Drug safety analysis in a real-life cohort of Parkinson s disease patients with polypharmacy

Transcription

1 Drug safety analysis in a real-life cohort of Parkinson s disease patients with polypharmacy Saskia Müller-Rebstein 1, 2, Claudia Trenkwalder 1, Jens Ebentheuer 1, Wolfgang H Oertel 3, Carsten Culmsee 4, Günter U Höglinger, MD 2, 5 1 Paracelsus-Elena Klinik Kassel, University Medical Center, Goettingen, Germany 2 German Center for Neurodegenerative Diseases (DZNE), Munich, Germany 3 Department of Neurology, Philipps Universität, Marburg, Germany 4 Department of Pharmacy, Philipps Universität, Marburg, Germany 5 Department of Neurology, Technische Universität München, Munich, Germany Correspondence to Prof Dr Günter U. Höglinger, Dept. of Translational Neurodegeneration, German Center for Neurodegenerative Diseases (DZNE), Feodor-Lynen Str. 17, D Munich, Germany. Phone: , guenter.hoeglinger@dzne.de.

2 Supplementary table 1: PD-related problems Most common conditions n (%) Motor problems Postural instability / tendency to fall 61 (48.0) Resting tremor 54 (42.5) Motor fluctuations and dyskinesias Neuropsychological problems Paroxysmal on-off fluctuations 72 (56.7) Freezing 63 (49.6) Wearing-off / End-of-dose akinesia 53 (41.7) Early morning akinesia 50 (39.4) Choreatic peak dose dyskinesia 41 (32.3) Nocturnal off-phases 26 (20.5) Biphasic dyskinesia 26 (20.5) Off dystonia 14 (11.0) Dementia / mild cognitive impairment 65 (51.2) Psychoses 48 (37.8) Drug-induced psychosis 19 (15.0) Depression 18 (14.2) Impulse control disorder Autonomic dysfunction Bladder function disorder 70 (55.1) Constipation 65 (51.2) Sialorrhoea 46 (36.2) Orthostatic hypotension 32 (25.2) Urinary incontinence 23 (18.1) Sleep disorders Disorders of maintaining sleep 61 (48.0) REM sleep behaviour disorder 42 (33.1) Daytime sleepiness 39 (30.7) Disorders of initiating sleep 23 (18.1) Sleep attack 14 (11.0) Supplementary table 1: Absolute numbers and frequency of specific PD-related problems [n (% of all n=127 patients)].

3 Supplementary table 2: Comorbidities Most common conditions n (%) Mental and behavioural Other mental disorders due to brain damage 97 (76.4) disorders and dysfunction and to physical disease such as organic mood disorders. organic hallucinosis or mild cognitive disorders Dementia in other diseases such as PD 22 (17.3) Diseases of the nervous (without PD) Diseases of the circulatory Endocrine, nutritional and metabolic diseases Diseases of the musculoskeletal and connective tissue Diseases of the genitourinary Symptoms, signs and abnormal clinical and laboratory findings, not elsewhere classified Diseases of the blood and bloodforming organs and certain disorders involving the immune mechanism Dieseases of the respiratory Habit and impulse disorders 10 (7.9) Other extrapyramidal and movement 64 (50.4) disorders such as drug-induced chorea or restless legs syndrome Sleep disorders 29 (22.8) Other polyneuropathies 9 (7.1) Essential (primary) hypertension, 63 (49.6) Chronic ischaemic heart disease, 18 (14.2) Atrial fibrillation and flutter 14 (11.0) Other hypothyroidism 17 (13.4) Disorders of lipoprotein metabolism and 17 (13.4) other lipidaemias Type 2 diabetes mellitus Other intervertebral disc disorders 12 (9.5) Spondylosis Other disorders of urinary such as 28 (22.1) specified urinary incontinence or urinary tract infection Hyperplasia of prostate 6 (4.7) Speech disturbances, not elsewhere classified 12 (9.5) Dysphagia 3 (2.4) Other anaemias 6 (4.7) Further relevant disorders of the 50 (39.4) hematopoetic diagnosed after laboratory results Chronic obstructive pulmonary disease 5 (3.9) Diseases of the eye and adnexa Glaucoma 3 (2.4) Other medical disorders diagnosed after laboratory results or ECG Renal impairment 67 (52.8) Cardiomyopathy 18 (14.2) AV block 17 (13.4) Heart valve disease 14 (11.0) Supplementary table 2: Absolute numbers and frequency of predominant comorbidities [n (% of all n=127 patients)].

