ADRs caused by potential. only. Patients (n, %) 132 (49.6%) 111 (41.7%) 10 (3.8%) 2 (0.8%) 9 (3.4%) 2 (0.8%)

Transcription

1 Journal: Drug Safety Study title: Self-medication with OTC and prescribed drugs causing ADR-related hospital admissions results of a prospective, long-term multi-centre study Authors: 1 S. Schmiedl*, 2 M. Rottenkolber*, 2 J. Hasford, 3 D. Rottenkolber, 4 K. Farker, 5 B. Drewelow, 6 M. Hippius, 7 K. Saljé, 1 P. Thürmann, for the German Network of Regional Pharmacovigilance Centres * equal contribution Affiliations: 1 Philipp-Klee Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Wuppertal, Germany/Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany; 2 Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany; 3 Institute of Health Economics and Health Care Management and Munich Centre of Health Sciences, Ludwig- Maximilians-Universität München, Munich, Germany/HelmholtzZentrum München German Research Centre for Environmental Health, Munich, Germany; 4 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany/Sophien- und Hufeland-Klinikum Weimar, Weimar, Germany; 5 Institute of Clinical Pharmacology, Centre for Pharmacology and Toxicology, University of Rostock, Rostock, Germany; 6 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany; 7 Institute of Clinical Pharmacology, University of Greifswald, Greifswald, Germany Electronic Supplementary Table 1: Demographics and characteristics of n=266 patients with ADR caused by self-medication (stratification by type of self-medication) ADRs caused by OTC-drugs only ADRs caused by formerly prescribed- Rx-drugs only ADRs caused by potential OTC-drugs only ADRs caused by OTC and potential OTC-drugs ADRs caused by OTC and formerly prescribed Rxdrugs ADRs caused by potential OTC and formerly prescribed Rxdrugs Patients (n, 132 ( ( (3.8 2 (0.8 9 (3.4 2 (0.8 Adverse drug reactions (n, Age in years (mean±sd) 141 ( ( (4.3 2 ( (3.6 2 ( ± ± ± ± ± ±3.6 Women (n, 64 ( ( ( ( ( (50.0 No. of diseases (median (Q1 Q3)) 2.0 ( ) 3.0 ( ) 3.5 ( ) 4.0 ( ) 4.0 ( ) 3.5 ( ) No. of drugs (median (Q1 Q3)) 2.0 ( ) 4.0 ( ) 6.5 ( ) 5.0 ( ) 5.0 ( ) 5.0 ( ) No. of suspected drugs (median (Q1 Q3)) 1.0 ( ) 1.0 ( ) 1.0 ( ) 2.5 ( ) 3.0 ( ) 3.5 ( ) Length of hospital stay (days) (median (Q1 Q3)) 7.0 ( ) 6.0 ( ) 11.0 ( ) 3.5 ( ) 7.0 ( ) 21.0 ( ) ADR: adverse drug reaction; OTC: over the counter; Q1: first quartile; Q3: third quartile; Rx: prescription; SD: standard deviation.

2 Journal: Drug Safety Study title: Self-medication with OTC and prescribed drugs causing ADR-related hospital admissions results of a prospective, long-term multi-centre study Authors: 1 S. Schmiedl*, 2 M. Rottenkolber*, 2 J. Hasford, 3 D. Rottenkolber, 4 K. Farker, 5 B. Drewelow, 6 M. Hippius, 7 K. Saljé, 1 P. Thürmann, for the German Network of Regional Pharmacovigilance Centres * equal contribution Affiliations: 1 Philipp-Klee Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Wuppertal, Germany/Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany; 2 Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany; 3 Institute of Health Economics and Health Care Management and Munich Centre of Health Sciences, Ludwig- Maximilians-Universität München, Munich, Germany/HelmholtzZentrum München German Research Centre for Environmental Health, Munich, Germany; 4 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany/Sophien- und Hufeland-Klinikum Weimar, Weimar, Germany; 5 Institute of Clinical Pharmacology, Centre for Pharmacology and Toxicology, University of Rostock, Rostock, Germany; 6 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany; 7 Institute of Clinical Pharmacology, University of Greifswald, Greifswald, Germany Electronic Supplementary Table 2: Type of ADRs stratified by type of self-medication ADR type A (n [ADR], ADR type B (n [ADR], Unknown/Others (n [ADR], OTC Potential OTC prescribed Rx-drugs OTC and potential OTC OTC and formerly prescribed Rxdrug prescribed Rxdrug and potential OTC 110 ( ( ( ( ( ( ( ( ( ( ( ( ( All (n [ADR]) ADR: adverse drug reaction; OTC: over the counter; Rx: prescription; SD: standard deviation.

