 Promethazine V03AB05 3 J05AE03 Ritonavir J05AR10 2 R06AD52 N06AB06 Sertraline 2 R06AD02 Promethazine 3 G04BD08 Solifenacin G04CA53 2 N05AH04 Quetiapine 3 J05AE11 Telaprevir 2 J05AG05 Rilpevirine 3 N06AX05 Trazodone 2 N05AX08 Risperidone 3 J02AC03 Voriconazole 2 J01FA06 Roxithromycin 3 G04CA01 Alfuzosin G04CA51 3 J05AE01 Saquinavir 3 G04BE07 Apomorphine 3 N05AE03 Sertindole 3 N04BC07 Apomorphine 3 L01XE05 Sorafenib 3 N05AX12 Aripiprazole 3 L01XE04 Sunitinib 3 J05AE08 Atazanavir 3 L02BA01 Tamoxifen 3 J04AK05 Bedaquiline 3 J01FA15 Telithromycin 3 L01XX32 Bortezomib 3 N07XX06 Tetrabenazine 3 L01XE14 Bosutinib 3 M03BX02 Tizanidine 3 N05AH02 Clozapine 3 G04BD07 Tolterodine 3 L01XE16 Crizotinib 3 G04BE09 Vardenafil 3 L01XE23 Dabrafenib 3 L01XE15 Vemurafenib 3 L01XE06 Dasatinib 3 N06AX16 Venlafaxine 3 P01BF05 Dihydroartemisinin 3 C01BD01 Amiodarone 4 + piperaquine L01XX35 Anagrelide 4 L01XX41 Eribulin 3 L01XX27 Arsenic trioxide 4 N03AX10 Felbamate 3 J01FA10 Azithromycin J01RA07 4 L04AA27 Fingolimod 3 S01AA26 Azithromycin 4 J05AD01 Foscarnet 3 P01BA01 Chloroquine 4 A04AA02 Granisetron 3 N06AB04 Citalopram 4 C08CA03 Isradipine 3 J01FA09 Clarithromycin A02BD06 4 L01XE07 Lapatinib 3 A02BD07 G03XB01 Mifepristone 3 A02BD09 A02BD05 G04BD12 Mirabegron G03XB51 3 A02BD04 N06AX11 Mirtazapine 3 C01BA03 Disopyramide 4 C09AA13 Moexipril/HCTZ C09BA13 3 A03FA03 Domperidone 4 C08CA04 Nicardipine 3 N05AD08 Droperidol 4 L01XE08 Nilotinib 3 D10AF02 Erythromycin D10AF52 4 J01MA06 Norfloxacin J01RA13 3 J01FA01 Erythromycin 4 S01AE02 Norfloxacin 3 S01AA17 Erythromycin 4 J01MA01 Ofloxacin J01RA09 3 N06AB10 Escitalopram 4 S01AE01 Ofloxacin 3 C01BC04 Flecainide 4 S02AA16 Ofloxacin 3 N05AD01 Haloperidol 4 N05AH03 Olanzapine 3 J01MA12 Levofloxacin A02BD10 4 J01RA05

S01AE05 Levofloxacin 4 C07AA07 Sotalol C07BA07 4 C07AA57 N07BC02 Methadone N02AC52 4 N05AL01 Sulpiride 4 J01MA14 Moxifloxacin 4 L01XE12 Vandetanib 4 S01AE07 Moxifloxacin 4

A04AA01 Ondansetron 4 P01CX01 Pentamidine 4 N05AG02 Pimozide 4 N01AB08 Sevoflurane 4

Appendix 4: AZCERT diagram for QT risk scores adopted from 21

Appendix 5: High potency (H) and low potency (L) ATC Drug name ATC Risk anticholinergic drugs: adopted from and adapted 28 combination score ATC Drug name ATC Risk N05AH03 Olanzapine L combination score N02AA05 Oxycodone N02AA55 L N06AA09 Amitriptyline N06CA01 H N06AB05 Paroxetine L A03BA01 Atropine S01FA01 H A03CB03 N05AH04 Quetiapine L A03BA04 Belladonna A03CB02 H (fumarate) alkaloids A06AB30 A02BA02 Ranitidine A02BA07 L R06AB04 Chlorphenamine R06AB54 H R03DA04 Theophylline R03DB04 L N06AA04 Clomipramine H R03DA54 R03DA74 N05AH02 Clozapine H N05CD05 Triazolam L R06AA02 Diphenhydramine D04AA32 H R06AD01 Alimemazine L D04AA33 R06AA52 M03BX01 Baclofen L N06AA12 Doxepin H N04BC01 Bromocriptine G02CB01 L N05BB01 Hydroxyzine N05BB51 H N03AF01 Carbamazepine L N06AA02 Imipramine N06AA03 H R06AE07 Cetirizine L N05AA02 Levomepromazin H N06AB04 Citalopram L e R05DA04 Codeine N02AA59 L R06AE05 Meclozine R06AE55 H N02AA79 N06AA10 Nortriptyline H C01BA03 Disopyramide L G04BD04 Oxybutynin H A03FA03 Domperidone L A04AD01 Scopolamine N05CM05 H N06AA16 Dosulepin L (hyoscine) S01FA02 N04BX02 Entacapone L A04AD51 G04BD07 Tolterodine H R06AX26 Fexofenadine L N04AA01 Trihexyphenidyl H N05AD01 Haloperidol L G04BD10 Darifenacin H M01AB15 Ketorolac S01BC05 L R06AA02 Dimenhydrinate H A07DA03 Loperamide A07DA05 L A07DA53 G04BD02 Flavoxate H R06AX13 Loratadine L R03BB01 Ipratropium R03AL01 H N07BC02 Methadone L R01AX03 R03AL02 N06AX11 Mirtazapine L N04AA04 Procyclidine H N02AA01 Morphine N02AG01 L R06AD02 Promethazine D04AA10 H A07DA52 R06AD52 N02AA51 V03AB05 R05DA05 R06AC01 Pyrilamine H N06AX06 Nefanzodone L M03BX02 Tizanidine H N03AF02 Oxcarbazepine L A02BA01 Cimetidine A02BA51 L N06AF03 Phenelzine L N03AE01 Clonazepam L N05AG02 Pimozide L N05BA01 Diazepam L N05AX08 Risperidone L N02AB03 Fentanyl N01AH01 L N02AX02 Tramadol N02AX52 L N01AH51 N06AX05 Trazodone L N06AB03 Fluoxetine N06CA03 L N06AB08 Fluvoxamine L

Appendix 6: ical list of drugs with anticholinergic (side-) effects by Rudolph et al. (available in Belgium): adopted and adapted from 31 ATC Drug name ATC combination Risk factor N06AA09 Amitriptyline hydrochloride N06CA01 3 A03BA01 Atropine producten S01FA01, A03CB03 3 R06AB02 Chlorpheniramine maleate 3 R06AA02 Diphenhydramine hydrochloride D04AA32, D04AA33, R06AA52 3 N05BB01 Hydroxyzine hydrochloride N05BB51 3 N05BB01 Hydroxyzine pamoate 3 N06AA02 Imipramine hydrochloride 3 R06AE05 Meclozine hydrochloride 3 G04BD04 Oxybutynin chloride 3 R06AD02 Promethazine hydrochloride D04AA10, R06AD52, V03AB05 3 M03BX02 Tizanidine hydrochloride 3 M03BX01 Baclofen 2 R06AE07 Cetirizine hydrochloride 2 A02BA01 Cimetidine A02BA51 2 N05AH02 Clozapine 2 A07DA03 Loperamide hydrochloride A07DA05, A07DA53 2 R06AX13 Loratadine 2 N06AA10 Nortriptyline hydrochloride 2 N05AH03 Olanzapine 2 R01BA02 Pseudoephedrine hydrochloride R01BA52 2 G04BD07 Tolterodine tartrate 2 N04BA01 Carbidopa-levodopa N04BA02, N04BA03 1 N04BX02 Entacapone 1 N05AD01 Haloperidol 1 A03FA01 Metoclopramide hydrochloride 1 N06AX11 Mirtazapine 1 N06AB05 Paroxetine hydrochloride 1 N04BC05 Pramipexole dihydrochloride 1 N05AH04 Quetiapine fumarate 1 A02BA02 Ranitidine hydrochloride 1 N05AX08 Risperidone 1 N04BD01 Selegiline hydrochloride 1 N06AX05 Trazodone hydrochloride 1

Appendix 7: Complete drug list community-dwelling A10BB08 Gliquidone 25 0.2 older adults A10BH01 Sitagliptin 21 0.2 ATC Drug name Freq % A10BB12 Glimepiride 11 0.1 A10BB01 Glibenclamide 6 0.1 B01A Antithrombotic agents 806 7.5 A10BD08 Metformin and vildagliptin 6 0.1 B01AC06 Acetylsalicylic acid 500 4.7 A10BH02 Vildagliptin 6 0.1 B01AA03 Warfarin 65 0.6 A10BH03 Saxagliptin 6 0.1 B01AC04 Clopidogrel 65 0.6 A10BH05 Linagliptin 6 0.1 B01AF01 Rivaroxaban 39 0.4 A10BX07 Liraglutide 2 0.0 B01AA07 Acenocoumarol 30 0.3 A10BD02 Metformin and 1 0.0 B01AA04 Phenprocoumon 29 0.3 A10BD10 sulfonamides 1 0.0 B01AE07 Dabigatran etexilate 26 0.2 A10BG03 Metformin and saxagliptin 1 0.0 B01AC07 Dipyridamole 12 0.1 A10BX04 Pioglitazone 1 0.0 B01AC30 Combinations 10 0.1 Exenatide B01AC05 Ticlopidine 9 0.1 N05B Anxiolytics 330 3.1 B01AF02 Apixaban 8 0.1 N05BA06 Lorazepam 121 1.1 B01AC24 Ticagrelor 7 0.1 B01AB06 Nadroparin 3 0.0 N05BA12 Alprazolam 98 0.9 N05BA08 Bromazepam 44 0.4 B01AB05 Enoxaparin 2 0.0 B01AC22 Prasugrel 1 0.0 N05BA11 Prazepam 15 0.1 N05BA01 Diazepam 12 0.1 C10A Lipid modifying agents, 719 6.7 N05BA21 Clotiazepam 12 0.1 C10AA01 plain 289 2.7 N05BA05 Potassium clorazepate 8 0.1 C10AA05 Simvastatin 165 1.5 N05BB01 Hydroxyzine 7 0.1 C10AA07 Atorvastatin 133 1.2 N05BA04 Oxazepam 4 0.0 C10AB05 Rosuvastatin 43 0.4 N05BA09 Clobazam 3 0.0 C10AA03 Fenofibrate 42 0.4 N05BA22 Cloxazolam 3 0.0 C10AX09 Pravastatin 18 0.2 N05BA18 Ethyl loflazepate 2 0.0 C10AX06 Ezetimibe 11 0.1 N05BA16 Nordazepam 1 0.0 Omega-3-triglycerides incl. N05BC01 Meprobamate 1 0.0 C10AA04 other esters and acids 7 0.1 N02B Other analgesics and 329 3.1 C10AB08 Fluvastatin 6 0.1 antipyretics C10AA02 Ciprofibrate 5 0.0 N02BE01 Paracetamol 303 2.8 Lovastatin N02BE51 Paracetamol, combinations 16 0.1 J07B Viral vaccines 686 6.4 excl. psycholeptics J07BB02 Influenza, inactivated, split 685 6.4 N02BA01 Acetylsalicylic acid 6 0.1 virus or surface antigen N02BA51 Acetylsalicylic acid, 4 0.0 J07BC01 Hepatitis B, purified antigen 1 0.0 combinations excl. C07A Beta blocking agents 586 5.5 psycholeptics C07AB07 Bisoprolol 317 3.0 N05C Hypnotics and sedatives 315 2.9 C07AB12 Nebivolol 64 0.6 N05CD06 Lormetazepam 122 1.1 C07AA07 Sotalol 49 0.5 N05CF02 Zolpidem 104 1.0 C07AG02 Carvedilol 48 0.4 N05CF01 Zopiclone 23 0.2 C07AB02 Metoprolol 33 0.3 N05CD01 Flurazepam 13 0.1 C07AA05 Propranolol 27 0.3 N05CD09 Brotizolam 11 0.1 C07AB03 Atenolol 26 0.2 N05CD05 Triazolam 10 0.1 C07AB08 Celiprolol 16 0.1 N05CD11 Loprazolam 7 0.1 C07AB04 Acebutolol 4 0.0 N05CM09 Valerianae radix 7 0.1 C07AA03 Pindolol 2 0.0 N05CD03 Flunitrazepam 6 0.1 A02B Drugs for peptic ulcer and 469 4.4 N05CH01 Melatonin 4 0.0 gastro-oesophageal reflux N05CD02 Nitrazepam 3 0.0 disease (GORD) N05CA06 Secobarbital 2 0.0 A02BC02 Pantoprazole 221 2.1 N05CX Hypnotics and sedatives in 2 0.0 A02BC01 Omeprazole 151 1.4 combination, excl. A02BA02 Ranitidine 42 0.4 barbiturates A02BC05 Esomeprazole 35 0.3 N05CA02 Amobarbital 1 0.0 A02BC03 Lansoprazole 10 0.1 N05CM Other hypnotics and 1 0.0 A02BX13 Alginic acid 9 0.1 sedatives A02BA01 Cimetidine 2 0.0 N06A Antidepressants 273 2.6 A10B Blood glucose lowering 431 4.0 N06AX05 Trazodone 49 0.5 drugs, excl. insulins N06AB10 Escitalopram 41 0.4 A10BA02 Metformin 245 2.3 N06AA09 Amitriptyline 30 0.3 A10BB09 Gliclazide 66 0.6 N06AB05 Paroxetine 27 0.3 A10BX02 Repaglinide 27 0.3 N06AX16 Venlafaxine 20 0.2