4 Supplementary table 3: Anti-Parkinson drugs (admission / discharge) (n =119 / 126) Pramipexole (n =44 / 24) Rotigotine (n =21 / 32) Ropinirole (n =16 / 11) Piribedil (n =12 / 14) Apomorphine (n =8 / 6) Entacapone (n =46 / 42) Tolcapone (n =2 / 5) Rasagiline (n =29 / 26) Selegiline (n =2 / 1) Amantadine (n =32 / 30) Budipine (n =1 / 2) Pharmacological interactions with (admission / discharge, n / n) CNS-active CYP-metabolized QT-time prolonging Other substances substances substances substances 42 / / 1 58 / / / / 4 3 / 3 4 / 5 16 / / / 9 1 / / / 31-8 / 11 1 / 0-1 / 1 0 / 2 - Supplementary table 3: Numbers of anti-parkinson drugs prescribed upon hospital admission and discharge, and their pharmacological interactions with other prescribed drugs, grouped in clusters. Note that the listed interactions represent both desired and unwanted interactions. The numbers indicate possible interactions reported in the manufacturers information, since their actual clinical relevancy was not evaluated in our cohort. Interactions with piribedil and apomorphin were not considered as comprehensive, since the manufacturers information does not contain detailed warnings for interactions.

5 Supplementary table 4: Group ATC code Agent N04BB01 Amantadine N06AB04 Citalopram N05AH02 Clozapine A03FA03 Domperidone C08CA03 Isradipine J01MA12 Levofloxacin C01CA17 Midodrine N05AH04 Quetiapine QT-time prolonging drugs R03AC02 Salbutamol N06AB06 Sertraline D11AH01 Tacrolimus L02BA01 Tamoxifen M03BX02 Tizanidine N06AX16 Venlafaxine N04BX03 Budipine P01BC01 Quinine N06AB10 Escitalopram N06AX11 Mirtazipine C07AB02 Metopolol N02AX02 Tramadol L02BA01 Tamoxifen C07AG02 Carvedilol CYP2D6 substrates S01ED51 Timolol combinations N06AA09 Amitriptyline N06AX16 Venlafaxine C07AB03 Atenolol N05AH02 Clozapine A02BC01 Omeprazole A10AB01 Insulin (human) A10AB05 Insulin aspart A10AD04 Insulin lispro CYP1A2 inhibitors or inductors A10AE04 Insulin glargine A10AE05 Insulin detemir J01MA12 Levofloxacin C08DA01 Verapamil G03CA04 Estriol N06AB08 Fluvoxamine M01AB05 Diclofenac M01AE01 Ibuprofen A10BB12 Glimpiride C09DA04 Irbesartan and diuretics C10AA04 Fluvastatin C03CA04 Torasemide CYP2C9 substrates B01AA04 Phenprocoumon C09CA01 Iosartan M01AE02 Naproxen N06AA09 Amitriptyline C09CA06 Candesartan B01AC04 Clopidogrel C09CA03 Valsartan Supplementary table 4: Relevant drugs causing interactions with and contraindications against anti- Parkinson drugs in our study population, clustered to QT-time prolonging drugs, CYP2D6 substrates, CYP1A2 inductors or inhibitors, and CYP2C9 substrates.

6 Supplementary table 5: Anti-Parkinson drug (admission / discharge) (n=119 / 126) Pramipexole (n=44 / 24) Rotigotine (n=21 / 32) Ropinirole (n=16 / 11) Piribedil (n=12 / 14) Apomorphine (n=8 / 6) Entacapone (n=46 / 42) Tolcapone (n=2 / 5) Rasagiline (n=29 / 26) Selegiline (n=2 / 1) Amantadine (n=32 / 30) Budipine (n=1 / 2) Medical diseases Neurologic diseases Contraindication cluster (admission / discharge, n / n) Diseases of the hematopoietic drugs QT-time prolonging Other risk factors 88 / / / 51-5 / 5 57 / / / / / / / / / 2 - Supplementary table 5: Numbers of anti-parkinson drugs prescribed upon hospital admission and discharge, and of their observed contraindications, grouped in clusters. Note that the list represents both absolute and relative contraindications.