3 Journal: Drug Safety Study title: Self-medication with OTC and prescribed drugs causing ADR-related hospital admissions results of a prospective, long-term multi-centre study Authors: 1 S. Schmiedl*, 2 M. Rottenkolber*, 2 J. Hasford, 3 D. Rottenkolber, 4 K. Farker, 5 B. Drewelow, 6 M. Hippius, 7 K. Saljé, 1 P. Thürmann, for the German Network of Regional Pharmacovigilance Centres * equal contribution Affiliations: 1 Philipp-Klee Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Wuppertal, Germany/Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany; 2 Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany; 3 Institute of Health Economics and Health Care Management and Munich Centre of Health Sciences, Ludwig- Maximilians-Universität München, Munich, Germany/HelmholtzZentrum München German Research Centre for Environmental Health, Munich, Germany; 4 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany/Sophien- und Hufeland-Klinikum Weimar, Weimar, Germany; 5 Institute of Clinical Pharmacology, Centre for Pharmacology and Toxicology, University of Rostock, Rostock, Germany; 6 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany; 7 Institute of Clinical Pharmacology, University of Greifswald, Greifswald, Germany

4 Electronic Supplementary Table 3: Number of patients receiving drugs causing self-medication related ADRs (self-medication only) stratified by type of selfmedication and causative drug Drug * (ATC [7-digit]) Total ** (n [patients]) Potential ADRs (three most frequent SOCs [SOC1,2,3] and respective three most frequent PTs [PT1,2,3]) prescribed Rx drug (n Acetylsalicylic acid (N02BA01) (100 SOC1: Gastrointestinal disorders (n=37) [PT1: Gastric ulcer haemorrhage (n=11); PT2: Gastrointestinal haemorrhage (n=10); PT3: Duodenal ulcer (n=4)] SOC2: Immune system disorders (n=3) [PT1: Type I hypersensitivity (n=1), Hypersensitivity (n=1), Anaphylactic reaction (n=1)] SOC3: Respiratory, thoracic and mediastinal disorders (n=2) [PT1: Asthma (n=1), Epistaxis (n=1)], Blood and lymphatic system disorders (n=2) [PT1: Anaemia (n=2)] 0 0 Diclofenac (M01AB05) (4.6 SOC1: Immune system disorders (n=1) [PT1: Hypersensitivity (n=1)] 21 (95.5 SOC1: Gastrointestinal disorders (n=17) [PT1: Gastrointestinal haemorrhage (n=4); PT2: Gastric ulcer haemorrhage (n=3); PT3: Gastritis haemorrhagic (n=2), Duodenal ulcer (n=2), Gastritis erosive (n=2)] SOC2: Immune system disorders (n=3) [PT1: Hypersensitivity (n=1), Anaphylactic reaction (n=1), Anaphylactic shock (n=1)] SOC3: Skin and subcutaneous tissue disorders (n=1) [PT1: Angioedema (n=1)] continued