N06AA16 Dosulepin 16 0.1 A12AA Calcium acetate anhydrous 1 0.0 N06AB04 Citalopram 16 0.1 A12AA12 Calcium 1 0.0 N06AB06 Sertraline 16 0.1 A12AA20 Calcium acetate anhydrous 1 0.0 N06AX11 Mirtazapine 15 0.1 Calcium (different salts in N06AX21 Duloxetine 15 0.1 combination) N06AB03 Fluoxetine 9 0.1 R03A Adrenergics, inhalants 194 1.8 N06AX03 Mianserin 8 0.1 R03AK06 Salmeterol and fluticasone 59 0.6 N06AX12 Bupropion 4 0.0 R03AK07 Formoterol and budesonide 47 0.4 N06AA10 Nortriptyline 2 0.0 R03AL01 Fenoterol and ipratropium 33 0.3 N06AA12 Doxepin 2 0.0 bromide N06AA04 Clomipramine 1 0.0 R03AC18 Indacaterol 15 0.1 N06AB08 Fluvoxamine 1 0.0 R03AK08 Formoterol and 14 0.1 N06AX25 Hyperici herba 1 0.0 beclometasone A11C Vitamin A and D, incl. 253 2.4 R03AC02 Salbutamol 12 0.1 combinations of the two R03AL02 Salbutamol and 9 0.1 A11CC05 Colecalciferol 246 2.3 ipratropium bromide A11CC03 Alfacalcidol 6 0.1 R03AC13 Formoterol 4 0.0 A11CC04 Calcitriol 1 0.0 R03AC12 Salmeterol 1 0.0 C09A Ace inhibitors, plain 236 2.2 C03C High-ceiling diuretics 193 1.8 C09AA04 Perindopril 105 1.0 C03CA02 Bumetanide 116 1.1 C09AA03 Lisinopril 70 0.7 C03CA01 Furosemide 76 0.7 C09AA05 Ramipril 43 0.4 C03CA04 Torasemide 1 0.0 C09AA06 Quinapril 8 0.1 A06A Drugs for constipation 170 1.6 C09AA01 Captopril 6 0.1 A06AD65 Macrogol, combinations 72 0.7 C09AA02 Enalapril 4 0.0 A06AD11 Lactulose 25 0.2 C08C Selective calcium channel 225 2.1 A06AC01 Ispaghula (psylla seeds) 13 0.1 blockers with mainly A06AD15 Macrogol 13 0.1 vascular effects A06AB02 Bisacodyl 12 0.1 C08CA01 Amlodipine 114 1.1 A06AB06 Senna glycosides 9 0.1 C08CA13 Lercanidipine 55 0.5 A06AB08 Sodium picosulfate 7 0.1 C08CA12 Barnidipine 33 0.3 A06AG11 Laurilsulfate, incl. 3 0.0 C08CA05 Nifedipine 12 0.1 combinations C08CA03 Isradipine 5 0.0 A06AX01 Glycerol 3 0.0 C08CA09 Lacidipine 3 0.0 A06AA01 Liquid paraffin 2 0.0 C08CA02 Felodipine 2 0.0 A06AB52 Bisacodyl, combinations 2 0.0 C08CA07 Nisoldipine 1 0.0 A06AB56 Senna glycosides, 2 0.0 M01A Anti-inflammatory and 225 2.1 combinations antirheumatic products, A06AC51 Ispaghula, combinations 2 0.0 non-steroids A06AB20 Contact laxatives in 1 0.0 M01AX05 Glucosamine 56 0.5 combination M01AE01 Ibuprofen 40 0.4 A06AC03 Sterculia 1 0.0 M01AB05 Diclofenac 26 0.2 A06AC05 Linseed 1 0.0 M01AC01 Piroxicam 21 0.2 A06AD18 Sorbitol 1 0.0 M01AH01 Celecoxib 18 0.2 A06AG01 Sodium phosphate 1 0.0 M01AC06 Meloxicam 14 0.1 H03A Thyroid preparations 168 1.6 M01AB16 Aceclofenac 12 0.1 H03AA01 Levothyroxine sodium 168 1.6 M01AX01 Nabumetone 11 0.1 N02A Opioids 161 1.5 M01AE02 Naproxen 10 0.1 N02AX02 Tramadol 55 0.5 M01AH05 Etoricoxib 4 0.0 N02AX52 Tramadol, combinations 36 0.3 M01AB14 Proglumetacin 3 0.0 N02AB03 Fentanyl 29 0.3 M01AX25 Chondroitin sulfate 3 0.0 N02AA59 Codeine, combinations excl. 15 0.1 M01AE12 Oxaprozin 2 0.0 psycholeptics M01AE52 Naproxen and 2 0.0 N02AE01 Buprenorphine 9 0.1 esomeprazole N02AA05 Oxycodone 8 0.1 M01AB01 Indometacin 1 0.0 N02AX01 Tilidine 7 0.1 M01AC02 Tenoxicam 1 0.0 N02AA01 Morphine 1 0.0 M01AX26 Avocado and soyabean oil, 1 0.0 N02AA55 Oxycodone, combinations 1 0.0 unsaponifiables M04A Antigout preparations 160 1.5 A12A Calcium 213 2.0 M04AA01 Allopurinol 138 1.3 A12AX Calcium, combinations with 117 1.1 M04AC01 Colchicine 16 0.1 vitamin D and/or other M04AA03 Febuxostat 6 0.1 A12AA04 drugs 87 0.8 C09C Angiotensin II antagonists, 144 1.3 A12AA12 Calcium carbonate 6 0.1 plain

C09CA01 Losartan 44 0.4 S01XA20 Artificial tears and other 94 0.9 C09CA06 Candesartan 23 0.2 indifferent preparations C09CA08 Olmesartan medoxomil 23 0.2 M05B Drugs affecting bone 93 0.9 C09CA03 Valsartan 22 0.2 structure and C09CA04 Irbesartan 12 0.1 M05BA04 mineralization 30 0.3 C09CA07 Telmisartan 11 0.1 M05BX04 Alendronic acid 24 0.2 C09CA02 Eprosartan 9 0.1 M05BB03 Denosumab 18 0.2 S01E Antiglaucoma preparations 139 1.3 Alendronic acid and and miotics M05BA06 colecalciferol 7 0.1 S01EE01 Latanoprost 37 0.3 M05BA07 Ibandronic acid 6 0.1 S01ED51 Timolol, combinations 29 0.3 M05BA08 Risedronic acid 5 0.0 S01ED01 Timolol 15 0.1 M05BB04 Zoledronic acid 2 0.0 S01ED05 Carteolol 15 0.1 Risedronic acid, calcium S01EC04 Brinzolamide 11 0.1 M05BX03 and colecalciferol, 1 0.0 S01EE04 Travoprost 10 0.1 sequential S01ED02 Betaxolol 7 0.1 Strontium ranelate S01EA05 Brimonidine 5 0.0 R03B Other drugs for obstructive 91 0.9 S01EE03 Bimatoprost 5 0.0 airway diseases, inhalants S01ED03 Levobunolol 2 0.0 R03BB04 Tiotropium bromide 60 0.6 S01EA03 Apraclonidine 1 0.0 R03BA02 Budesonide 15 0.1 S01EC01 Acetazolamide 1 0.0 R03BA01 Beclometasone 5 0.0 S01EC03 Dorzolamide 1 0.0 R03BB01 Ipratropium bromide 5 0.0 C01D Vasodilators used in 121 1.1 R03BA05 Fluticasone 4 0.0 cardiac diseases R03BB06 Glycopyrronium bromide 2 0.0 C01DX12 Molsidomine 89 0.8 A10A Insulines and analogues 86 0.8 C01DA02 Glyceryl trinitrate 19 0.2 A10AD05 Insulin aspart 22 0.2 C01DA08 Isosorbide dinitrate 13 0.1 A10AE04 Insulin glargine 19 0.2 C09D Angiotensin II antagonists, 115 1.1 A10AD01 Insulin (human) 12 0.1 combinations A10AB05 Insulin aspart 10 0.1 C09DA01 Losartan and diuretics 20 0.2 A10AC01 Insulin (human) 6 0.1 C09DA04 Irbesartan and diuretics 15 0.1 A10AD04 Insulin lispro 5 0.0 C09DB02 Olmesartan medoxomil and 15 0.1 A10AB01 Insulin (human) 4 0.0 amlodipine A10AB04 Insulin lispro 4 0.0 C09DA03 Valsartan and diuretics 10 0.1 A10AB06 Insulin glulisine 3 0.0 C09DA07 Telmisartan and diuretics 10 0.1 A10AE05 Insulin detemir 1 0.0 C09DA08 Olmesartan medoxomil and 10 0.1 C01B Antiarrhythmics, class I 84 0.8 diuretics and III C09DA06 Candesartan and diuretics 9 0.1 C01BD01 Amiodarone 46 0.4 C09DX03 Olmesartan medoxomil, 9 0.1 C01BC04 Flecainide 29 0.3 amlodipine and C01BC03 Propafenone 7 0.1 hydrochlorothiazide C01BA03 Disopyramide 1 0.0 C09DB01 Valsartan and amlodipine 8 0.1 C01BG07 Cibenzoline 1 0.0 C09DX01 Valsartan, amlodipine and 5 0.0 C09B Ace inhibitors, 84 0.8 hydrochlorothiazide C09BB04 combinations 31 0.3 C09DA02 Eprosartan and diuretics 4 0.0 C09BA03 Perindopril and amlodipine 23 0.2 A11A Multivitamins, 113 1.1 C09BA04 Lisinopril and diuretics 20 0.2 A11AA03 combinations 109 1.0 C09BB05 Perindopril and diuretics 4 0.0 Multivitamins and other C09BB02 Ramipril and felodipine 3 0.0 A11AA04 minerals, incl. combinations 2 0.0 C09BA02 Enalapril and lercanidipine 2 0.0 Multivitamins and trace C09BA08 Enalapril and diuretics 1 0.0 A11AH02 elements 2 0.0 Cilazapril and diuretics Multivitamins, N07C Antivertigo preparations 83 0.8 combinations N07CA01 Betahistine 71 0.7 G04C Drugs used in benign 102 1.0 N07CA02 Cinnarizine 10 0.1 prostatic hypertrophy N07CA03 Flunarizine 1 0.0 G04CA02 Tamsulosin 47 0.4 N07CA52 Cinnarizine, combinations 1 0.0 G04CA03 Terazosin 20 0.2 C03D Potassium-sparing agents 78 0.7 G04CA52 Tamsulosin and dutasteride 13 0.1 C03DA01 Spironolactone 78 0.7 G04CX02 Sabalis serrulatae fructus 13 0.1 C07B Beta blocking agents and 74 0.7 G04CA04 Silodosin 4 0.0 thiazides G04CB01 Finasteride 4 0.0 C07BB07 Bisoprolol and thiazides 69 0.6 G04CB02 Gutasteride 1 0.0 C07BB12 Nebivolol and thiazides 4 0.0 S01X Other ophthalmologicals 94 0.9 C07BB04 Acebutolol and thiazides 1 0.0

N03A Antiepileptics 74 0.7 R01AD05 Budesonide 1 0.0 N03AE01 Clonazepam 20 0.2 R01AD53 Dexamethasone, 1 0.0 N03AX12 Gabapentin 19 0.2 combinations N03AX16 Pregabalin 9 0.1 C05C Capillary stabilizing agents 66 0.6 N03AF01 Carbamazepine 6 0.1 C05CA53 Diosmin, combinations 35 0.3 N03AG01 Valproic acid 5 0.0 C05CA04 Troxerutin 21 0.2 N03AX09 Lamotrigine 5 0.0 C05CX Other capillary stabilizing 7 0.1 N03AA03 Primidone 3 0.0 agents N03AA02 Phenobarbital 2 0.0 C05CX02 Naftazone 2 0.0 N03AX11 Topiramate 2 0.0 C05CA03 Diosmin 1 0.0 N03AX14 Levetiracetam 2 0.0 H02A Corticosteroids for 66 0.6 N03AB02 Phenytoin 1 0.0 systemic use, plain A12C Other mineral supplements 73 0.7 H02AB04 Methylprednisolone 37 0.3 A12CC10 Magnesium oxide 66 0.6 H02AB06 Prednisolone 14 0.1 A12CB01 Zinc sulfate 3 0.0 H02AB09 Hydrocortisone 7 0.1 A12CB02 Zinc gluconate 1 0.0 H02AB01 Betamethasone 4 0.0 A12CC03 Magnesium gluconate 1 0.0 H02AA02 Fludrocortisone 2 0.0 A12CC04 Magnesium citrate 1 0.0 H02AB02 Dexamethasone 1 0.0 A12CE Selenium 1 0.0 H02AB08 Triamcinolone 1 0.0 R05C Expectorants, excl. 71 0.7 C03E Diuretics and potassium- 59 0.6 combinations with cough sparing agents in suppressants combination R05CB01 Acetylcysteine 55 0.5 C03EA04 Altizide and potassium- 49 0.5 R05CB02 Bromhexine 5 0.0 sparing agents R05CB03 Carbocisteine 5 0.0 C03EA01 Hydrochlorothiazide and 10 0.1 R05CB15 Erdosteine 4 0.0 potassium-sparing agents R05CA03 Guaifenesin 1 0.0 V06X General nutrients 57 0.5 R05CA10 Combinations 1 0.0 V06XX02 57 0.5 (expectorants) N04B Dopaminergic agents 53 0.5 R06A Antihistamines for 71 0.7 N04BA02 Levodopa and 27 0.3 systemic use decarboxylase inhibitor R06AE07 Cetirizine 25 0.2 N04BD02 Rasagiline 9 0.1 R06AE09 Levocetirizine 15 0.1 N04BC05 Pramipexole 6 0.1 R06AX27 Desloratadine 11 0.1 N04BA03 Levodopa, decarboxylase 4 0.0 R06AX22 Ebastine 4 0.0 inhibitor and COMT R06AE05 Meclozine 3 0.0 inhibitor R06AB03 Dimetindene 2 0.0 N04BC04 Ropinirole 4 0.0 R06AX28 Rupatadine 2 0.0 N04BB01 Amantadine 2 0.0 R06AX29 Bilastine 2 0.0 N04BC01 Bromocriptine 1 0.0 R06AA02 Diphenhydramine 1 0.0 M02A Topical products for joint 52 0.5 R06AA52 Diphenhydramine, 1 0.0 and muscular pain combinations M02AA15 Diclofenac 26 0.2 R06AD01 Alimemazine 1 0.0 M02AC Preparations with salicylic 8 0.1 R06AX13 Loratadine 1 0.0 acid derivatives R06AX17 Ketotifen 1 0.0 M02AA06 Etofenamate 7 0.1 R06AX25 Mizolastine 1 0.0 M02AA10 Ketoprofen 7 0.1 R06AX26 Fexofenadine 1 0.0 M02AX10 Other topical products for 3 0.0 R01A Decongestantsand other 69 0.6 joint and muscular pain nasal preparations for M02AA13 Ibuprofen 1 0.0 topical use C02A Antiadrenergic agents, 50 0.5 R01AD09 Mometasone 22 0.2 centrally acting R01AD12 Fluticasone furoate 13 0.1 C02AC05 Moxonidine 49 0.5 R01AA07 Xylometazoline 7 0.1 C02AC01 Clonidine 1 0.0 R01AD08 Fluticasone 6 0.1 A03F Propulsives 47 0.4 R01AA05 Oxymetazoline 3 0.0 A03FA03 Domperidone 35 0.3 R01AA09 Tramazoline 3 0.0 A03FA01 Metoclopramide 9 0.1 R01AD52 Prednisolone, combinations 3 0.0 A03FA05 Alizapride 3 0.0 R01AA03 Ephedrine 2 0.0 A11D Vitamin B1, plain and in 47 0.4 R01AA08 Naphazoline 2 0.0 combination with vitamin R01AB01 Phenylephrine 2 0.0 B6 and B12 R01AB06 Xylometazoline 2 0.0 A11DB Vitamin B1 in combination 43 0.4 R01AX10 Other nasal preparations 2 0.0 with vitamin B6 and/or R01AB02 Naphazoline 1 0.0 A11DA01 Vitamin B12 4 0.0

