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Adverse Reactions of Anticholinergic Medications: An Analysis of the WHO Pharmacovigilance Database
By: Fayyaz Ahamed, BS, University of California San Francisco; Charles Jones, MD, University of California San Francisco; Behzad Abbasi, MD, University of California San Francisco; Benjamin N. Breyer, MD, University of California San Francisco; Nathan M. Shaw, MD, University of California San Francisco, MedStar Georgetown University Hospital, Washington, DC | Posted on: 15 Dec 2023
Anticholinergic agents are widely prescribed for patients with a variety of urological conditions, including urinary urgency, incontinence, or detrusor overactivity.1,2 Data suggest increasing prescription numbers in the last 20 years with 1 study noting a doubling over that time to reach 10% of the geriatric population.3 Despite their efficacy, use of anticholinergics has also been shown to have potential adverse cognitive effects.4
This study aimed to evaluate the largest international safety database for the safety profiles of commonly used anticholinergics in a large international pharmacovigilance dataset. A particular focus was paid to cognitive and neurologic adverse drug reactions (ADRs) reported for each drug in this category.
In this retrospective case-non-case study, we used VigiBase, the WHO’s global database of individual ADRs developed and maintained by Uppsala Monitoring Centre.5 VigiBase is the largest pharmacovigilance database globally, with over 30 million reports of ADRs from 140 countries (https://who-umc.org/vigibase). It contains data on the region of origin, patient (age group and sex), ADR, (onset/end date, seriousness, and outcome), and medication data (indication, start/end dates, dose, regimen, and administration route). It began in 1968 when 10 countries pooled data from their existing national adverse reaction reporting systems with the intention to enable early detection of drug-related problems.5 The majority of reports are submitted from industrialized nations like the US, United Kingdom, Canada, etc, with Europe having 33 members in the WHO International Drug Monitoring Programme while Asia/Pacific has 24 members and Africa has 9 members.5 Most national monitoring centers review the case reports and code them to the MedDRA standardized dictionary of terms. VigiBase is used directly by national centers as well as by the pharmaceutical industry and academia through data requests on specific drugs.5 Here we utilized a disproportionality analysis, whereby VigiBase studies drug-ADR combinations by selecting all ADRs for the anticholinergic agents oxybutynin, tolterodine, darifenacin, solifenacin, trospium, and fesoterodine for analysis that were reported from 1985 until September 2021 regardless of indication. This analysis provides aggregate, deidentified data without patient or drug characteristics.
First-pass ADRs were selected by manually including cognitive and visual ADRs. After identification of these ADRs in our dataset, we measured reporting odds ratio (ROR) and the 95% CI for each anticholinergic-ADR combination. ROR is an alternative for the odds ratio in case-control studies and corresponds to the exposure odds among cases of a specific ADR over the odds of exposure among noncases (ie, other queried drugs in a dataset)6:
ROR = [a × c/b × d]; a = drug of interest–ADR of interest, b = drug of interest–other ADRs, c = other drugs–ADR of interest, and d = other drugs–other ADRs.6
For a drug of interest, cases (a) were considered cognitive ADR reports, and noncases (b) were all other ADR reports during the same time period. When using the VigiBase disproportionality analysis database, the ROR provided by VigiBase is relative to the entire VigiBase dataset. An ROR for a drug-ADR was deemed statistically significant if the ROR and its lower bound of 95% CI were > 1 and the total number of events were ≥ 3.7,8 A significant ROR implies a potential association between the drug and the ADR that needs to be confirmed by clinical studies.6 In the second pass, we manually chose ADRs that solely pertained to cognition, for which ≥ 4 agents showed significant RORs.
There was a total of 493,819 ADRs reported for the 6 anticholinergic agents out of a total of 1,167,199 ADRs within the database. The first- and second-pass ADR reports numbered 8255 and 3059, respectively (Table).