5 Drug * (ATC [7-digit]) Total ** (n [patients]) Potential ADRs (three most frequent SOCs [SOC1,2,3] and respective three most frequent PTs [PT1,2,3]) prescribed Rx drug (n Ibuprofen (M01AE01) 22 8 (36.4 SOC1: Gastrointestinal disorders (n=6) [PT1: Duodenal ulcer (n=2); PT2: Gastric ulcer haemorrhage (n=1), Anastomotic ulcer (n=1), Gastrointestinal haemorrhage (n=1), Gastritis (n=1)] SOC2: Immune system disorders (n=1) [PT1: Anaphylactic reaction (n=1)], Nervous system disorders (n=1) [PT1: Headache (n=1)] 7 (31.8 SOC1: Gastrointestinal disorders (n=6) [PT1: Gastric ulcer haemorrhage (n=2); PT2: Vomiting (n=1), Colitis (n=1), Gastric ulcer perforation, obstructive (n=1), Abdominal discomfort (n=1)] SOC2: Immune system disorders (n=1) [PT1: Hypersensitivity (n=1)] 7 (31.8 SOC1: Gastrointestinal disorders (n=5) [PT1: Gastritis erosive (n=2); PT2: Gastric ulcer haemorrhage (n=1), Anastomotic ulcer (n=1), Gastrointestinal haemorrhage (n=1)] SOC2: Immune system disorders (n=1) [PT1: Hypersensitivity (n=1)], Blood and lymphatic system disorders (n=1) [PT1: Leukopenia] Paracetamol (acetaminophen), combinations excl. psycholeptics (N02BE51) Low-dose acetylsalicylic acid (B01AC06) (87.5 SOC1: Gastrointestinal disorders (n=11) [PT1: Gastrointestinal haemorrhage (n=4); PT2: Gastric ulcer haemorrhage (n=3), Anastomotic ulcer (n=2), Duodenal ulcer (n=2)] SOC2: Skin and subcutaneous tissue disorders (n=1) [PT1: Leukocytoclastic vasculitis (n=1)], Immune system disorders (n=1) [PT1: Anaphylactic reaction (n=1)], Hepatobiliary disorders (n=1) [PT1: Jaundice (n=1)] 10 2 (20.0 SOC1: Gastrointestinal disorders (n=2) [PT1: Gastritis erosive (n=1), Gastrointestinal haemorrhage (n=1)] 0 2 (12.5 SOC1 Gastrointestinal disorders (n=2) [PT1: Gastrointestinal haemorrhage (n=1), Gastritis haemorrhagic (n=1)] 0 8 (80.0 SOC1: Gastrointestinal disorders (n=7) [PT1: Gastric ulcer haemorrhage (n=3); PT2: Gastritis erosive (n=2); PT3: Gastrointestinal haemorrhage (n=1), Duodenal ulcer (n=1)] SOC2: Skin and subcutaneous tissue disorders (n=1) [PT1: Leukocytoclastic vasculitis (n=1)] continued

6 Drug * (ATC [7-digit]) Total ** (n [patients]) Potential ADRs (three most frequent SOCs [SOC1,2,3] and respective three most frequent PTs [PT1,2,3]) prescribed Rx drug (n Acetylsalicylic acid, combinations excl. psycholeptics (N02BA51) 7 7 (100.0 SOC1: Gastrointestinal disorders (n=5) [PT1: Gastric ulcer haemorrhage (n=2); PT2: Anastomotic ulcer (n=1), Gastrointestinal haemorrhage (n=1), Gastritis erosive (n=1)] SOC2: Immune system disorders (n=2) [PT1: Anaphylactic shock (n=1), Anaphylactic reaction (n=1)] 0 0 Dipyrone (metamizole sodium, N02BB02) Glyceryl trinitrate (C01DA02) (100.0 SOC1: Immune system disorders (n=2) [PT1: Hypersensitivity (n=1), Anaphylactic reaction (n=1)] SOC2: Skin and subcutaneous tissue disorders (n=1) [PT1: Angioedema (n=1)], Respiratory, thoracic and mediastinal disorders (n=1) [PT1: Status asthmaticus (n=1)], Blood and lymphatic system disorders (n=1) [PT1: Leukopenia (n=1)], Hepatobiliary disorders (n=1) [PT1: Jaundice (n=1)] (100.0 SOC1: Nervous system disorders (n=3) [PT1: Syncope (n=3)], Vascular disorders (n=1) [PT1: Orthostatic hypotension (n=1)], Cardiac disorders (n=1) [PT1: Tachycardia (n=1)] continued