thiamine (vit B1) A02AH Antacids with sodium 10 0.1 bicarbonate N05A Antipsychotics 47 0.4 N05AL01 Sulpiride 23 0.2 A02AD02 Magaldrate 2 0.0 N05AX07 Prothipendyl 9 0.1 G03C Estrogens 32 0.3 N05AH04 Quetiapine 5 0.0 G03CA04 Estriol 19 0.2 N05AF01 Flupentixol 2 0.0 G03CA03 Estradiol 9 0.1 N05AA02 Levomepromazine 1 0.0 G03CX01 Tibolone 4 0.0 N05AD01 Haloperidol 1 0.0 A07F Antidiarrheal 31 0.3 N05AH02 Clozapine 1 0.0 microorganisms N05AH03 Olanzapine 1 0.0 A07FA02 Saccharomyces boulardii 14 0.1 N05AL05 Amisulpride 1 0.0 A07FA51 Lactic acid producing 10 0.1 N05AN01 Lithium 1 0.0 organisms, combinations N05AX08 Risperidone 1 0.0 A07FA01 Lactic acid producing 4 0.0 N05AX13 Paliperidone 1 0.0 organisms G04B Urologicals 46 0.4 A07FA Antidiarrheal 3 0.0 G04BD04 Oxybutynin 17 0.2 microorganisms G04BD06 Propiverine 8 0.1 B03A Iron preparations 31 0.3 G04BD08 Solifenacin 6 0.1 B03AA07 Ferrous sulfate 23 0.2 G04BD11 Fesoterodine 3 0.0 B03AA03 Ferrous gluconate 3 0.0 G04BX Other urologicals 3 0.0 B03AB02 Saccharated iron oxide 2 0.0 G04BD07 Tolterodine 2 0.0 B03AC Iron, parenteral 1 0.0 G04BE09 Vardenafil 2 0.0 preparations G04BD12 Mirabegron 1 0.0 B03AD02 Ferrous fumarate 1 0.0 G04BE01 Alprostadil 1 0.0 B03AE02 Iron, multivitamins and folic 1 0.0 G04BE03 Sildenafil 1 0.0 acid G04BE08 Tadalafil 1 0.0 N06C Psycholeptics and 29 0.3 G04BX06 Phenazopyridine 1 0.0 psychoanaleptics in C01A Cardiac glucosides 45 0.4 combination C01AA05 Digoxin 40 0.4 N06CA02 Melitracen and 29 0.3 C01AA08 Metildigoxin 5 0.0 psycholeptics C03B Low-ceiling diuretics, excl. 45 0.4 A03A Drugs for functional 27 0.3 thiazides gastrointestinal disorders C03BA11 Indapamide 40 0.4 A03AB06 Otilonium bromide 14 0.1 C03BA04 Chlortalidone 5 0.0 A03AA04 Mebeverine 11 0.1 L04A Immunosuppressants 44 0.4 A03AD01 Papaverine 2 0.0 L04AX03 Methotrexate 19 0.2 D07A Corticosteroids, plain 27 0.3 L04AA13 Leflunomide 4 0.0 D07AC01 Betamethasone 9 0.1 L04AB04 Adalimumab 4 0.0 D07AB02 Hydrocortisone butyrate 6 0.1 L04AD02 Tacrolimus 4 0.0 D07AD01 Clobetasol 6 0.1 L04AX01 Azathioprine 3 0.0 D07AC13 Mometasone 4 0.0 L04AA06 Mycophenolic acid 2 0.0 D07AC06 Diflucortolone 1 0.0 L04AC07 Tocilizumab 2 0.0 D07AC14 Methylprednisolone 1 0.0 L04AD01 Ciclosporin 2 0.0 aceponate L04AB01 Etanercept 1 0.0 J07A Bacterial vaccines 27 0.3 L04AB02 Infliximab 1 0.0 J07AL01 Pneumococcus, purified 19 0.2 L04AB06 Golimumab 1 0.0 polysaccharides antigen L04AX02 Thalidomide 1 0.0 J07AM51 tetanus toxoid, 4 0.0 R03D Other systemic drugs for 39 0.4 combinations with obstructive airway Diphtheria toxoid diseases J07AX Other bacterial vaccines 4 0.0 R03DC03 Montelukast 21 0.2 N06D Anti-dementia drugs 27 0.3 R03DA04 Theophylline 18 0.2 N06DX02 Ginkgo folium 17 0.2 C08D Selective calcium channel 38 0.4 N06DA02 Donepezil 7 0.1 blockers with direct cardiac N06DA03 Rivastigmine 2 0.0 effects N06DX01 Memantine 1 0.0 C08DB01 Diltiazem 33 0.3 A07D Antipropulsives 26 0.2 C08DA01 Verapamil 5 0.0 A07DA03 Loperamide 26 0.2 B03B Vitamin B12 and folic acid 36 0.3 D01A Antifungals for topical use 25 0.2 B03BB01 Folic acid 32 0.3 D01AC02 Miconazole 11 0.1 B03BA01 Cyanocobalamin 4 0.0 D01AA20 Antibiotics combinations 4 0.0 A02A Antacids 35 0.3 D01AC08 Ketoconazole 3 0.0 A02AD01 Ordinary salt combinations 23 0.2 D01AC20 Imidazole and triazole 3 0.0 derivatives, combinations

D01AC52 Miconazole, combinations 3 0.0 R05FA02 Opium derivatives and 15 0.1 D01AA01 Nystatin 1 0.0 expectorants R05D Cough suppressants, excl. 24 0.2 S01B Antiinflammatory agents 15 0.1 combinations with S01BC01 Indometacin 10 0.1 expectorants S01BA01 Dexamethasone 2 0.0 R05DA Opium alkaloids and 8 0.1 S01BC03 Diclofenac 2 0.0 derivatives S01BA04 Prednisolone 1 0.0 R05DA09 Dextromethorphan 7 0.1 M09A Other drugs for disorders 14 0.1 R05DA04 Codeine 5 0.0 of the musculo-skeletal R05DB13 Butamirate 2 0.0 system R05DB Other cough suppressants 1 0.0 M09AA01 Hydroquinine 13 0.1 R05DB21 Cloperastine 1 0.0 M09AX01 Hyaluronic acid 1 0.0 J01X Other antibacterials 23 0.2 S01C Antiinflammatory agents 14 0.1 J01XX01 Fosfomycin 13 0.1 and antiinfectives in J01XE01 Nitrofurantoin 5 0.0 combination J01XE02 Nifurtoinol 5 0.0 S01CA01 Dexamethasone and anti- 13 0.1 L02B Hormone antagonists and 23 0.2 infectives related agents S01CC01 Diclofenac and anti- 1 0.0 L02BB03 Bicalutamide 7 0.1 infectives L02BG04 Letrozole 6 0.1 A03B Belladonna and derivates, 13 0.1 L02BA01 Tamoxifen 5 0.0 plain L02BG03 Anastrozole 3 0.0 A03BB01 Butylscopolamine 11 0.1 L02BG06 Exemestane 2 0.0 A03BA04 Belladonna total alkaloids 1 0.0 A11J Other vitamin products, 18 0.2 A03BB01 Butylscopolamine 1 0.0 combinations C05B Antivaricose therapy 12 0.1 A11JA Combinations of vitamins 11 0.1 C05BA01 Organo-heparinoid 12 0.1 A11JC Vitamins, other 7 0.1 C07C Beta blocking agents and 12 0.1 combinations other diuretics J01C Beta-lactam antibacterials, 17 0.2 C07CB03 Atenolol and other diuretics 10 0.1 penicillins C07CA03 Pindolol and other diuretics 2 0.0 J01CR02 Amoxicillin and enzyme 9 0.1 A01A Stomatological 11 0.1 inhibitor preparations J01CA04 Amoxicillin 7 0.1 A01AB12 Hexetidine 5 0.0 J01CF05 Flucloxacillin 1 0.0 A01AB09 Miconazole 3 0.0 S01A Anti-infectives 17 0.2 A01AB11 Various anti-infectives and 2 0.0 S01AA12 Tobramycin 6 0.1 antiseptics for local oral S01AA13 Fusidic acid 4 0.0 treatment S01AA30 Combinations of different 3 0.0 A01AD11 Various (Other agents for 1 0.0 antibiotics local oral treatment) S01AA02 Chlortetracycline 2 0.0 C10B Lipid modifying agents, 11 0.1 S01AD03 Aciclovir 1 0.0 combinations S01AE01 Ofloxacin 1 0.0 C10BA02 Simvastatin and ezetimibe 11 0.1 J01F Macrolides, lincosamides 16 0.1 C04A Peripheral vasodilators 10 0.1 and streptogramins C04AX21 Naftidrofuryl 7 0.1 J01FA10 Azithromycin 9 0.1 C04AE01 Ergoloid mesylates 2 0.0 J01FA09 Clarithromycin 5 0.0 C04AD03 Pentoxifylline 1 0.0 J01FF01 Clindamycin 2 0.0 D06A Antibiotics for topical use 10 0.1 N06B Psychostimulants, agents 16 0.1 D06AX01 Fusidic acid 5 0.0 used for ADHD and D06AX09 Mupirocin 3 0.0 nootropics D06AA03 Oxytetracycline 1 0.0 N06BX03 Piracetam 14 0.1 D06AX05 Bacitracin 1 0.0 N06BC01 Caffeine 1 0.0 H03B Antithyroid preparations 10 0.1 N06BX18 Vinpocetine 1 0.0 H03BB02 Thiamazole 9 0.1 V03A All other therapeutic 16 0.1 H03BA02 Propylthiouracil 1 0.0 products L02A Hormones and related 10 0.1 V03AE01 Polystyrene sulfonate 7 0.1 agents V03AN01 Oxygen 5 0.0 L02AE02 Leuprorelin 4 0.0 V03AE02 Sevelamer 3 0.0 L02AE04 Triptorelin 3 0.0 V03AE04 Calcium acetate and 1 0.0 L02AE03 Goserelin 2 0.0 magnesium carbonate L02AB02 Medroxyprogesterone 1 0.0 R05F Cough suppressants and 15 0.1 C01E Other cardiac preparations 9 0.1 expectorants, C01EB09 Ubidecarenone 4 0.0 combinations C01EB09 Ubidecarenone 3 0.0

C01EB04 Crataegus glycosides 1 0.0 L01B Antimetabolites 5 0.0 C01EB17 Ivabradine 1 0.0 L01BA01 Methotrexate 4 0.0 C05A Agents for treatment of 9 0.1 L01BC02 Fluorouracil 1 0.0 hemorrhoids and anal N02C Antimigraine preparations 5 0.0 fissures for topical use N02CC01 Sumatriptan 3 0.0 C05AA04 Prednisolone 3 0.0 N02CC02 Naratriptan 1 0.0 C05AA12 Triamcinolone 3 0.0 N02CX02 Clonidine 1 0.0 C05AX03 Other preparations, 2 0.0 R01B Nasal decongestants for 5 0.0 combinations systemic use C05AE01 Glyceryl trinitrate 1 0.0 R01BA52 Pseudoephedrine, 3 0.0 A05A Bile therapy 8 0.1 combinations A05AX Other drugs for bile therapy 5 0.0 R01BA02 Pseudoephedrine 1 0.0 A05AA02 Ursodeoxycholic acid 2 0.0 R01BA53 Phenylephrine, 1 0.0 A05AX02 Hymecromone 1 0.0 combinations C09X Other agents acting on the 8 0.1 A09A Digestives, incl.enzymes 4 0.0 renin-angiotensin system A09AA02 Multienzymes (lipase, 4 0.0 C09XA02 Aliskiren 6 0.1 protease etc.) C09XA52 Aliskiren and 2 0.0 A11H Other plain vitamin 4 0.0 hydrochlorothiazide preparations G03X Other sex hormones and 8 0.1 A11HA03 Tocopherol (vit E) 2 0.0 modulators of the genital A11HA04 riboflavin (vit B2) 2 0.0 system J02A Antimycotics for systemic 4 0.0 G03XC01 Raloxifene 8 0.1 use J01M Quinolone antibacterials 8 0.1 J02AC01 Fluconazole 4 0.0 J01MA14 Moxifloxacin 3 0.0 J05A Direct acting antivirals 4 0.0 J01MA06 Norfloxacin 2 0.0 J05AB01 Aciclovir 4 0.0 J01MA12 Levofloxacin 2 0.0 N07A Parasympathomimetics 4 0.0 J01MA01 Ofloxacin 1 0.0 N07AA02 Pyridostigmine 3 0.0 A11G Ascorbic acid (vitamin C), 7 0.1 N07AB02 Bethanechol 1 0.0 incl. combinations P01B Antimalarials 4 0.0 A11GA01 Ascorbic acid (vit C) 7 0.1 P01BA02 Hydroxychloroquine 4 0.0 G03D Progestogens 7 0.1 A07A Intestinal anti-infectives 3 0.0 G03DA04 Progesterone 7 0.1 A07AA06 Paromomycin 3 0.0 L01X Other antineoplastic 7 0.1 B03X Other antianemic 3 0.0 agents preparations L01XX05 Hydroxycarbamide 5 0.0 B03XA02 Darbepoetin alfa 3 0.0 L01XE02 Gefitinib 0 0.0 C02D Arteriolar smooth muscle, 3 0.0 L01XE08 Nilotinib 0 0.0 agents acting on A07E Intestinal anti- 6 0.1 C02DB01 Dihydralazine 3 0.0 inflammatory agents C07F Beta blocking agents and 3 0.0 A07EA06 Budesonide 5 0.0 other antihypertensives A07EC02 Mesalazine 1 0.0 C07FB02 Metoprolol and other 3 0.0 A14A Anabolic steroids 6 0.1 antihypertensives A14AB01 Nandrolone 4 0.0 D02A Emollients and protectives 3 0.0 A14AA07 Prasterone 2 0.0 D02AE01 Carbamide 2 0.0 R02A Throat preparations 6 0.1 D02AB Zinc products 1 0.0 R02AA20 Antiseptics 3 0.0 D06B Chemotherapeutics for 3 0.0 R02AA05 Chlorhexidine 2 0.0 topical use R02AB03 Fusafungine 1 0.0 D06BB03 Aciclovir 2 0.0 D07C Corticosteroids, 5 0.0 D06BA01 Silver sulfadiazine 1 0.0 combinations with J01A Tetracyclines 3 0.0 antibiotics J01AA02 Doxycycline 3 0.0 D07CC01 Betamethasone and 4 0.0 J01E Sulfonamides and 3 0.0 antibiotics trimethoprim D07CA01 Hydrocortisone and 1 0.0 J01EE01 Sulfamethoxazole and 3 0.0 antibiotics trimethoprim D08A Antiseptics and 5 0.0 M03B Muscle relaxants, centrally 3 0.0 disinfectants acting agents D08AG02 Povidone-iodine 2 0.0 M03BB03 Chlorzoxazone 1 0.0 D08AC02 Chlorhexidine 1 0.0 M03BB53 Chlorzoxazone, 1 0.0 D08AC52 Chlorhexidine, 1 0.0 combinations excl. combinations psycholeptics D08AX02 Eosin 1 0.0

M03BX01 Baclofen 1 0.0 D03BA52 Collagenase, combinations 1 0.0 S01G Decongestants and 3 0.0 D04A Antipruritics, incl. 1 0.0 antiallergics antihistamines, S01GX02 Levocabastine 2 0.0 anesthetics, etc. S01GX07 Azelastine 1 0.0 D04AB01 Lidocaine 1 0.0 A07B Intestinal adsorbents 2 0.0 D07X Corticosteroids, other 1 0.0 A07BA01 Medicinal charcoal 1 0.0 combinations A07BC04 Attapulgite 1 0.0 D07XC01 Betamethasone 1 0.0 A12B Potassium 2 0.0 D09A Medicated dressings 1 0.0 A12BA01 Potassium chloride 1 0.0 D09AA02 Fusidic acid 1 0.0 A12BA02 Potassium citrate 1 0.0 D10B Anti-acne preparations for 1 0.0 A13A Tonics 2 0.0 systemic use D10BA01 Isotretinoin 1 0.0 A16A Other alimentary tract and 2 0.0 metabolism products G01A Anti-infectives and 1 0.0 A16AX02 Anethole trithione 2 0.0 antiseptics, excl. combinations with D05A Antipsoriatics for topical 2 0.0 use 2 0.0 corticosteroids G01AF04 Miconazole 1 0.0 D05AX52 Calcipotriol, combinations G03F Progestogens and 1 0.0 G02C Other gynecologicals 2 0.0 G02CX04 Cimicifugae rhizoma 2 0.0 estrogens in combination G03FB01 Norgestrel and estrogen 1 0.0 G03H Antiandrogens 2 0.0 G03HA01 Cyproterone 2 0.0 H01B Posterior pituitary lobe 1 0.0 hormones H05B Anti-parathyroid agents 2 0.0 H01BA02 Desmopressin 1 0.0 H05BA01 Calcitonin (salmon 1 0.0 synthetic) 1 0.0 H05A Parathyroid hormones and 1 0.0 analogues H05BX01 Cinacalcet H05AA02 Teriparatide 1 0.0 L01A Alkylating agents 2 0.0 J01B Amphenicols 1 0.0 L01AA02 Chlorambucil 1 0.0 J01BA52 Thiamphenicol, 1 0.0 L01AB01 Busulfan 1 0.0 combinations N01A Anesthetics, general 2 0.0 J01D Other beta-lactam 1 0.0 N01AX25 2 0.0 antibacterials N07B Drugs used in addictive 2 0.0 J01DC02 Cefuroxime 1 0.0 disorders J04A Drugs for treatment of 1 0.0 N07BA01 Nicotine 2 0.0 tuberculosis S02C Corticosteroids and anti- 2 0.0 J04AC01 Isoniazid 1 0.0 infectives in combination L03A Immunostimulants 1 0.0 S02CA07 Fludrocortisone and 2 0.0 L03AX03 BCG vaccine 1 0.0 antiinfectives N04A Anticholinergic agents 1 0.0 S02D Other otologicals 2 0.0 S02DA01 Lidocaine 1 0.0 N04AA01 Trihexphenidyl 1 0.0 S02DC Indifferent preparations 1 0.0 R03C Adrenergics for systemic 1 0.0 use 1 0.0 A05B Liver therapy, lipotropics 1 0.0 A05BA03 Silymarin 1 0.0 R03CC02 Salbutamol S01F Mydriatics and cycloplegics 1 0.0 A11B Multivitamins, plain 1 0.0 A11BA Multivitamins, plain 1 0.0 S01FA06 Tropicamide 1 0.0 A11E Vitamin B-complex, incl. 1 0.0 S01L Ocular vascular disorder 1 0.0 agents combinations A11EB Vitamin B-complex with 1 0.0 S01LA04 Ranibizumab 1 0.0 vitamin C S03A Anti-infectives 1 0.0 S03AA07 Ciprofloxacin 1 0.0 C01C Cardiac stimulants excl. 1 0.0 cardiac glycosides S03C Corticosteroids and anti- 1 0.0 C01CA01 Etilefrine 1 0.0 infectives in combination D01B Antifungals for systemic 1 0.0 S03CA04 Hydrocortisone and 1 0.0 antiinfectives use D01BA02 Terbinafine 1 0.0 Total 107 100 D03B Enzymes 1 0.0 05