Table. First-Pass Adverse Drug Reactions Defined as Loosely Cognitive or Vision Relateda
| oxybutynin | tolterodine | darifenacin | solifenacin | trospium | fesoterodine | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | ROR (95% CI) | n | ROR (95% CI) | n | ROR (95% CI) | n | ROR (95% CI) | n | ROR (95% CI) | n | ROR (95% CI) | |
| Accommodation disorder | 8 | 5.3 (2.65-10.62) | 13 | 8.6 (4.99-14.83) | 1 | 4.32 (0.61-30.68) | 4 | 2.12 (0.79-5.65) | 12 | 61.04 (34.56-107.8) | 2 | 2.47 (0.62-9.9) |
| Agitation | 102 | 1.87 (1.54-2.27) | 44 | 0.8 (0.59-1.07) | 5 | 0.6 (0.25-1.43) | 28 | 0.41 (0.28-0.59) | 10 | 1.39 (0.75-2.59) | 15 | 0.51 (0.31-0.85) |
| Altered state of consciousness | 5 | 0.71 (0.29-1.7) | 2 | 0.28 (0.07-1.12) | 0 | - | 6 | 0.68 (0.3-1.51) | 3 | 3.23 (1.04-10.02) | 0 | - |
| Amnesia | 65 | 1.82 (1.43-2.32) | 99 | 2.77 (2.27-3.37) | 11 | 2.01 (1.11-3.63) | 73 | 1.63 (1.3-2.06) | 6 | 1.28 (0.57-2.84) | 25 | 1.31 (0.88-1.93) |
| Anaesthetic complication neurological | 4 | 35.19 (13.08-94.63) | 0 | - | 0 | - | 0 | - | 0 | - | 0 | - |
| Asthenopia | 1 | 0.34 (0.05-2.39) | 9 | 3.02 (1.57-5.81) | 0 | - | 8 | 2.16 (1.08-4.31) | 0 | - | 0 | - |
| Attention deficit hyperactivity disorder | 5 | 1.6 (0.66-3.84) | 16 | 5.1 (3.12-8.33) | 0 | - | 1 | 0.26 (0.04-1.81) | 0 | - | 1 | 0.6 (0.08-4.23) |
| Behavior disorder | 12 | 5.18 (2.94-9.14) | 3 | 1.29 (0.41-3.99) | 0 | - | 5 | 1.72 (0.72-4.15) | 1 | 3.28 (0.46-23.31) | 1 | 0.81 (0.11-5.72) |
| Blindness | 5 | 0.34 (0.14-0.82) | 24 | 1.63 (1.09-2.43) | 7 | 3.12 (1.48-6.55) | 14 | 0.76 (0.45-1.29) | 2 | 1.04 (0.26-4.15) | 9 | 1.15 (0.6-2.2) |
| Blindness unilateral | 3 | 0.62 (0.2-1.91) | 12 | 2.45 (1.39-4.32) | 2 | 2.68 (0.67-10.72) | 3 | 0.49 (0.16-1.53) | 0 | - | 2 | 0.77 (0.19-3.07) |
| Cerebral atrophy | 4 | 3.36 (1.26-8.97) | 1 | 0.84 (0.12-5.93) | 0 | - | 1 | 0.67 (0.09-4.77) | 0 | - | 0 | - |
| Cerebral disorder | 1 | 0.47 (0.07-3.33) | 2 | 0.93 (0.23-3.73) | 0 | - | 3 | 1.13 (0.36-3.49) | 1 | 3.57 (0.5-25.37) | 5 | 4.39 (1.82-10.55) |
| Cerebrovascular accident | 36 | 0.53 (0.38-0.74) | 95 | 1.4 (1.15-1.72) | 10 | 0.97 (0.52-1.8) | 64 | 0.76 (0.59-0.97) | 1 | 0.11 (0.02-0.8) | 45 | 1.25 (0.93-1.67) |
| Cerebrovascular disorder | 5 | 0.68 (0.28-1.64) | 15 | 2.04 (1.23-3.38) | 0 | - | 0 | - | 1 | 1.04 (0.15-7.36) | 0 | - |
| Cognitive disorder | 41 | 2.42 (1.78-3.28) | 27 | 1.58 (1.08-2.31) | 2 | 0.77 (0.19-3.07) | 46 | 2.17 (1.62-2.9) | 8 | 3.59 (1.79-7.2) | 26 | 2.87 (1.95-4.21) |
| Concussion | 2 | 0.72 (0.18-2.88) | 4 | 1.43 (0.54-3.82) | 1 | 2.35 (0.33-16.7) | 6 | 1.73 (0.78-3.85) | 1 | 2.74 (0.39-19.49) | 7 | 4.72 (2.25-9.91) |
| Confusional state | 329 | 3.7 (3.31-4.12) | 221 | 2.45 (2.15-2.8) | 29 | 2.1 (1.46-3.03) | 229 | 2.04 (1.79-2.32) | 54 | 4.64 (3.54-6.08) | 98 | 2.03 (1.67-2.48) |
| Delirium | 65 | 4.09 (3.2-5.22) | 18 | 1.12 (0.71-1.78) | 6 | 2.46 (1.1-5.47) | 45 | 2.26 (1.69-3.03) | 9 | 4.31 (2.24-8.29) | 8 | 0.94 (0.47-1.87) |
| Dementia | 24 | 2.78 (1.86-4.15) | 49 | 5.66 (4.28-7.5) | 8 | 6.05 (3.02-12.12) | 60 | 5.58 (4.33-7.19) | 4 | 3.52 (1.32-9.4) | 51 | 11.11 (8.43-14.63) |