7 Drug * (ATC [7-digit]) Paracetamol (acetaminophen, N02BE01) Glibenclamide (A10BB01) Furosemide (C03CA01) Sildenafil (G04BE03) Naproxen (M01AE02) Propyphenazone (N02BB04) Total ** (n [patients]) 5 5 (100.0 SOC1: Skin and subcutaneous tissue disorders (n=1) [PT1: Drug eruption (n=1)], Gastrointestinal disorders (n=1) [PT1: Nausea (n=1)], Immune system disorders (n=1) [PT1: Hypersensitivity (n=1)], Hepatobiliary disorders (n=1) [PT1: Hepatitis acute (n=1)], Investigations (n=1) [PT1: Transaminases increased (n=1)] Potential ADRs (three most frequent SOCs [SOC1,2,3] and respective three most frequent PTs [PT1,2,3]) prescribed Rx drug (n (100.0 SOC1: Metabolism and nutrition disorders (n=3) [PT1: Hypoglycaemia (n=2); PT2: Shock hypoglycaemic (n=1)] (100.0 SOC1: Vascular disorders (n=2) [PT1: Circulatory collapse (n=1), Orthostatic hypotension (n=1)] (100.0 SOC1: Cardiac disorders (n=2) [PT1: Myocardial infarction (n=2)] 2 2 (100.0 SOC1: Gastrointestinal disorders (n=2) [PT1: Anastomotic ulcer (n=1), Gastric ulcer haemorrhage (n=1)] 2 2 (100.0 SOC1: Immune system disorders (n=2) [PT1: Hypersensitivity (n=2)] Other drugs ( (52.8 ADR: adverse drug reaction; ATC: anatomical therapeutic chemical; OTC: over the counter; PT: preferred term according to MedDRA classification; SOC: system organ class. *Drugs with one case only are shown in the group Other drugs. **Comment: n exceeds the number of patients with self-medication only ADR (n=164 patients [n=144 patients with one self-medication, n=20 patients with self-medication drug drug interaction]) due to multiple counting of a patient if receiving more than one ADR-causative drug.

8 Journal: Drug Safety Study title: Self-medication with OTC and prescribed drugs causing ADR-related hospital admissions results of a prospective, long-term multi-centre study Authors: 1 S. Schmiedl*, 2 M. Rottenkolber*, 2 J. Hasford, 3 D. Rottenkolber, 4 K. Farker, 5 B. Drewelow, 6 M. Hippius, 7 K. Saljé, 1 P. Thürmann, for the German Network of Regional Pharmacovigilance Centres * equal contribution Affiliations: 1 Philipp-Klee Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Wuppertal, Germany/Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany; 2 Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany; 3 Institute of Health Economics and Health Care Management and Munich Centre of Health Sciences, Ludwig- Maximilians-Universität München, Munich, Germany/HelmholtzZentrum München German Research Centre for Environmental Health, Munich, Germany; 4 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany/Sophien- und Hufeland-Klinikum Weimar, Weimar, Germany; 5 Institute of Clinical Pharmacology, Centre for Pharmacology and Toxicology, University of Rostock, Rostock, Germany; 6 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany; 7 Institute of Clinical Pharmacology, University of Greifswald, Greifswald, Germany Electronic Supplementary Table 4: Drug drug interactions in n=20 patients with ADRs caused by self-medication only Drug combination n (patients) Acetylsalicylic acid (N02BA01) / acetylsalicylic acid (N02BA01) 3 Diclofenac (M01AB05) / acetylsalicylic acid (N02BA01) 2 Acetylsalicylic acid (B01AC06) / combination of codeine and paracetamol (N02AA59) 1 Combinations (platelet aggregation inhibitors excl. heparin) (B01AC30) / diclofenac (M01AB05) 1 Doxycycline (J01AA02) / paracetamol (N02BE01) 1 Indometacin (M01AB01) / diclofenac (M01AB05) 1 Diclofenac (M01AB05) / acemetacin (M01AB11) 1 Diclofenac (M01AB05) / ibuprofen (M01AE01) 1 Diclofenac (M01AB05) / ibuprofen (M01AE01) / acetylsalicylic acid, combinations excl. psycholeptics (N02BA51) Diclofenac (M01AB05) / metamizole sodium (N02BB02) 1 Ibuprofen (M01AE01) / ibuprofen (M01AE01) 1 Ibuprofen (M01AE01) / metamizole sodium (N02BB02) 1 Ibuprofen (M01AE01) / paracetamol, combinations excl. psycholeptics (N02BE51) 1 Ibuprofen (M01AE01) / various antiseptic throat preparation (R02AA20) 1 Acetylsalicylic acid (N02BA01) / paracetamol, combinations excl. psycholeptics (N02BE51) 1 Diphenhydramine (R06AA02) / doxylamine (R06AA09) 1 Acetylsalicylic acid (N02BA01) / eucalyptus oil (R05X) 1 1