Appendix 8: complete drug list institutionalized older N06AB03 Fluoxetine 3 0.1 adults N06AA10 Nortriptyline 2 0.0 ATC code Drug name Freq % N06AX03 Mianserin 1 0.0 B01A Antithrombotic agents 295 63 N02B Other analgesics and 166 3.6 B01AC06 Acetylsalicylic acid 158 3.4 antipyretics B01AB05 Enoxaparin 38 0.8 N02BE01 Paracetamol 159 3.4 B01AA03 Warfarin 26 0.6 N02BE51 Paracetamol, combinations 5 0.1 B01AB06 Nadroparin 21 0.5 N02BA01 Acetylsalicylic acid 2 0.0 B01AC04 Clopidogrel 21 0.5 C07A Beta blocking agents 163 3.5 B01AF01 Rivaroxaban 10 0.2 C07AB07 Bisoprolol 112 2.4 B01AA04 Phenprocoumon 5 0.1 C07AB02 Metoprolol 10 0.2 B01AA07 Acenocoumarol 5 0.1 C07AA05 Propranolol 9 0.2 B01AE07 Dabigatran etexilate 3 0.1 C07AA07 Sotalol 9 0.2 B01AB10 Tinzaparin 2 0.0 C07AB12 Nebivolol 9 0.2 B01AC05 Ticlopidine 2 0.0 C07AB03 Atenolol 6 0.1 B01AC07 Dipyridamole 2 0.0 C07AB08 Celiprolol 2 0.0 B01AC24 Ticagrelor 1 0.0 C07AG02 Carvedilol 2 0.0 B01AC30 Platelet aggregation 1 0.0 C03C High-ceiling diuretics 148 3.2 inhibitors excl. Heparin C03CA02 Bumetanide 74 1.6 combinations C03CA01 Furosemide 73 1.6 A06A Drugs for constipation 276 5.9 N05C Hypnotics and sedatives 144 3.1 A06AD65 Macrogol, combinations 153 3.3 N05CD06 Lormetazepam 76 1.6 A06AD11 Lactulose 54 1.2 N05CF02 Zolpidem 45 1.0 A06AG10 Docusate sodium, incl. 24 0.5 N05CD03 Flunitrazepam 5 0.1 combinations N05CF01 Zopiclone 4 0.1 A06AG01 Sodium phosphate 11 0.2 N05CM09 Valerianae radix 4 0.1 A06AD15 Macrogol 9 0.2 N05CD05 Triazolam 3 0.1 A06AB08 Sodium picosulfate 5 0.1 N05CD01 Flurazepam 2 0.0 A06AB02 Bisacodyl 4 0.1 N05CM05 Scopolamine 2 0.0 A06AG11 Laurilsulfate, incl. 4 0.1 N05CD09 Brotizolam 1 0.0 combinations N05CD11 Loprazolam 1 0.0 A06AX01 Glycerol 4 0.1 N05CM Other hypnotics and 1 0.0 A06AD17 Sodium phosphate 2 0.0 sedatives A06AD18 Sorbitol 2 0.0 N05CX Hypnotics and sedatives in 1 0.0 A06AA01 Liquid paraffin 1 0.0 combination, excl. A06AB52 Bisacodyl, combinations 1 0.0 barbiturates A06AB56 Senna glycosides, 1 0.0 N05A Antipsychotics 131 2.8 combinations N05AH04 Quetiapine 36 0.8 A02B Drugs for peptic ulcer and 212 4.6 N05AX08 Risperidone 34 0.7 gastro-oesophageal reflux N05AD01 Haloperidol 19 0.4 disease (GORD) N05AH03 Olanzapine 13 0.3 A02BC02 Pantoprazole 118 2.5 N05AL01 Sulpiride 7 0.2 A02BC01 Omeprazole 46 1.0 N05AD05 Pipamperone 6 0.1 A02BA02 Ranitidine 36 0.8 N05AH02 Clozapine 6 0.1 A02BC05 Esomeprazole 10 0.2 N05AA02 Levomepromazine 2 0.0 A02BC03 Lansoprazole 1 0.0 N05AD07 Benperidol 2 0.0 A02BX13 Alginic acid 1 0.0 N05AH06 Clotiapine 2 0.0 N06A Antidepressants 211 4.5 N05AL05 Amisulpride 2 0.0 N06AX05 Trazodone 55 1.2 N05AN01 Lithium 1 0.0 N06AB10 Escitalopram 51 1.1 N05AX12 Aripiprazole 1 0.0 N06AX11 Mirtazapine 25 0.5 N05B Anxiolytics 121 2.6 N06AB06 Sertraline 16 0.3 N05BA06 Lorazepam 43 0.9 N06AA09 Amitriptyline 14 0.3 N05BA12 Alprazolam 35 0.8 N06AB04 Citalopram 13 0.3 N05BA08 Bromazepam 16 0.3 N06AX16 Venlafaxine 7 0.2 N05BA05 Potassium clorazepate 9 0.2 N06AX21 Duloxetine 7 0.2 N05BB01 Hydroxyzine 5 0.1 N06AB05 Paroxetine 5 0.1 N05BA01 Diazepam 4 0.1 N06AX12 Bupropion 4 0.1 N05BA11 Prazepam 3 0.1

N05BA04 Oxazepam 2 0.0 C08C Selective calcium channel 79 1.7 N05BA21 Clotiazepam 2 0.0 blockers with mainly N05BA09 Clobazam 1 0.0 vascular effects N05BA22 Cloxazolam 1 0.0 C08CA01 Amlodipine 59 1.3 N02A Opioids 111 2.4 C08CA13 Lercanidipine 6 0.1 N02AX02 Tramadol 36 0.8 C08CA12 Barnidipine 5 0.1 N02AB03 Fentanyl 30 0.6 C08CA05 Nifedipine 3 0.1 N02AX52 Tramadol, combinations 22 0.5 C08CA07 Nisoldipine 3 0.1 N02AE01 Buprenorphine 9 0.2 C08CA09 Lacidipine 2 0.0 N02AA01 Morphine 8 0.2 C08CA02 Felodipine 1 0.0 N02AA05 Oxycodone 3 0.1 C09A Ace inhibitors, plain 79 1.7 N02AA59 Codeine, combinations excl. 3 0.1 C09AA03 Lisinopril 34 0.7 psycholeptics C09AA04 Perindopril 27 0.6 N02AX01 Tilidine 2 0.0 C09AA05 Ramipril 10 0.2 N02AA03 Hydromorphone 1 0.0 C09AA06 Quinapril 3 0.1 A12A Calcium 106 2.3 C09AA01 Captopril 2 0.0 A12AX Calcium with vitamin D 95 2.0 C09AA02 Enalapril 2 0.0 A12AA04 Calcium carbonate 9 0.2 D01A Antifungals for topical use 77 1.7 A12AA12 Calcium acetate anhydrous 3 0.1 D01AC02 Miconazole 56 1.2 A12AA20 Calcium (different salts) 1 0.0 D01AC52 Miconazole, combinations 15 0.3 A10B Blood glucose lowering 98 2.1 D01AA20 Antibiotics combinations 2 0.0 drugs, excl. insulins D01AC08 Ketoconazole 1 0.0 A10BA02 Metformin 57 1.2 D01AC20 Imidazole and triazole 1 0.0 A10BB08 Gliquidone 17 0.4 derivatives combinations A10BB09 Gliclazide 16 0.3 R05C Expectorants, excl. 72 1.5 A10BH01 Sitagliptin 4 0.1 combinations with cough A10BX02 Repaglinide 3 0.1 suppressants A10BB12 Glimepiride 2 0.0 R05CB01 Acetylcysteine 52 1.1 A10BB01 Glibenclamide 1 0.0 R05CB03 Carbocisteine 12 0.3 R03A Adrenergics, inhalants 96 2.1 R05CB06 Ambroxol 4 0.1 R03AL01 Fenoterol and ipratropium 28 0.6 R05CA03 Guaifenesin 2 0.0 bromide R05CB15 Erdosteine 2 0.0 R03AK06 Salmeterol and fluticasone 23 0.5 R05CA10 Combinations 1 0.0 R03AC02 Salbutamol 14 0.3 expectorantia R03AL02 Salbutamol and 13 0.3 R05CB02 Bromhexine 1 0.0 ipratropium bromide A11C Vitamin A and D, incl. 68 1.5 R03AK07 Formoterol and budesonide 9 0.2 combinations of the two R03AC18 Indacaterol 5 0.1 A11CC05 Colecalciferol 68 1.5 R03AK08 Formoterol and 5 0.1 A11CC03 Alfacalcidol 2 0.0 beclometasone N04B Dopaminergic agents 66 1.4 R03AC13 Formoterol 1 0.0 N04BA02 Levodopa and 44 0.9 C10A Lipid modifying agents, 93 2.0 decarboxylase inhibitor plain N04BA03 Levodopa, decarboxylase 7 0.2 C10AA01 Simvastatin 46 1.0 inhibitor and COMT C10AA05 Atorvastatin 26 0.6 inhibitor C10AA07 Rosuvastatin 10 0.2 N04BD02 Rasagiline 4 0.1 C10AA03 Pravastatin 7 0.2 N04BC05 Pramipexole 3 0.1 C10AB08 Ciprofibrate 3 0.1 N04BC04 Ropinirole 2 0.0 C10AA04 Fluvastatin 1 0.0 N04BD01 Selegiline 2 0.0 C10AX09 Ezetimibe 1 0.0 D02A Emollients and protectives 57 1.2 J01C Beta-lactam antibacterials, 88 1.9 D02AB Zinc products 48 1.0 penicillins D02AE01 Carbamide 7 0.2 J01CR02 Amoxicillin and enzyme 41 0.9 A03F Propulsives 56 1.2 inhibitor A03FA03 Domperidone 38 0.8 J01CA04 Amoxicillin 40 0.9 A03FA01 Metoclopramide 15 0.3 J01CF05 Flucloxacillin 5 0.1 A03FA05 Alizapride 5 0.1 J01CA01 Ampicillin 1 0.0 J01M Quinolone antibacterials 54 1.2 J01CE08 Benzathine benzylpenicillin 1 0.0 J01MA14 Moxifloxacin 29 0.6

J01MA02 Ciprofloxacin 14 0.3 M01AE03 Ketoprofen 1 0.0 J01MA12 Levofloxacin 7 0.2 M01AE09 Flurbiprofen 1 0.0 J01MA01 Ofloxacin 3 0.1 A10A Insulins and analogues 43 0.9 J01MA06 Norfloxacin 1 0.0 A10AD05 Insulin aspart 14 0.3 N03A Antiepileptics 53 1.1 A10AB01 Insulin (human) 8 0.2 N03AG01 Valproic acid 15 0.3 A10AD01 Insulin (human) 8 0.2 N03AX14 Levetiracetam 10 0.2 A10AB05 Insulin aspart 5 0.1 N03AE01 Clonazepam 9 0.2 A10AC01 Insulin (human) 5 0.1 N03AX09 Lamotrigine 4 0.1 A10AE04 Insulin glargine 4 0.1 N03AA03 Primidone 3 0.1 A10AE05 Insulin detemir 1 0.0 N03AB02 Phenytoin 3 0.1 H02A Corticosteroids for 42 0.9 N03AX16 Pregabalin 3 0.1 systemic use, plain N03AB52 Phenytoin, combinations 2 0.0 H02AB04 Methylprednisolone 34 0.7 N03AX12 Gabapentin 2 0.0 H02AB01 Betamethasone 6 0.1 N03AF01 Carbamazepine 1 0.0 H02AB06 Prednisolone 3 0.1 N06D Anti-dementia drugs 52 1.1 S01E Antiglaucoma preparations 41 0.9 N06DA02 Donezepil 30 0.6 and miotics N06DA04 Galantamine 10 0.2 S01ED01 Timolol 12 0.3 N06DA03 Rivastigmine 6 0.1 S01EE01 Latanoprost 8 0.2 N06DX01 Memantine 3 0.1 S01ED02 Betaxolol 5 0.1 N06DX02 Ginkgo folium 2 0.0 S01ED51 Timolol, combinations 5 0.1 R06A Antihistamines for 52 1.1 S01EC04 Brinzolamide 2 0.0 systemic use S01ED05 Carteolol 2 0.0 R06AE07 Cetirizine 21 0.5 S01EE03 Bimatoprost 2 0.0 R06AE09 Levocetirizine 13 0.3 S01EA05 Brimonidine 1 0.0 R06AX27 Desloratadine 9 0.2 S01ED03 Levobunolol 1 0.0 R06AB03 Dimetindene 4 0.1 S01EE04 Travoprost 1 0.0 R06AD02 Promethazine 3 0.1 B03A Iron preparations 40 0.9 R06AB04 Chlorphenamine 1 0.0 B03AA07 Ferrous sulfate 14 0.3 R06AX22 Ebastine 1 0.0 B03AA03 Ferrous gluconate 12 0.3 R06AX28 Rupatadine 1 0.0 B03AE01 Iron, vitamin B12 and folic 8 0.2 C01D Vasodilators used in 51 1.1 acid cardiac diseases B03AB02 Saccharated iron oxide 5 0.1 C01DX12 Molsidomine 28 0.6 B03AD Iron in combination with 1 0.0 C01DA02 Glyceryl trinitrate 21 0.5 folic acid C01DA08 Isosorbide dinitrate 5 0.1 B03AD02 Ferrous fumarate 1 0.0 R03B Other drugs for obstructive 51 1.1 M02A Topical products for joint 38 0.8 airway diseases, inhalants and muscular pain R03BA02 Budesonide 30 0.6 M02AA15 Diclofenac 17 0.4 R03BB01 Ipratropium bromide 14 0.3 M02AC Preparations with salicylic 9 0.2 R03BA05 Fluticasone 7 0.2 acid derivatives R03BB04 Tiotropium bromide 2 0.0 M02AA06 Etofenamate 7 0.2 H03A Thyroid preparations 46 1.0 M02AA10 Ketoprofen 3 0.1 H03AA01 Levothyroxine sodium 46 1.0 M02AA Antiinflammatory 1 0.0 C03D Potassium-sparing agents 45 1.0 preparations, non-steroids C03DA01 Spironolactone 43 0.9 for topical use M01A Antiinflammatory and 45 1.0 M02AA13 Ibuprofen 1 0.0 antirheumatic products, R05D Cough suppressants, excl. 37 0.8 non-steroids combinations with M01AB05 Diclofenac 12 0.3 expectorants M01AE01 Ibuprofen 10 0.2 R05DA09 Dextromethorphan 17 0.4 M01AC01 Piroxicam 5 0.1 R05DB13 Butamirate 8 0.2 M01AC06 Meloxicam 5 0.1 R05DB05 Pentoxyverine 6 0.1 M01AB16 Aceclofenac 4 0.1 R05DA Opium alkaloids and 5 0.1 M01AX01 Nabumetone 4 0.1 derivatives M01AH01 Celecoxib 3 0.1 R05DA04 Codeine 2 0.0 M01AX05 Glucosamine 2 0.0 R05DB27 Levodropropizine 2 0.0 M01AE02 Naproxen 1 0.0 R05DB Other cough suppressants 1 0.0