7 Supplementary figure 1: A B C Anti-Parkinson agent groups Anticholinergics MAO-B inhibitors NMDA antagonists COMT inhibitors Dopamine agonists Budipine Selegiline Tolcapone Apomorphine Piribedil Ropinirole Rotigotine Rasagiline Amantadine Pramipexole Entacapone 0 (0) 0 (0) Anti-Parkinson drugs 5 (3.9) 8 (6.3) 6 (4.7) 14 (11.0) 16 (12.6) 21 (16.5) 32 (25.2) 29 (22.8) 26 (20.5) 32 (25.2) 30 (23.6) 44 (34.6) 24 (18.9) 46 (36.2) 42 (33.1) 27 (24.4) 31 (21.3) 32 (26.0) 33 (25.2) 47 (37.8) 48 (37.0) 87 (79.5) 101 (68.5) 126 (93.7) 119 (99.2) Drugs of the comedication on the 1st level of ATC classification Antiparasitic Antiinfectives Antineoplastic and immunomodulating immunomodulating agents Dermatologicals Respiratory Sensory organs Genito urinary Systemic hormonal Musculo-skeletal Blood and Blood blood and forming blood forming organs organs Alimentary tract and metabolism metabolism Nervous Cardiovascular Admission 0 (0.0) 3 (2.4) 5 (3.9) 9 (7.1) 15 (11.8) 15 (11.8) 13 (10.2) 17 (13.4) 23 (18.1) 22 (17.3) 27 (21.3) 28 (22.0) Discharge 48 (37.8) 56 (44.1) 64 (50.4) C.1 C (93.7) 126 (99.2) C (64.6) 90 (70.9) 80 (63.0) 99 (78.0) 83 (65.4) 86 (67.7) C.2.2 C.3 Drugs in the 2nd level ATC classification group of the cardiovascular Vasoprotectives Antihypertensives Cardiac therapy Calcium channel blockers Lipid modifying agents Beta blocking agents Diuretics Renin-angiotensin agents Other Anesthetics Antiepileptics* Analgetics Psycholeptics Psychoanaleptics 10 (7.9) 19 (15.0) 19 (15.0) 36 (28.3) 34 (26.8) 39 (30.7) 40 (31.5) 52 (40.9) 50 (39.4) Drugs in the 2nd level ATC classification group of the nervous (without anti-parkinson drugs) Psychostimulants Anti-dementia drugs Antidepressants 0 (0.0) 17 (13.4) 31 (24.4) 36 (28.3) 56 (44.1) 42 (33.1) 43 (33.9) Drugs in the 3rd level ATC classification group of psychoanaleptics Anxiolytics Hypnotics and sedatives Antipsychotics 27 (21.3) Drugs in the 3rd level ATC classification group of psycholeptics 10 (7.9) 14 (11.0) 18 (14.2) 0 (0.0) 19 (15.0) 40 (31.5) Drugs in the 2nd level ATC classification group of the alimentary tract Stomatological preparations Drugs used in diabetics Vitamins Mineral supplements Drugs for gastrointestinal disorders disorders Drugs for constipation Drugs for acid related disorders 10 (7.9) 13 (10.2) 13 (10.2) 17 (13.4) 31 (24.4) 45 (35.4) 44 (34.6) 45 (35.4) Supplementary figure 1: The absolute numbers and frequencies [n (% of all n=127 patients)] of drugs prescribed upon hospital admission (dark columns) and discharge (bright columns) for anti-parkinson agent groups (A), specific anti-parkinson drugs (B), and drugs in the comedication [displayed on the 1 st level of the ATC-classification (C); on the 2 nd ATC-level for the cardiovascular (C.1) and nervous (without Parkinson medication) (C.2); on the 3 rd ATC-level for psychoanaleptics (C.2.1) and psycholeptics (C.2.2); and on the 2 nd ATC-level for the alimentary tract (C.3)]. *Antiepileptics were mainly used for pain and RLS treatment (e.g. Pregabalin or Gabapentin).