9 Journal: Drug Safety Study title: Self-medication with OTC and prescribed drugs causing ADR-related hospital admissions results of a prospective, long-term multi-centre study Authors: 1 S. Schmiedl*, 2 M. Rottenkolber*, 2 J. Hasford, 3 D. Rottenkolber, 4 K. Farker, 5 B. Drewelow, 6 M. Hippius, 7 K. Saljé, 1 P. Thürmann, for the German Network of Regional Pharmacovigilance Centres * equal contribution Affiliations: 1 Philipp-Klee Institute for Clinical Pharmacology, HELIOS Clinic Wuppertal, Wuppertal, Germany/Department of Clinical Pharmacology, School of Medicine, Faculty of Health, Witten/Herdecke University, Witten, Germany; 2 Institute for Medical Information Sciences, Biometry, and Epidemiology, Ludwig-Maximilians-Universität München, Munich, Germany; 3 Institute of Health Economics and Health Care Management and Munich Centre of Health Sciences, Ludwig- Maximilians-Universität München, Munich, Germany/HelmholtzZentrum München German Research Centre for Environmental Health, Munich, Germany; 4 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany/Sophien- und Hufeland-Klinikum Weimar, Weimar, Germany; 5 Institute of Clinical Pharmacology, Centre for Pharmacology and Toxicology, University of Rostock, Rostock, Germany; 6 Department of Clinical Pharmacology, Institute of Pharmacology and Toxicology, Jena University Hospital Friedrich Schiller University Jena, Jena, Germany; 7 Institute of Clinical Pharmacology, University of Greifswald, Greifswald, Germany Electronic Supplementary Table 5: Number of patients with drug-drug interactions (three most frequent ADR causative self-medication) and interacting Rx-drugs (ATC [7 digit]) Self-medication (n [patients])* Acetylsalicylic acid (N02BA01) (n=34) Diclofenac (M01AB05) (n=19) Rx-drugs (n [patients]) Diclofenac (M01AB05) (n=11), low-dose acetylsalicylic acid (B01AC06) (n=8), ibuprofen (M01AE01) (n=7), phenprocoumon (B01AA04) (n=4), meloxicam (M01AC06) (n=4), dexibuprofen (M01AE14) (n=2), acetylsalicylic acid (N02BA01) (n=2), gingko biloba (N06DX02) (n=2), omeprazole (A02BC01) (n=1), enoxaparin (B01AB05) (n=1), clopidogrel (B01AC04) (n=1), ticlopidine (B01AC05) (n=1), spironolactone and high-ceiling diuretics (C03ED01) (n=1), amlodipine (C08CA01) (n=1), verapamil (C08DA01) (n=1), trandolapril and verapamil (C09BB10) (n=1), fluvastatin (C10AA04) (n=1), levofloxacin (J01MA12) (n=1), indometacin (M01AB01) (n=1), acemetacin (M01AB11) (n=1), rofecoxib (M01AH02) (n=1), etoricoxib (M01AH05) (n=1) Acetylsalicylic acid (B01AC06) (n=7), phenprocoumon (B01AA04) (n=2), clopidogrel (B01AC04) (n=2), torasemide (C03CA04) (n=2), erythromycin (J01FA01) (n=2), enoxaparin (B01AB05) (n=1), ticlopidine (B01AC05) (n=1), hydrochlorothiazide (C03AA03) (n=1), xipamide (C03BA10) (n=1), furosemide (C03CA01) (n=1), perindopril and diuretics (C09BA04) (n=1), azathioprine (L04AX01) (n=1), allopurinol (M04AA01) (n=1), acetylsalicylic acid (N02BA01) (n=1), theophylline (R03DA04) (n=1) continued

10 Self-medication (n [patients])* Ibuprofen (M01AE01) (n=8) Rx: prescription. Rx-drugs (n [patients]) Acetylsalicylic acid (B01AC06) (n=2), insulin (human) (A10AD01) (n=1), phenprocoumon (B01AA04) (n=1), enoxaparin (B01AB05) (n=1), heparin (C05BA03) (n=1), metoprolol (C07AB02) (n=1), captopril and diuretics (C09BA01) (n=1), progestogens and estrogens, fixed combinations (G03AA) (n=1), diclofenac (M01AB05) (n=1), etoricoxib (M01AH05) (n=1), acetylsalicylic acid (N02BA01) (n=1), carbamazepine (N03AF01) (n=1) * The same compound (e.g. diclofenac, low-dose acetylsalicylic acid) could be assessed differently depending on patient s drug history.