B03B Vitamin B12 and folic acid 36 0.8 D07AC01 Betamethasone 12 0.3 B03BB01 Folic acid 29 0.6 D07AB02 Hydrocortisone butyrate 6 0.1 B03BA01 Cyanocobalamin 3 0.1 D07AA02 Hydrocortisone 2 0.0 A07F Antidiarrheal 33 0.7 D07AC06 Diflucortolone 2 0.0 microorganisms D07AC13 Mometasone 2 0.0 A07FA02 Saccharomyces boulardii 30 0.6 D07AC14 Methylprednisolone 1 0.0 A07FA01 Lactic acid producing 3 0.1 aceponate organisms D07AD01 Clobetasol 1 0.0 R01A Decongestants and other 32 0.7 D08A Antiseptics and 24 0.5 nasal preparations for desinfectants topical use D08AG02 Povidone-iodine 12 0.3 R01AD52 Prednisolone, combinations 11 0.2 D08AC52 Chlorhexidine, 8 0.2 R01AD53 Dexamethasone, 4 0.1 combinations combinations D08AX02 Eosin 2 0.0 R01AX02 Retinol 4 0.1 D08AC02 Chlorhexidine 1 0.0 R01AA05 Oxymetazoline 3 0.1 N07C Antivertigo preparations 24 0.5 R01AA07 Xylometazoline 3 0.1 N07CA01 Betahistine 22 0.5 R01AD08 Fluticasone 3 0.1 N07CA03 Flunarizine 1 0.0 R01AD09 Mometasone 3 0.1 C09C Angiotensin II antogonists, 23 0.5 R01AD12 Fluticasone furoate 2 0.0 plain R01AC01 Cromoglicic acid 1 0.0 C09CA01 Losartan 8 0.2 R01AX03 Ipratropium bromide 1 0.0 C09CA03 Valsartan 4 0.1 J01X Other antibacterials 31 0.7 C09CA06 Candesartan 4 0.1 J01XX01 Fosfomycin 20 0.4 C09CA08 Olmesartan medoxomil 4 0.1 J01XE01 Nitrofurantoin 7 0.2 C09CA04 Irbesartan 3 0.1 J01XE02 Nifurtoinol 5 0.1 C09CA07 Telmisartan 3 0.1 M05B Drugs affecting bone 31 0.7 R05F Cough suppressants and 23 0.5 structure and expectorants, mineralization combinations M05BA04 Alendronic acid 21 0.5 R05FA02 Opium derivatives and 22 0.5 M05BX03 Strontium ranelate 4 0.1 expectorants M05BB03 Alendronic acid and 3 0.1 R05FB02 Cough suppressants and 1 0.0 colecalciferol expectorants M05BX04 Denosumab 3 0.1 G04C Drugs used in benign 22 0.5 M05BA07 Risedronic acid 1 0.0 prostatic hypertrophy G04B Urologicals 30 0.6 G04CA02 Tamsulosin 17 0.4 G04BD04 Oxybutynin 19 0.4 G04CX02 Sabalis serrulatae fructus 3 0.1 G04BD11 Fesoterodine 3 0.1 G04CB01 Finasteride 2 0.0 G04BD06 Propiverine 2 0.0 G04CA03 Terazosin 1 0.0 G04BD08 Solifenacin 2 0.0 A07D Antipropulsives 21 0.5 G04BD02 Flavoxate 1 0.0 A07DA03 Loperamide 20 0.4 G04BD07 Tolterodine 1 0.0 C01A Cardiac glycosides 20 0.4 G04BX Other urologicals 1 0.0 C01AA05 Digoxin 19 0.4 M04A Antigout preparations 27 0.6 C01B Antiarrhythmics, class I 20 0.4 M04AA01 Allopurinol 23 0.5 and III M04AC01 Colchicine 3 0.1 C01BD01 Amiodarone 19 0.4 A11D Vitamin B1, plain and in 26 0.6 C01BC04 Flecainide 1 0.0 combination with vitamin C03E Diuretics and potassium- 20 0.4 B6 and B12 sparing agents in A11DB Vitamin B1 in combination 24 0.5 combination with Vitamin B6 and/or C03EA04 Altizide and potassium- 14 0.3 vitamin B12 sparing agents A11DA01 Thiamine (vit B1) 2 0.0 C03EA01 Hydrochlorothiazide and 5 0.1 S01X Other ophthalmologicals 26 0.6 potassium-sparing agents S01XA20 Artificial tears and other 23 0.5 A11A Multivitamins, 17 0.4 indifferent preparations combinations S01XA15 Ascorbic acid 3 0.1 A11AA03 Multivitamins and other 10 0.2 D07A Corticosteroids, plain 25 0.5 minerals, incl. combinations

A11AA04 Multivitamins and trace 5 0.1 thiazides elements C03BA11 Indapamide 11 0.2 A11AA01 Multivitamins and iron 2 0.0 C03BA04 Chlortalidone 1 0.0 S01C Antiinflammatory agents 16 0.3 H03B Antithyroid preparations 12 0.3 and antiinfectives in H03BB02 Thiamazole 11 0.2 combination J07A Bacterial vaccines 11 0.2 S01CA01 Dexamethasone and 16 0.3 J07AL01 Pneumococcus, purified 9 0.2 antiinfectives polysaccharides antigen S01CC01 Diclofenac and 1 0.0 J07AM51 Tetanus toxoid, 1 0.0 antiinfectives combinations with J01F Macrolides, lincosamides 15 0.3 J07AX diphtheria toxoid 1 0.0 and streptogramins Other bacterial vaccines J01FA10 Azithromycin 10 0.2 R03D Other systemic drugs for 11 0.2 J01FF01 Clindamycin 4 0.1 obstructive airway J01FA09 Clarithromycin 3 0.1 diseases A12C Other mineral supplements 14 0.3 R03DA04 Theophylline 10 0.2 A12CC Magnesium 8 0.2 R03DC03 Fenspiride 2 0.0 A12CC03 Magnesium gluconate 4 0.1 R03DC01 Zafirlukast 1 0.0 A12CC10 Magnesium oxide 3 0.1 S03C Corticosteroids and 11 0.2 C05C Capillary stabilizing agents 13 0.3 antiinfectives in C05CA53 Diosmin, combinations 6 0.1 combination C05CA04 Troxerutin 5 0.1 S03CA04 Hydrocortisone and 11 0.2 C05CX Other capillary stabilizing 1 0.0 antiinfectives agents J01D Other beta-lactam 10 0.2 C05CX02 Naftazone 1 0.0 antibacterials C07B Beta blocking agents and 13 0.3 J01DC02 Cefuroxime 7 0.2 thiazides J01DB04 Cefazolin 4 0.1 C07BB07 Bisoprolol and thiazides 11 0.2 A11J Other vitamin products, 9 0.2 C07BB02 Metoprolol and thiazides 1 0.0 combinations C07BB04 Acebutolol and thiazides 1 0.0 A11JA Combinations of vitamins 5 0.1 C09D Angiotensin II antagonists, 13 0.3 A11JC Vitamins, other 3 0.1 combinations combinations C09DA01 Losartan and diuretics 3 0.1 C02A Antiadrenergic agents, 9 0.2 C09DA03 Valsartan and diuretics 2 0.0 centrally acting C09DA04 Irbesartan and diuretics 2 0.0 C02AC05 Moxonidine 6 0.1 C09DA06 Candesartan and diuretics 2 0.0 C02AC01 Clonidine 2 0.0 C09DA07 Telmisartan and diuretics 2 0.0 C05B Antivaricose therapy 9 0.2 C09DA08 Olmesartan medoxomil and 1 0.0 C05BA01 Organo-heparinoid 8 0.2 diuretics C09B Ace inhibitors, 9 0.2 C09DX03 Olmesartan medoxomil, 1 0.0 combinations amlodipine and C09BA04 Perindopril and diuretics 4 0.1 hydrochlorothiazide C09BB04 Perindopril and amlodipine 4 0.1 S01A Antiinfectives 13 0.3 C09BA03 Lisinopril and diuretics 1 0.0 S01AA13 Fusidic acid 5 0.1 L02B Hormone antagonists and 9 0.2 S01AE01 Ofloxacin 4 0.1 related agents S01AA12 Tobramycin 2 0.0 L02BA01 Tamoxifen 4 0.1 S01AA30 Combinations of different 2 0.0 L02BG03 Anastrozole 2 0.0 antibiotics L02BG04 Letrozole 2 0.0 S01AX03 Zinc compounds 2 0.0 S02D Other otologicals 9 0.2 S01B Antiinflammatory agents 13 0.3 S02DC Indifferent preparations 8 0.2 S01BC01 Indometacin 5 0.1 D06A Antibiotics for topical use 8 0.2 S01BC03 Diclofenac 3 0.1 D06AX09 Mupirocin 4 0.1 S01BA01 Dexamethasone 1 0.0 D06AX01 Fusidic acid 2 0.0 S01BA04 Prednisolone 1 0.0 D06AX05 Bacitracin 2 0.0 S01BA07 Fluorometholone 1 0.0 A01A Stomatological 7 0.2 S01BC05 Ketorolac 1 0.0 preparations S01BC09 Pranoprofen 1 0.0 A01AB03 Chlorhexidine 4 0.1 C03B Low-ceiling diuretics, excl. 12 0.3 A01AB09 Miconazole 1 0.0

A01AD Other agents for local oral 1 0.0 A03A Drugs for functional 4 0.1 treatment gastrointestinal disorders B05B I.V. solutions 7 0.2 A03AB06 Otilonium bromide 3 0.1 B05BA03 Carbohydrates 5 0.1 A03AA04 Mebeverine 1 0.0 B05BC01 Mannitol 2 0.0 A07B Intestinal adsorbents 4 0.1 C05A Agents for treatment of 7 0.2 A07BA01 Medicinal charcoal 2 0.0 hemorrhoids and anal A07BC05 Diosmectite 2 0.0 fissures for topical use A07E Intestinal 4 0.1 C05AA04 Prednisolone 4 0.1 antiinflammatory agents C05AA12 Triamcinolone 3 0.1 A07EA Corticosteroids acting 2 0.0 D07C Corticosteroids, 7 0.2 locally combinations with A07EA06 Budesonide 1 0.0 antibiotics A07EC01 Sulfasalazine 1 0.0 D07CC01 Betamethasone and 6 0.1 C04A Peripheral vasodilators 4 0.1 antibiotics C04AE01 Ergoloid mesylates 4 0.1 D07CA01 Hydrocortisone and 1 0.0 D04A Antipruritics, incl. 4 0.1 antibiotics antihistamines, J01E Sulfonamides and 7 0.2 anesthetics, etc. trimethoprim D04AA32 Diphenhydramine 2 0.0 J01EE01 Sulfamethoxazole and 6 0.1 D04AB01 Lidocaine 1 0.0 trimethoprim L04A Immunosuppressants 4 0.1 S01K Surgical aids 7 0.2 L04AX03 Methotrexate 2 0.0 S01KA01 Hyaluronic acid 7 0.2 L04AB01 Etanercept 1 0.0 S01KA51 Hyaluronic acid, 1 0.0 L04AD01 Ciclosporin 1 0.0 combinations N04A Anticholinergic agents 4 0.1 N06B Psychostimulants, agents 6 0.1 N04AA01 Trihexyphenidyl 3 0.1 used for ADHD and N04AA02 Biperiden 1 0.0 nootropics A07X Other antidiarrheals 3 0.1 N06BX03 Piracetam 6 0.1 A07XA04 Racecadotril 3 0.1 A03B Belladonna and 5 0.1 A11H Other plain vitamin 3 0.1 derivatives, plain preparations A03BB01 Butylscopolamine 6 0.1 A11HA01 Nicotinamide 1 0.0 A12B Potassium 5 0.1 A11HA04 Riboflavin (vit B2) 1 0.0 A12BA05 Potassium gluconate 3 0.1 C07C Beta blocking agents and 3 0.1 A12BA01 Potassium chloride 2 0.0 other diuretics G03C Estrogens 5 0.1 C07CB03 Atenolol and other diuretics 3 0.1 G03CA04 Estriol 4 0.1 D06B Chemotherapeutics for 3 0.1 J02A Antimycotics for systemic 5 0.1 topical use use D06BA01 Silver sulfadiazine 2 0.0 J02AC01 Fluconazole 5 0.1 D06BX01 Metronidazole 1 0.0 M03B Muscle relaxants, centrally 5 0.1 G01A Antiinfectives and 3 0.1 acting agents antiseptics, excl. M03BX01 Baclofen 3 0.1 combinations with M03BB53 Chlorzoxazone, 1 0.0 corticosteroids combinations excl. G01AF04 Miconazole 2 0.0 psycholeptics G01AF07 Isoconazole 1 0.0 N06C Psycholeptics and 5 0.1 H04A Glycogenolytic hormones 3 0.1 psychoanaleptics in H04AA01 Glucagon 3 0.1 combination J01A Tetracyclines 3 0.1 N06CA02 Melitracen and 5 0.1 J01AA02 Doxycycline 2 0.0 psycholeptics J01AA08 Minocycline 1 0.0 R02A Throat preparations 5 0.1 N01B Anethetics, local 3 0.1 R02AA05 Chlorhexidine 3 0.1 N01BB02 Lidocaine 2 0.0 R02AA03 Dichlorobenzyl alcohol 1 0.0 N07A Parasympathomimetics 3 0.1 R02AB02 Tyrothricin 1 0.0 N07AA02 Pyridostigmine 2 0.0 A02A Antacids 4 0.1 V03A All other therapeutic 3 0.1 A02AD02 Magaldrate 3 0.1 products A02AD01 Ordinary salt combinations 1 0.0 V03AE01 Polystyrene sulfonate 1 0.0

V03AE02 Sevelamer 1 0.0 B05C Irrigating solutions 1 0.0 V03AE03 Lanthanum carbonate 1 0.0 B05CB01 Sodium chloride 1 0.0 V06X General nutrients 3 0.1 B05X I.V. solution additives 1 0.0 V06XX02 Other combinations of 3 0.1 B05XA02 Sodium bicarbonate 1 0.0 nutrients C01C Cardiac stimulants excl. 1 0.0 B02A Antifibrinolytics 2 0.0 cardiac glycosides B02AA02 Tranexamic acid 2 0.0 C01CA01 Etilefrine 1 0.0 C08D Selective calcium channel 2 0.0 C02C Antiadrenergic agents, 1 0.0 blockers with direct cardiac peripherally acting effects C02CA01 Prazosin 2 0.0 C08DB01 Diltiazem 3 0.1 C02D Arteriolar smooth muscle, 1 0.0 C10B Lipid modifying agents, 2 0.0 agents acting on combinations C02DB01 Dihydralazine 1 0.0 C10BA02 Simvastatin and ezetimibe 2 0.0 C09X Other agents acting on the 1 0.0 D05A Antipsoriatics for topical 2 0.0 renin-angiotensin system use C09XA02 Aliskiren 1 0.0 D05AX52 Calcipotriol, combinations 2 0.0 D03B Enzymes 1 0.0 D11A Other dermatological 2 0.0 D03BA52 Collagenase, combinations 1 0.0 preparations D05B Antipsoriatics for systemic 1 0.0 D11AC03 Selenium compounds 1 0.0 use D11AH02 Pimecrolimus 1 0.0 D05BB02 Acitretin 1 0.0 L02A Hormones and related 2 0.0 G03X Other sex hormones and 1 0.0 agents modulators of the genital L02AE02 Leuprorelin 2 0.0 system M09A Other drugs for disorders 2 0.0 G03XC01 Raloxifene 1 0.0 of the musculo-skeletal H01B Posterior pituitary lobe 1 0.0 system hormones M09AA01 Hydroquinine 1 0.0 H01BA02 Desmopressin 1 0.0 M09AX01 Hyaluronic acid 1 0.0 H05B Anti-parathyroid agents 1 0.0 R01B Nasal decongestants for 2 0.0 H05BA01 Calcitonin (salmon 1 0.0 systemic use synthetic) R01BA52 Pseudoephedrine, 1 0.0 J05A Direct acting antivirals 1 0.0 combinations J05AB01 Aciclovir 1 0.0 R01BA53 Phenylephrine, 1 0.0 J07B Viral vaccines 1 0.0 combinations J07BB02 Influenza, inactivated, split 1 0.0 S01G Decongestants and 2 0 virus or surface antigen antiallergics L01X Other antineoplastic 1 0.0 S01GA01 Naphazoline 1 0 agents S01GA02 Tetryzoline 1 0 L01XX05 Hydroxycarbamide 1 0.0 S02C Corticosteroids and 2 0.0 N02C Antimigraine preparations 1 0.0 antiinfectives in N02CX02 Clonidine 1 0.0 combination R05 Cough and cold 1 0.0 S02CA07 Fludrocortisone and 2 0.0 preparations antiinfectives R05 Cough and cold 1 0.0 A05A Bile therapy 1 0.0 preparations A05AX02 Hymecromone 1 0.0 S03A Antiinfectives 1 0.0 A07A Intestinal antiinfectives 1 0.0 S03AA07 Ciprofloxacin 1 0.0 A07AA02 Nystatin 1 0.0 V07A All other non-therapeutic 1 0.0 A11B Multivitamins, plain 1 0.0 V07AB products A11BA Multivitamins, plain 1 0.0 Solvents and diluting 1 0.0 A11E Vitamin B-complex, incl. 1 0.0 agents, incl. irrigating combinations solutions A11EB Vitamin B-complex with 1 0.0 Total 4647 100 vitamin C

Appendix 9: Complete list of QT-prolonging drugs Drug name ATC code Risk No. of % community-dwelling older adults score pts Drug name ATC code Risk No. of % Azithromycin 4 9 0.9 score pts J01FA10 9 0.9 Pantoprazole 2 221 21.8 J01RA07 0 0.0 A02BC02 221 21.8 A02BD04 0 0.0 Fluoxetine 2 9 0.9 N06AB03 9 0.9 Furosemide 2 76 7.5 N06CA03 0 0.0 (frusemide) C03CA01 76 7.5 C03CB01 0 0.0 Metoclopramide A03FA01 2 9 0.9 C03EB01 0 0.0 Hydroxyzine 2 7 0.7 N05BB01 7 0.7 Formoterol 1 65 6.4 N05BB51 0 0.0 R03AK07 47 4.6 R03AK08 14 1.4 Solifenacin 2 6 0.6 R03AC13 4 0.4 G04BD08 6 0.6 R03AL05 0 0.0 G04CA53 0 0.0 R03AK11 0 0.0 Clarithromycin 4 5 0.5 R03AK09 0 0.0 J01FA09 5 0.5 Salmeterol R03AK06 1 59 5.8 A02BD06 0 0.0 A02BD07 0 0.0 Sotalol 4 49 4.8 A02BD09 0 0.0 C07AA07 49 4.8 A02BD05 0 0.0 C07BA07 0 0.0 A02BD04 0 0.0 C07AA57 0 0.0 Isradipine C08CA03 3 5 0.5 Trazodone N06AX05 2 49 4.8 Quetiapine N05AH04 3 5 0.5 Amiodarone C01BD01 4 46 4.5 Tamoxifen L02BA01 3 5 0.5 Escitalopram N06AB10 4 41 4.0 Fluconazole 2 4 0.4 Indapamide 2 40 3.9 J02AC01 4 0.4 C03BA11 40 3.9 J01RA07 0 0.0 C09BX01 0 0.0 D01AC15 0 0.0 Domperidone A03FA03 4 35 3.4 Hydroxychloroquine P01BA02 2 4 0.4 Amitriptyline 2 30 3.0 Pseudoephedrine 1 4 0.4 N06AA09 30 3.0 R01BA52 3 0.3 N06CA01 0 0.0 R01BA02 1 0.1 Flecainide C01BC04 4 29 2.9 Ketoconazole D01AC08 2 3 0.3 Paroxetine N06AB05 2 27 2.7 Moxifloxacin 4 3 0.3 Hydrochlorothiazide 2 26 2.6 J01MA14 3 0.3 C03EA01 10 1.0 S01AE07 0 0.0 C09DX03 9 0.9 Phenylephrine 1 3 0.3 C09DX01 5 0.5 R01AB01 2 0.2 C09XA52 2 0.2 R01BA53 1 0.1 C09XA54 0 0.0 S01GA55 0 0.0 C03AB03 0 0.0 R01AA04 0 0.0 C03AX01 0 0.0 C01CA06 0 0.0 C03AA03 0 0.0 R01BA03 0 0.0 Sulpiride N05AL01 4 23 2.3 S01FB01 0 0.0 S01GA05 0 0.0 Venlafaxine N06AX16 3 20 2.0 Citalopram N06AB04 4 16 1.6 Doxepin N06AA12 2 2 0.2 Sertraline N06AB06 2 16 1.6 Ephedrine 1 2 0.2 R01AA03 2 0.2 Mirtazapine N06AX11 3 15 1.5 R01AB05 0 0.0 Albuterol 1 11 1.1 R03CA02 0 0.0 (salbutamol) R03AL02 9 0.9 S01FB02 0 0.0 R03CC02 1 0.1 Levofloxacin 4 2 0.2 R03AC12 1 0.1 J01MA12 2 0.2 R03AK04 0 0.0 A02BD10 0 0.0 J01RA05 0 0.0 S01AE05 0 0.0

Drug name ATC code Risk No. of % Drug name ATC code Risk No. of % score pts score pts Norfloxacin 3 2 0.2 Bosutinib L01XE14 3 0 0.0 J01MA06 2 0.2 Chloral hydrate N05CC01 2 0 0.0 S01AE02 0 0.0 J01RA13 0 0.0 Chloroquine P01BA01 4 0 0.0 Nortriptyline N06AA10 2 2 0.2 Crizotinib L01XE16 3 0 0.0 Ofloxacin 3 2 0.2 Dabrafenib L01XE23 3 0 0.0 J01MA01 1 0.1 Dasatinib L01XE06 3 0 0.0 S01AE01 1 0.1 Dexmedetomidine N05CM18 3 0 0.0 J01RA09 0 0.0 S02AA16 0 0.0 Dihydroartemisinin + P01BF05 3 0 0.0 piperaquine Tolterodine G04BD07 3 2 0.2 Dobutamine C01CA07 1 0 0.0 Vardenafil G04BE09 3 2 0.2 Droperidol N05AD08 4 0 0.0 Amisulpride N05AL05 2 1 0.1 Ephedrine 1 0 0.0 Ciprofloxacin 2 1 0.1 C01CA26 0 0.0 S03AA07 1 0.1 A08AA56 0 0.0 S01AE03 0 0.0 Epinephrine 1 0 0.0 J01RA10 0 0.0 (adrenaline) A01AD01 0 0.0 J01RA12 0 0.0 R03AK01 0 0.0 J01RA11 0 0.0 S01EA51 0 0.0 S02AA15 0 0.0 B02BC09 0 0.0 J01MA02 0 0.0 C01CA24 0 0.0 Clomipramine N06AA04 2 1 0.1 R01AA14 0 0.0 Clozapine N05AH02 3 1 0.1 R03AA01 0 0.0 S01EA01 0 0.0 Diphenhydramine 2 2 0.2 R06AA52 1 0.1 Eribulin L01XX41 3 0 0.0 R06AA02 1 0.1 Erythromycin 4 0 0.0 D04AA32 0 0.0 D10AF02 0 0.0 D04AA33 0 0.0 D10AF52 0 0.0 Disopyramide C01BA03 4 1 0.1 J01FA01 0 0.0 S01AA17 0 0.0 Haloperidol N05AD01 4 1 0.1 Felbamate N03AX10 3 0 0.0 Ivabradine C01EB17 2 1 0.1 Fingolimod L04AA27 3 0 0.0 Mirabegron G04BD12 3 1 0.1 Foscarnet J05AD01 3 0 0.0 Nilotinib L01XE08 3 1 0.1 Galantamine N06DA04 2 0 0.0 Olanzapine N05AH03 3 1 0.1 Granisetron A04AA02 3 0 0.0 Paliperidone N05AX13 3 1 0.1 Imipramine 2 0 0.0 Risperidone N05AX08 3 1 0.1 (melipramine) N06AA02 0 0.0 N06AA03 0 0.0 Alfuzosin 3 0 0.0 G04CA01 0 0.0 Isoproterenol 1 0 0.0 G04CA51 0 0.0 (isoprenaline) C01CA02 0 0.0 Anagrelide L01XX35 4 0 0.0 R03AK02 0 0.0 R03CB51 0 0.0 Apomorphine 3 0 0.0 R03AB02 0 0.0 G04BE07 0 0.0 R03CB01 0 0.0 N04BC07 0 0.0 Aripiprazole N05AX12 3 0 0.0 Itraconazole J02AC02 2 0 0.0 Arsenic trioxide L01XX27 4 0 0.0 Ketoconazole 2 0 0.0 G01AF11 0 0.0 Atazanavir J05AE08 3 0 0.0 J02AB02 0 0.0 Atomoxetine N06BA09 1 0 0.0 Lapatinib L01XE07 3 0 0.0 Azithromycin S01AA26 4 0 0.0 Methadone 4 0 0.0 Bedaquiline J04AK05 3 0 0.0 N07BC02 0 0.0 N02AC52 0 0.0 Bortezomib L01XX32 3 0 0.0 Methylphenidate N06BA04 1 0 0.0

Drug name ATC code Risk No. of % Drug name ATC code Risk No. of % score pts score pts Metronidazole 2 0 0.0 Pipamperone N05AD05 3 0 0.0 A01AB17 0 0.0 Posaconazole J02AC04 2 0 0.0 A02BD08 0 0.0 J01RA03 0 0.0 Promethazine 3 0 0.0 J01RA10 0 0.0 D04AA10 0 0.0 A02BD03 0 0.0 V03AB05 0 0.0 A02BD02 0 0.0 R06AD52 0 0.0 P01AB51 0 0.0 R06AD02 0 0.0 A02BD01 0 0.0 Rilpevirine J05AG05 3 0 0.0 J01RA04 0 0.0 D06BX01 0 0.0 Ritonavir 2 0 0.0 G01AF01 0 0.0 J05AE03 0 0.0 J01XD01 0 0.0 J05AR10 0 0.0 P01AB01 0 0.0 Roxithromycin J01FA06 3 0 0.0 Mifepristone 3 0 0.0 Saquinavir J05AE01 3 0 0.0 G03XB01 0 0.0 G03XB51 0 0.0 Sertindole N05AE03 3 0 0.0 Moexipril/HCTZ 3 0 0.0 Sevoflurane N01AB08 4 0 0.0 C09AA13 0 0.0 Sorafenib L01XE05 3 0 0.0 C09BA13 0 0.0 Sunitinib L01XE04 3 0 0.0 Nicardipine C08CA04 3 0 0.0 Telaprevir J05AE11 2 0 0.0 Norepinephrine C01CA03 1 0 0.0 Telithromycin J01FA15 3 0 0.0 (noradrenaline) Ondansetron A04AA01 4 0 0.0 Tetrabenazine N07XX06 3 0 0.0 Oxytocin 3 0 0.0 Tizanidine M03BX02 3 0 0.0 H01BB02 0 0.0 Vandetanib L01XE12 4 0 0.0 G02AC01 0 0.0 Vemurafenib L01XE15 3 0 0.0 Pazopanib L01XE11 3 0 0.0 Voriconazole J02AC03 2 0 0.0 Pentamidine P01CX01 4 0 0.0 Perflutren lipid V08DA04 3 0 0.0 microspheres Pimozide N05AG02 4 0 0.0

Appendix 10: Complete list QT-prolonging drugs Drug name ATC Risk No. % institutionalized older adults score score of Drug name ATC code Risk No. % pts score of Formoterol 1 15 3.8 pts R03AK07 9 2.3 Pantoprazole 2 118 29.5 R03AC13 1 0.3 A02BC02 118 29.5 R03AL05 0 0.0 A02BD04 0 0.0 R03AK08 5 1.3 Furosemide 2 73 18.0 R03AK11 0 0.0 (frusemide) C03CA01 73 18.0 R03AK09 0 0.0 C03CB01 0 0.0 Sotalol 4 9 2.3 C03EB01 0 0.0 C07AA07 9 2.3 Trazodone N06AX05 2 55 13.8 C07BA07 0 0.0 C07AA57 0 0.0 Escitalopram N06AB10 4 51 12.8 Levofloxacin 4 7 1.8 Domperidone A03FA03 4 38 9.5 J01MA12 7 1.8 S01AE05 0 0.0 Quetiapine N05AH04 3 36 9.0 A02BD10 0 0.0 Risperidone N05AX08 3 34 8.5 J01RA05 0 0.0 Moxifloxacin 4 29 7.3 Sulpiride N05AL01 4 7 1.8 J01MA14 29 7.3 Venlafaxine N06AX16 3 7 1.8 S01AE07 0 0.0 Ofloxacin 3 7 1.8 Mirtazapine N06AX11 3 25 6.3 S01AE01 4 1.0 Salmeterol 1 23 5.8 J01MA01 3 0.8 R03AK06 23 5.8 S02AA16 0 0.0 R03AC12 0 0.0 J01RA09 0 0.0 Amiodarone C01BD01 4 19 4.8 Clozapine N05AH02 3 6 1.5 Haloperidol N05AD01 4 19 4.8 Pipamperone N05AD05 3 6 1.5 Sertraline N06AB06 2 16 4.0 Hydrochlorothiazide 2 6 1.5 Metoclopramide A03FA01 2 15 3.8 C03EA01 5 1.3 C09DX03 1 0.3 Amitriptyline 2 14 3.5 C03AA03 0 0.0 N06AA09 14 3.5 C09XA52 0 0.0 N06CA01 0 0.0 C09XA54 0 0.0 Ciprofloxacin 2 14 3.5 C03AB03 0 0.0 J01MA02 13 3.3 C03AX01 0 0.0 S03AA07 1 0.3 C09DX01 0 0.0 S02AA15 0 0.0 Fluconazole 2 5 1.3 J01RA10 0 0.0 J02AC01 5 1.3 J01RA12 0 0.0 D01AC15 0 0.0 J01RA11 0 0.0 J01RA07 0 0.0 S01AE03 0 0.0 Albuterol 1 13 3.3 Hydroxyzine 2 5 1.3 (salbutamol) R03AL02 13 3.3 N05BB01 5 1.3 R03CC02 0 0.0 N05BB51 0 0.0 R03AK04 0 0.0 Paroxetine N06AB05 2 5 1.3 R03AC12 0 0.0 Tamoxifen L02BA01 3 4 1.0 Citalopram N06AB04 4 13 3.3 Clarithromycin 4 3 0.8 Olanzapine N05AH03 3 13 3.3 J01FA09 3 0.8 A02BD06 0 0.0 Indapamide 2 11 2.8 A02BD07 0 0.0 C03BA11 11 2.8 A02BD09 0 0.0 C09BX01 0 0.0 A02BD05 0 0.0 Azithromycin 4 10 2.5 A02BD04 0 0.0 J01FA10 10 2.5 S01AA26 0 0.0 Fluoxetine 2 3 0.8 J01RA07 0 0.0 N06AB03 3 0.8 Galantamine N06DA04 2 10 2.5 N06CA03 0 0.0 Amisulpride N05AL05 2 2 0.5

Drug name ATC code Risk No. % Drug name ATC code Risk No. % score of score of pts pts Diphenhydramine 2 2 0.5 Ephedrine 1 0 0.0 D04AA32 2 0.5 C01CA26 0 0.0 R06AA02 0 0.0 A08AA56 0 0.0 D04AA33 0 0.0 R01AA03 0 0.0 R06AA52 0 0.0 R01AB05 0 0.0 Nortriptyline N06AA10 2 2 0.2 R03CA02 0 0.0 S01FB02 0 0.0 Solifenacin 2 2 0.5 Epinephrine 1 0 0.0 G04BD08 2 0.5 (adrenaline) A01AD01 0 0.0 G04CA53 0 0.0 R03AK01 0 0.0 Aripiprazole N05AX12 3 1 0.3 S01EA51 0 0.0 Flecainide C01BC04 4 1 0.3 B02BC09 0 0.0 C01CA24 0 0.0 Ketoconazole 2 1 0.3 R01AA14 0 0.0 D01AC08 1 0.3 R03AA01 0 0.0 G01AF11 0 0.0 S01EA01 0 0.0 J02AB02 0 0.0 Erythromycin 4 0 0.0 Norfloxacin 3 1 0.3 D10AF02 0 0.0 J01MA06 1 0.3 J01FA01 0 0.0 S01AE02 0 0.0 S01AA17 0 0.0 J01RA13 0 0.0 D10AF52 0 0.0 Tolterodine G04BD07 3 1 0.3 Foscarnet J05AD01 3 0 0.0 Alfuzosin 3 0 0.0 Granisetron A04AA02 3 0 0.0 G04CA01 0 0.0 Hydroxychloroquine P01BA02 2 0 0.0 G04CA51 0 0.0 Imipramine N06AA02 2 0 0.0 Anagrelide L01XX35 4 0 0.0 (melipramine) N06AA03 0 0.0 Apomorphine 3 0 0.0 0 0.0 G04BE07 0 0.0 Isoproterenol 1 0 0.0 N04BC07 0 0.0 (isoprenaline) C01CA02 0 0.0 R03AK02 0 0.0 Arsenic trioxide L01XX27 4 0 0.0 R03CB51 0 0.0 Atazanavir J05AE08 3 0 0.0 R03AB02 0 0.0 Atomoxetine N06BA09 1 0 0.0 R03CB01 0 0.0 Isradipine C08CA03 3 0 0.0 Bedaquiline J04AK05 3 0 0.0 Itraconazole J02AC02 2 0 0.0 Bortezomib L01XX32 3 0 0.0 Ivabradine C01EB17 2 0 0.0 Bosutinib L01XE14 3 0 0.0 Lapatinib L01XE07 3 0 0.0 Chloral hydrate N05CC01 2 0 0.0 Methadone 4 0 0.0 Chloroquine P01BA01 4 0 0.0 N07BC02 0 0.0 Clomipramine N06AA04 2 0 0.0 N02AC52 0 0.0 Crizotinib L01XE16 3 0 0.0 Methylphenidate N06BA04 1 0 0.0 Dabrafenib L01XE23 3 0 0.0 Metronidazole 2 1 0.3 D06BX01 1 0.3 Dasatinib L01XE06 3 0 0.0 A01AB17 0 0.0 Dexmedetomidine N05CM18 3 0 0.0 A02BD08 0 0.0 J01RA03 0 0.0 Dihydroartemisinin P01BF05 3 0 0.0 J01RA10 0 0.0 + piperaquine A02BD03 0 0.0 Disopyramide C01BA03 4 0 0.0 A02BD02 0 0.0 Dobutamine C01CA07 1 0 0.0 P01AB51 0 0.0 Doxepin N06AA12 2 0 0.0 A02BD01 0 0.0 J01RA04 0 0.0 Droperidol N05AD08 4 0 0.0 G01AF01 0 0.0 Eribulin L01XX41 3 0 0.0 J01XD01 0 0.0 Felbamate N03AX10 3 0 0.0 P01AB01 0 0.0 Fingolimod L04AA27 3 0 0.0

Drug name ATC code Risk No. % Drug name ATC code Risk No. % score of score of pts pts Mifepristone 3 0 0.0 Posaconazole J02AC04 2 0 0.0 G03XB01 0 0.0 Promethazine 3 3 0.8 G03XB51 0 0.0 R06AD02 3 0.8 Mirabegron G04BD12 3 0 0.0 D04AA10 0 0.0 Moexipril/HCTZ 3 0 0.0 V03AB05 0 0.0 C09AA13 0 0.0 R06AD52 0 0.0 C09BA13 0 0.0 Pseudoephedrine 1 1 0.3 Nicardipine C08CA04 3 0 0.0 R01BA02 0 0.0 Nilotinib L01XE08 3 0 0.0 R01BA52 1 0.3 Norepinephrine C01CA03 1 0 0.0 Rilpevirine J05AG05 3 0 0.0 (noradrenaline) Ritonavir 2 0 0.0 Ondansetron A04AA01 4 0 0.0 J05AR10 0 0.0 Oxytocin 3 0 0.0 J05AE03 0 0.0 H01BB02 0 0.0 Roxithromycin J01FA06 3 0 0.0 G02AC01 0 0.0 Saquinavir J05AE01 3 0 0.0 Paliperidone N05AX13 3 0 0.0 Sertindole N05AE03 3 0 0.0 Pazopanib L01XE11 3 0 0.0 Sevoflurane N01AB08 4 0 0.0 Pentamidine P01CX01 4 0 0.0 Sorafenib L01XE05 3 0 0.0 Perflutren lipid V08DA04 3 0 0.0 Sunitinib L01XE04 3 0 0.0 microspheres Phenylephrine 1 1 0.3 Telaprevir J05AE11 2 0 0.0 R01BA53 1 0.3 Telithromycin J01FA15 3 0 0.0 C01CA06 0 0.0 R01AA04 0 0.0 Tetrabenazine N07XX06 3 0 0.0 R01AB01 0 0.0 Tizanidine M03BX02 3 0 0.0 R01BA03 0 0.0 Vandetanib L01XE12 4 0 0.0 S01FB01 0 0.0 S01GA05 0 0.0 Vardenafil G04BE09 3 0 0.0 S01GA55 0 0.0 Vemurafenib L01XE15 3 0 0.0 Pimozide N05AG02 4 0 0.0 Voriconazole J02AC03 2 0 0.0

Appendix 11: Complete list QT-prolonging drugs with risk Drug name ATC code Risk No. of % score 4 community-dwelling older adults score pts Drug name ATC code Risk No. of % score pts Disopyramide C01BA03 4 1 0.1 Sotalol 4 49 4.8 Haloperidol N05AD01 4 1 0.1 C07AA07 49 4.8 Anagrelide L01XX35 4 0 0.0 C07BA07 0 0.0 C07AA57 0 0.0 Arsenic trioxide L01XX27 4 0 0.0 Amiodarone C01BD01 4 46 4.5 Azithromycin S01AA26 4 0 0.0 Escitalopram N06AB10 4 41 4.0 Chloroquine P01BA01 4 0 0.0 Domperidone A03FA03 4 35 3.4 Flecainide C01BC04 4 29 2.9 Droperidol N05AD08 4 0 0.0 Sulpiride N05AL01 4 23 2.3 Erythromycin 4 0 0.0 Citalopram N06AB04 4 16 1.6 D10AF02 0 0.0 Azithromycin 4 9 0.9 D10AF52 0 0.0 J01FA10 9 0.9 J01FA01 0 0.0 J01RA07 0 0.0 S01AA17 0 0.0 Clarithromycin 4 5 0.5 Methadone 4 0 0.0 J01FA09 5 0.5 N07BC02 0 0.0 A02BD06 0 0.0 N02AC52 0 0.0 A02BD07 0 0.0 Ondansetron A04AA01 4 0 0.0 A02BD09 0 0.0 Pentamidine P01CX01 4 0 0.0 A02BD05 0 0.0 A02BD04 0 0.0 Pimozide N05AG02 4 0 0.0 Moxifloxacin 4 3 0.3 Sevoflurane N01AB08 4 0 0.0 J01MA14 3 0.3 Vandetanib L01XE12 4 0 0.0 S01AE07 0 0.0 Levofloxacin 4 2 0.2 J01MA12 2 0.2 A02BD10 0 0.0 J01RA05 0 0.0 S01AE05 0 0.0

Appendix 12: Complete list QT-prolonging drugs with risk Drug name ATC code Risk No. % score 4 institutionalized older adults score of pts Drug name ATC code Risk No. % score of pts Escitalopram N06AB10 4 51 12.8 Flecainide C01BC04 4 1 0.3 Domperidone A03FA03 4 38 9.5 Anagrelide L01XX35 4 0 0.0 Moxifloxacin 4 29 7.3 Arsenic trioxide L01XX27 4 0 0.0 J01MA14 29 7.3 S01AE07 0 0.0 Chloroquine P01BA01 4 0 0.0 Amiodarone C01BD01 4 19 4.8 Disopyramide C01BA03 4 0 0.0 Haloperidol N05AD01 4 19 4.8 Droperidol N05AD08 4 0 0.0 Citalopram N06AB04 4 13 3.3 Erythromycin 4 0 0.0 Azithromycin 4 10 2.5 D10AF02 0 0.0 J01FA10 10 2.5 J01FA01 0 0.0 S01AA26 0 0.0 S01AA17 0 0.0 J01RA07 0 0.0 D10AF52 0 0.0 Methadone 4 0 0.0 Sotalol 4 9 2.3 N07BC02 0 0.0 C07AA07 9 2.3 N02AC52 0 0.0 C07BA07 0 0.0 C07AA57 0 0.0 Ondansetron A04AA01 4 0 0.0 Levofloxacin 4 7 1.8 Pentamidine P01CX01 4 0 0.0 J01MA12 7 1.8 Pimozide N05AG02 4 0 0.0 S01AE05 0 0.0 A02BD10 0 0.0 Sevoflurane N01AB08 4 0 0.0 J01RA05 0 0.0 Vandetanib L01XE12 4 0 0.0 Sulpiride N05AL01 4 7 1.8 Clarithromycin 4 3 0.8 J01FA09 3 0.8 A02BD06 0 0.0 A02BD07 0 0.0 A02BD09 0 0.0 A02BD05 0 0.0 A02BD04 0 0.0

Appendix 13: Complete list of drugs with anticholinergic Drug name ATC code Risk No. % properties according to Duran et al. community-dwelling score of older adults pts Drug name ATC code Risk No. % Hydroxyzine H 7 0.7 score of N05BB01 7 0.7 pts N05BB51 0 0.0 Tramadol N02AX02 L 91 9.0 Carbamazepine N03AF01 L 6 0.6 Trazodone N06AX05 L 49 4.8 Quetiapine N05AH04 L 5 0.5 Ipratropium H 47 4.6 (fumarate) R03AL01 33 3.2 Meclozine H 3 0.3 R03AL02 9 0.9 R06AE05 3 0.3 R03BB01 5 0.5 R06AE55 0 0.0 R01AX03 0 0.0 Dimenhydrinate/ H 2 0.2 Ranitidine L 42 4.1 diphenhydramine R06AA02 1 0.1 A02BA02 42 4.1 R06AA52 1 0.1 A02BA07 0 0.0 D04AA32 0 0.0 D04AA33 0 0.0 Combinations with N02AX52 L 36 3.5 tramadol or Doxepin N06AA12 H 2 0.2 methadone Nortriptyline N06AA10 H 2 0.2 Domperidone A03FA03 L 35 3.4 Tolterodine G04BD07 H 2 0.2 Amitriptyline H 30 3.0 Cimetidine L 2 0.2 N06AA09 30 3.0 A02BA01 2 0.2 N06CA01 0 0.0 A02BA51 0 0.0 Fentanyl L 29 2.9 N02AB03 29 2.9 Belladona alkaloids H 1 0.1 N01AH01 0 0.0 A03BA04 1 0.1 N01AH51 0 0.0 A03CB02 0 0.0 A06AB30 0 0.0 Paroxetine N06AB05 L 27 2.7 Clomipramine N06AA04 H 1 0.1 Loperamide L 26 2.6 A07DA03 26 2.6 Clozapine N05AH02 H 1 0.1 A07DA05 0 0.0 Levomepromazine N05AA02 H 1 0.1 A07DA53 0 0.0 Trihexyphenidyl N04AA01 H 1 0.1 Cetirizine R06AE07 L 25 2.5 Fluvoxamine N06AB08 L 1 0.1 Clonazepam N03AE01 L 20 2.0 Olanzapine N05AH03 L 1 0.1 Codeine L 20 2.0 Alimemazine R06AD01 L 1 0.1 N02AA59 15 1.5 R05DA04 5 0.5 Baclofen M03BX01 L 1 0.1 N02AA79 0 0.0 Bromocriptine L 1 0.1 Theophylline L 18 1.8 N04BC01 1 0.1 R03DA04 18 1.8 G02CB01 0 0.0 R03DB04 0 0.0 Disopyramide C01BA03 L 1 0.1 R03DA54 0 0.0 Fexofenadine R06AX26 L 1 0.1 R03DA74 0 0.0 Oxybutynin G04BD04 H 17 1.7 Haloperidol N05AD01 L 1 0.1 Citalopram N06AB04 L 16 1.6 Loratadine R06AX13 L 1 0.1 Dosulepin N06AA16 L 16 1.6 Morphine L 1 0.1 N02AA01 1 0.1 Mirtazapine N06AX11 L 15 1.5 N02AG01 0 0.0 Diazepam N05BA0F1 L 12 1.2 A07DA52 0 0.0 Triazolam N05CD05 L 10 1.0 N02AA51 0 0.0 R05DA05 0 0.0 Fluoxetine L 9 0.9 Risperidone N05AX08 L 1 0.1 N06AB03 9 0.9 N06CA03 0 0.0 Atropine H 0 0.0 A03BA01 0 0.0 Oxycodone L 9 0.9 S01FA01 0 0.0 N02AA05 8 0.8 A03CB03 0 0.0 N02AA55 1 0.1

Drug name ATC code Risk No. % Drug name ATC code Risk No. % score of score of pts pts Chlorphenamine H 0 0.0 Tizanidine M03BX02 H 0 0.0 R06AB04 0 0.0 Entacapone N04BX02 L 0 0.0 R06AB54 0 0.0 Promethazine H 0 0.0 Imipramine H 0 0.0 R06AD02 0 0.0 N06AA02 0 0.0 D04AA10 0 0.0 N06AA03 0 0.0 R06AD52 0 0.0 Scopolamine H 0 0.0 V03AB05 0 0.0 (hyoscine) A04AD01 0 0.0 Ketorolac L 0 0.0 N05CM05 0 0.0 M01AB15 0 0.0 S01FA02 0 0.0 S01BC05 0 0.0 A04AD51 0 0.0 Methadone N07BC02 L 0 0.0 Darifenacin G04BD10 H 0 0.0 Nefanzodone N06AX06 L 0 0.0 Flavoxate G04BD02 H 0 0.0 Oxcarbazepine N03AF02 L 0 0.0 Procyclidine N04AA04 H 0 0.0 Phenelzine N06AF03 L 0 0.0 Pyrilamine R06AC01 H 0 0.0 Pimozide N05AG02 L 0 0.0

Appendix 14: Complete list of drugs with anticholinergic Drug name ATC code Risk No. % properties according to Duran et al. institutionalized older score of adults pts Drug name ATC code Risk No. % Paroxetine N06AB05 L 5 1.3 score of Diazepam N05BA01 L 4 1.0 pts Ipratropium H 56 14.0 Trihexyphenidyl N04AA01 H 3 0.8 R03AL01 28 7.0 Promethazine H 3 0.8 R03BB01 14 3.5 R06AD02 3 0.8 R03AL02 13 3.3 D04AA10 0 0.0 R01AX03 1 0.3 R06AD52 0 0.0 Trazodone N06AX05 L 55 13.8 V03AB05 0 0.0 Domperidone A03FA03 L 38 9.5 Fluoxetine L 3 0.8 N06AB03 3 0.8 Quetiapine N05AH04 L 36 9.0 N06CA03 0 0.0 (fumarate) Oxycodone L 3 0.8 Ranitidine L 36 9.0 N02AA05 3 0.8 A02BA02 36 9.0 N02AA55 0 0.0 A02BA07 0 0.0 Triazolam N05CD05 L 3 0.8 Tramadol N02AX02 L 36 9.0 Baclofen M03BX01 L 3 0.8 Risperidone N05AX08 L 34 8.5 Codeine L 5 1.3 Fentanyl L 30 7.5 N02AA59 3 0.8 N02AB03 30 7.5 R05DA04 2 0.5 N01AH01 0 0.0 N02AA79 0 0.0 N01AH51 0 0.0 Levomepromazine N05AA02 H 2 0.5 Mirtazapine N06AX11 L 25 6.3 Nortriptyline N06AA10 H 2 0.5 Combinations with N02AX52 L 22 5.5 Diphenhydramine H 2 0.5 tramadol or D04AA32 2 0.5 methadone R06AA02 0 0.0 Cetirizine R06AE07 L 21 5.3 D04AA33 0 0.0 Loperamide L 20 5.0 R06AA52 0 0.0 A07DA03 20 5.0 Scopolamine H 2 0.5 A07DA05 0 0.0 (hyoscine) N05CM05 2 0.5 A07DA53 0 0.0 A04AD01 0 0.0 Oxybutynin G04BD04 H 19 4.8 S01FA02 0 0.0 A04AD51 0 0.0 Haloperidol N05AD01 L 19 4.8 Chlorphenamine H 1 0.3 Amitriptyline H 14 3.5 R06AB04 1 0.3 N06AA09 14 3.5 R06AB54 0 0.0 N06CA01 0 0.0 Olanzapine N05AH03 L 13 3.3 Tolterodine G04BD07 H 1 0.3 Citalopram N06AB04 L 13 3.3 Flavoxate G04BD02 H 1 0.3 Theophylline L 10 2.5 Carbamazepine N03AF01 L 1 0.3 R03DA04 10 2.5 Ketorolac L 1 0.3 R03DB04 0 0.0 S01BC05 1 0.3 R03DA54 0 0.0 M01AB15 0 0.0 R03DA74 0 0.0 Atropine H 0 0.0 Clonazepam N03AE01 L 9 2.3 A03BA01 0 0.0 Morphine L 8 2.0 S01FA01 0 0.0 N02AA01 8 2.0 A03CB03 0 0.0 N02AG01 0 0.0 Belladona alkaloids H 0 0.0 A07DA52 0 0.0 A03BA04 0 0.0 N02AA51 0 0.0 A03CB02 0 0.0 R05DA05 0 0.0 A06AB30 0 0.0 Clozapine N05AH02 H 6 1.5 Clomipramine N06AA04 H 0 0.0 Hydroxyzine H 5 1.3 Doxepin N06AA12 H 0 0.0 N05BB01 5 1.3 N05BB51 0 0.0

Drug name ATC code Risk No. % Drug name ATC code Risk No. % score of score of pts pts Imipramine H 0 0.0 Alimemazine R06AD01 L 0 0.0 N06AA02 0 0.0 Bromocriptine L 0 0.0 N06AA03 0 0.0 N04BC01 0 0.0 Meclozine H 0 0.0 G02CB01 0 0.0 R06AE05 0 0.0 Disopyramide C01BA03 L 0 0.0 R06AE55 0 0.0 Dosulepin N06AA16 L 0 0.0 Darifenacin G04BD10 H 0 0.0 Entacapone N04BX02 L 0 0.0 Dimenhydrinate R06AA02 H 0 0.0 Fexofenadine R06AX26 L 0 0.0 Procyclidine N04AA04 H 0 0.0 Loratadine R06AX13 L 0 0.0 Pyrilamine R06AC01 H 0 0.0 Methadone N07BC02 L 0 0.0 Tizanidine M03BX02 H 0 0.0 Nefanzodone N06AX06 L 0 0.0 Cimetidine L 0 0.0 A02BA01 0 0.0 Oxcarbazepine N03AF02 L 0 0.0 A02BA51 0 0.0 Phenelzine N06AF03 L 0 0.0 Fluvoxamine N06AB08 L 0 0.0 Pimozide N05AG02 L 0 0.0

Appendix 15: Complete list of drugs with a high Drug name ATC code Risk No. of % anticholinergic activity according to Duran et al. score pts community-dwelling older adults Clomipramine N06AA04 H 1 0.1 Drug name ATC code Risk No. of % Clozapine N05AH02 H 1 0.1 score pts Ipratropium H 47 4.6 Levomepromazine N05AA02 H 1 0.1 R03AL01 33 3.2 Trihexyphenidyl N04AA01 H 1 0.1 R03AL02 9 0.9 R03BB01 5 0.5 Atropine H 0 0.0 R01AX03 0 0.0 A03BA01 0 0.0 S01FA01 0 0.0 Amitriptyline H 30 3.0 A03CB03 0 0.0 N06AA09 30 3.0 N06CA01 0 0.0 Chlorphenamine H 0 0.0 R06AB04 0 0.0 Oxybutynin G04BD04 H 17 1.7 R06AB54 0 0.0 Hydroxyzine H 7 0.7 Imipramine H 0 0.0 N05BB01 7 0.7 N06AA02 0 0.0 N05BB51 0 0.0 N06AA03 0 0.0 Meclozine H 3 0.3 Scopolamine H 0 0.0 R06AE05 3 0.3 (hyoscine) A04AD01 0 0.0 R06AE55 0 0.0 N05CM05 0 0.0 Dimenhydrinate/ H 2 0.2 S01FA02 0 0.0 diphenhydramine R06AA02 1 0.1 A04AD51 0 0.0 R06AA52 1 0.1 Darifenacin G04BD10 H 0 0.0 D04AA32 0 0.0 Flavoxate G04BD02 H 0 0.0 D04AA33 0 0.0 Procyclidine N04AA04 H 0 0.0 Doxepin N06AA12 H 2 0.2 Promethazine H 0 0.0 Nortriptyline N06AA10 H 2 0.2 R06AD02 0 0.0 Tolterodine G04BD07 H 2 0.2 D04AA10 0 0.0 R06AD52 0 0.0 Belladona alkaloids H 1 0.1 V03AB05 0 0.0 A03BA04 1 0.1 A03CB02 0 0.0 Pyrilamine R06AC01 H 0 0.0 A06AB30 0 0.0 Tizanidine M03BX02 H 0 0.0

Appendix 16: Complete list of drugs with a high Drug name ATC code Risk No. % anticholinergic activity according to Duran et al. score of pts institutionalized older adults Chlorphenamine H 1 0.3 Drug name ATC code Risk No. % R06AB04 1 0.3 score of pts R06AB54 0 0.0 Ipratropium H 56 14.0 R03AL01 28 7.0 Tolterodine G04BD07 H 1 0.3 R03BB01 14 3.5 Flavoxate G04BD02 H 1 0.3 R03AL02 13 3.3 R01AX03 1 0.3 Atropine H 0 0.0 A03BA01 0 0.0 Oxybutynin G04BD04 H 19 4.8 S01FA01 0 0.0 A03CB03 0 0.0 Amitriptyline H 14 3.5 N06AA09 14 3.5 Belladona alkaloids H 0 0.0 N06CA01 0 0.0 A03BA04 0 0.0 Clozapine N05AH02 H 6 1.5 A03CB02 0 0.0 A06AB30 0 0.0 Hydroxyzine H 5 1.3 N05BB01 5 1.3 Clomipramine N06AA04 H 0 0.0 N05BB51 0 0.0 Doxepin N06AA12 H 0 0.0 Trihexyphenidyl N04AA01 H 3 0.8 Imipramine H 0 0.0 Promethazine H 3 0.8 N06AA02 0 0.0 R06AD02 3 0.8 N06AA03 0 0.0 D04AA10 0 0.0 Meclozine H 0 0.0 R06AD52 0 0.0 R06AE05 0 0.0 V03AB05 0 0.0 R06AE55 0 0.0 Levomepromazine N05AA02 H 2 0.5 Darifenacin G04BD10 H 0 0.0 Nortriptyline N06AA10 H 2 0.5 Dimenhydrinate R06AA02 H 0 0.0 Diphenhydramine H 2 0.5 Procyclidine N04AA04 H 0 0.0 D04AA32 2 0.5 Pyrilamine R06AC01 H 0 0.0 R06AA02 0 0.0 D04AA33 0 0.0 Tizanidine M03BX02 H 0 0.0 R06AA52 0 0.0 Scopolamine H 2 0.5 (hyoscine) N05CM05 2 0.5 A04AD01 0 0.0 S01FA02 0 0.0 A04AD51 0 0.0

Appendix 17: Complete list of drugs with anticholinergic Drug name ATC code Risk No. % properties according to Rudolph et al. community- score of pts dwelling older adults Diphenhydramine 3 2 0.2 Drug name ATC code Risk No. % hydrochloride R06AA02 1 0.1 score of pts R06AA52 1 0.1 Trazodone N06AX05 1 49 4.8 D04AA32 0 0.0 hydrochloride D04AA33 0 0.0 Ranitidine A02BA02 1 42 4.1 Cimetidine 2 2 0.2 hydrochloride A02BA01 2 0.2 Carbidopa-levodopa 1 31 3.1 A02BA51 0 0.0 N04BA02 27 2.7 Nortriptyline N06AA10 2 2 0.2 N04BA01 0 0.0 hydrochloride N04BA03 4 0.4 Tolterodine tartrate G04BD07 2 2 0.2 Amitryptyline 3 30 3.0 Baclofen M03BX01 2 1 0.1 hydrochloride N06AA09 30 3.0 N06CA01 0 0.0 Clozapine N05AH02 2 1 0.1 Paroxetine N06AB05 1 27 2.7 Loratadine R06AX13 2 1 0.1 hydrochloride Olanzapine N05AH03 2 1 0.1 Loperamide 2 26 2.6 hydrochloride A07DA03 26 2.6 Haloperidol N05AD01 1 1 0.1 A07DA05 0 0.0 Risperidone N05AX08 1 1 0.1 A07DA53 0 0.0 Atropine producten 3 0 0.0 Cetirizine R06AE07 2 25 2.5 A03BA01 0 0.0 hydrochloride S01FA01 0 0.0 Oxybutynin chloride G04BD04 3 17 1.7 A03CB03 0 0.0 Mirtazapine N06AX11 1 15 1.5 Chlorpheniramine R06AB02 3 0 0.0 Metoclopramide A03FA01 1 9 0.9 maleate hydrochloride Imipramine N06AA02 3 0 0.0 Hydroxyzine 3 7 0.7 hydrochloride N05BB01 7 0.7 Promethazine 3 0 0.0 N05BB51 0 0.0 hydrochloride R06AD02 0 0.0 D04AA10 0 0.0 Pramipexole N04BC05 1 6 0.6 R06AD52 0 0.0 dihydrochloride V03AB05 0 0.0 Quetiapine fumarate N05AH04 1 5 0.5 Tizanidine M03BX02 3 0 0.0 Pseudoephedrine 2 4 0.4 hydrochloride hydrochloride R01BA52 3 0.3 Entacapone N04BX02 1 0 0.0 R01BA02 1 0.1 Selegiline N04BD01 1 0 0.0 Meclizine R06AE05 3 3 0.3 hydrochloride hydrochloride

Appendix 18: Complete list of drugs with anticholinergic Drug name ATC code Risk No. % properties according to Rudolph et al. institutionalized score of older adults pts Drug name ATC code Risk No. % Promethazine 3 3 0.8 score of hydrochloride R06AD02 3 0.8 pts D04AA10 0 0.0 Trazodone N06AX05 1 55 13.8 R06AD52 0 0.0 hydrochloride V03AB05 0 0.0 Carbidopa-levodopa 1 51 12.8 Pramipexole N04BC05 1 3 0.8 N04BA02 44 11.0 dihydrochloride N04BA01 0 0.0 Diphenhydramine 3 2 0.5 N04BA03 7 1.8 hydrochloride D04AA32 2 0.5 R06AA02 0 0.0 Quetiapine fumarate N05AH04 1 36 9.0 D04AA33 0 0.0 Ranitidine A02BA02 1 36 9.0 R06AA52 0 0.0 hydrochloride Nortriptyline N06AA10 2 2 0.5 Risperidone N05AX08 1 34 8.5 hydrochloride Mirtazapine N06AX11 1 25 6.3 Selegiline N04BD01 1 2 0.5 Cetirizine R06AE07 2 21 5.3 hydrochloride hydrochloride Tolterodine tartrate G04BD07 2 1 0.3 Loperamide 2 20 5.0 Pseudoephedrine 2 1 0.3 hydrochloride A07DA03 20 5.0 hydrochloride R01BA02 0 0.0 A07DA05 0 0.0 R01BA52 1 0.3 A07DA53 0 0.0 Atropine producten 3 0 0.0 Oxybutynin chloride G04BD04 3 19 4.8 A03BA01 0 0.0 S01FA01 0 0.0 Haloperidol N05AD01 1 19 4.8 A03CB03 0 0.0 Metoclopramide A03FA01 1 15 3.8 Chlorpheniramine R06AB02 3 0 0.0 hydrochloride maleate Amitryptyline 3 14 3.5 Imipramine N06AA02 3 0 0.0 hydrochloride N06AA09 14 3.5 hydrochloride N06CA01 0 0.0 Meclizine R06AE05 3 0 0.0 Olanzapine N05AH03 2 13 3.3 hydrochloride Tizanidine M03BX02 3 0 0.0 Clozapine N05AH02 2 6 1.5 hydrochloride Hydroxyzine 3 5 1.3 Cimetidine 2 0 0.0 N05BB01 5 1.3 A02BA01 0 0.0 N05BB51 0 0.0 A02BA51 0 0.0 Paroxetine N06AB05 1 5 1.3 Loratadine R06AX13 2 0 0.0 hydrochloride Entacapone N04BX02 1 0 0.0 Baclofen M03BX01 2 3 0.8

LECTURES

1. March 4, 2015: Research on the causes of human cancer and scientific strategies for cancer prevention and control by Dr. Inge Huybrechts

There are about 200 types of cancer, leading to about 7.6 million deaths annually worldwide and most of them occur in low- and middle- income countries. This prevalence is still increasing. There are many risk factors for cancer but eight of them account for 50% of all cancer deaths. These risk factors are more common in low- and middle- income countries and smoking is the most common of them. Apparently there is a genetic predisposition as well as a geographical influence either.

There are however some UN organizations researching cancer and striving for cancer control such as the WHO, the International Agency for Research on Cancer (IARC) as well as government cancer institutions such as the National Cancer Institute (NCI) and local initiatives. Dr. Huybrechts, who works for IARC, then explained IARC’s process for classifying potential cancer hazards. IARC mainly researches the literature on cancer research and classifies those cancer hazards in five categories depending on the scientific evidence. These monographs include chemicals, complex mixtures, occupational exposures, physical and biological agents and lifestyle factors. Over the years, they created an “Encyclopaedia of carcinogens” with over 400 possibly carcinogenic agents.

I thought this was an interesting presentation on cancer and cancer research, but the explanation on how IARC reaches a verdict for a certain cancer hazard and how they work was a little long. In my opinion, a more general presentation on cancer research would have been more interesting.

2. March 19, 2015: The evolution of microbiology in cystic fibrosis: Prof.dr. Li Puma

In this lecture the definition and evolution of microbiology and cystic fibrosis (CF) and the evolution of thinking about the microbiology of CF were discussed. There are different parts in microbiology. In this lecture, infectious diseases were the focus. CF is multiple system disease causing problems mainly in the patient’s lungs possibly leading to death at a very young age.

In the 1940’s the main therapy for CF was inhalation of penicillin but children died before the age of 40 months due to S. aureus infections in the lungs. The treatment of CF between the ’40s and 1967 was mainly to, without any evidence-based studies, give the patient various antibiotics and see what happens. This approach seemed to work and overall survival increased to 5 years and older. Thanks to antibiotic susceptibility testing, the antibiotics were adapted and overall survival increased even more. Because of this, the population of patients with CF changed into an older population in need of social support but CF in itself changed as well and a mutated P. aeruginosa became the most

84 prevalent bacterium in the lungs. More research showed that resistance against the antibiotics was transmissible between the patients and soon the summer camps and specialized clinics were closed or adapted. To avoid resistance, antibiotics are first tested before they are administered to the patients and the FDA specifically asks for documents on how active the new medicines are against P. aeruginosa. There is however a wide variety of bacteria present in the lungs of CF patients who seem to communicate with each other. Current research focuses on the different bacteria: which are present, which communicate and is this communication positive or negative, what is the relative abundance and how can we best eradicate them? These questions allow for an exciting future.

In my opinion, this was a very fascinating lecture most of which I will definitely remember for quite some time. Prof. Dr. Li Puma kept me interested throughout the entire lecture and made me very excited about this topic. I can’t wait what the future holds for the microbiology of CF and it’s medication.

3. April 22, 2015: Are management skills in pharmaceutical care important for the future? A view from “Nether-Belgian” perspective: Hendrik De Rocker

Recently there has been some evolutions in pharmaceutical care. The patient became the main focus in community-pharmacies instead of the drug. Besides that, preventing diseases is becoming more important than curing them. Because of changes in society and the patients’ expectations, the pharmacists their main activity is evaluating as well. Patients are becoming more empowered and they should be approached with an integrated vision. The pharmacist’s activities are based on three pillars: drug use, prevention and ‘referral center’.

The second part of the lecture focused on management in community-pharmacies. Mr. De Rocker started by explaining the definition and evolution of management as well as the different levels of management in the pharmaceutical cares system. Management is also important in the daily operation of community-pharmacies. The pharmacist should look for the most effective, appropriate and safe combination of drugs for the patient while also taking the patients’ wishes into account. The goal of this is the improvement of the patient’s quality of life. This is called Pharmaceutical patient care (FPZ). Mr. De Rocker continued by giving some examples and challenges in the Netherlands and Belgium. The conclusion of this lecture was that pharmacists will have to limit the impact of chronic diseases on the population in the future. He will have to cooperate with physicians and patients, acquire specific skills, offer preventive care and focus on the patient in order the reach this goal.

In my opinion, this was a very interesting lecture on what we can expect in the future and how pharmaceutical care should evolve to meet the changing needs and to still be valuable in the future. Unfortunately, the lecture stayed very theoretical and didn’t focus on daily life examples.