| Dementia Alzheimer’s type | 3 | 1.19 (0.38-3.69) | 26 | 10.32 (7.02-15.18) | 1 | 2.59 (0.36-18.38) | 14 | 4.45 (2.63-7.52) | 1 | 3.02 (0.42-21.44) | 5 | 3.71 (1.54-8.91) |
| Disorientation | 43 | 2.11 (1.56-2.84) | 63 | 3.08 (2.4-3.94) | 5 | 1.6 (0.66-3.84) | 53 | 2.08 (1.59-2.72) | 9 | 3.36 (1.75-6.47) | 7 | 0.64 (0.3-1.34) |
| Dissociation | 5 | 2.89 (1.2-6.96) | 2 | 1.15 (0.29-4.6) | 1 | 3.77 (0.53-26.81) | 0 | - | 0 | - | 0 | - |
| Dizziness | 513 | 0.9 (0.82-0.98) | 797 | 1.41 (1.32-1.52) | 108 | 1.25 (1.03-1.51) | 658 | 0.92 (0.85-0.99) | 97 | 1.31 (1.07-1.61) | 277 | 0.9 (0.8-1.02) |
| Frustration tolerance decreased | 1 | 0.25 (0.03-1.75) | 5 | 1.22 (0.51-2.94) | 0 | - | 4 | 0.79 (0.3-2.1) | 0 | - | 10 | 4.61 (2.48-8.57) |
| Gait disturbance | 76 | 0.87 (0.69-1.09) | 120 | 1.37 (1.15-1.64) | 15 | 1.12 (0.68-1.87) | 63 | 0.58 (0.45-0.74) | 13 | 1.14 (0.66-1.96) | 73 | 1.57 (1.25-1.98) |
| Hallucination | 255 | 5.89 (5.2-6.67) | 131 | 2.98 (2.51-3.54) | 21 | 3.13 (2.04-4.81) | 115 | 2.1 (1.75-2.52) | 18 | 3.13 (1.97-4.98) | 21 | 0.89 (0.58-1.37) |
| Hallucination, auditory | 18 | 2.91 (1.83-4.61) | 8 | 1.28 (0.64-2.57) | 0 | - | 7 | 0.9 (0.43-1.89) | 3 | 3.68 (1.19-11.44) | 2 | 0.6 (0.15-2.41) |
| Hallucination, tactile | 3 | 15.27 (4.9-47.58) | 0 | - | 0 | - | 0 | - | 0 | - | 0 | - |
| Hallucination, visual | 59 | 6.6 (5.11-8.53) | 18 | 1.99 (1.26-3.17) | 4 | 2.91 (1.09-7.75) | 28 | 2.49 (1.72-3.62) | 9 | 7.65 (3.97-14.73) | 6 | 1.25 (0.56-2.78) |
| Hallucinations, mixed | 8 | 6.88 (3.44-13.78) | 2 | 1.71 (0.43-6.83) | 0 | - | 4 | 2.75 (1.03-7.33) | 0 | - | 0 | - |
| Loss of personal independence | 13 | 0.56 (0.32-0.96) | 9 | 0.39 (0.2-0.74) | 3 | 0.84 (0.27-2.62) | 16 | 0.55 (0.34-0.9) | 7 | 2.3 (1.09-4.83) | 19 | 1.53 (0.98-2.4) |
| Memory impairment | 52 | 0.97 (0.74-1.27) | 108 | 2.01 (1.66-2.43) | 10 | 1.22 (0.65-2.26) | 105 | 1.57 (1.29-1.9) | 4 | 0.57 (0.21-1.51) | 94 | 3.3 (2.69-4.05) |
| Mental impairment | 7 | 0.59 (0.28-1.24) | 24 | 2.02 (1.35-3.02) | 3 | 1.65 (0.53-5.13) | 13 | 0.88 (0.51-1.51) | 3 | 1.93 (0.62-5.99) | 14 | 2.21 (1.31-3.74) |
| Mental status changes | 33 | 3.22 (2.29-4.53) | 7 | 0.68 (0.32-1.42) | 1 | 0.63 (0.09-4.51) | 11 | 0.86 (0.47-1.55) | 1 | 0.74 (0.1-5.26) | 2 | 0.36 (0.09-1.45) |
| Mydriasis | 42 | 6.04 (4.46-8.18) | 7 | 1 (0.47-2.09) | 0 | - | 6 | 0.69 (0.31-1.53) | 3 | 3.27 (1.05-10.15) | 0 | - |
| Nervousness | 42 | 1.01 (0.75-1.37) | 106 | 2.55 (2.11-3.09) | 8 | 1.26 (0.63-2.52) | 22 | 0.42 (0.28-0.64) | 5 | 0.92 (0.38-2.2) | 24 | 1.08 (0.72-1.61) |
| Personality disorder | 15 | 3.26 (1.96-5.41) | 4 | 0.86 (0.32-2.3) | 0 | - | 0 | - | 0 | - | 0 | - |
| Psychomotor hyperactivity | 16 | 1.72 (1.05-2.81) | 16 | 1.71 (1.05-2.8) | 1 | 0.7 (0.1-4.98) | 4 | 0.34 (0.13-0.92) | 2 | 1.64 (0.41-6.55) | 2 | 0.4 (0.1-1.61) |
| Psychotic disorder | 28 | 1.74 (1.2-2.52) | 13 | 0.8 (0.47-1.38) | 4 | 1.62 (0.61-4.32) | 6 | 0.3 (0.13-0.66) | 3 | 1.42 (0.46-4.39) | 2 | 0.23 (0.06-0.93) |
| Refraction disorder | 4 | 24.9 (9.28-66.78) | 0 | - | 0 | - | 0 | - | 0 | - | 1 | 11.52 (1.62-82.06) |
| Sedation | 53 | 3.01 (2.29-3.94) | 168 | 9.59 (8.23-11.17) | 2 | 0.74 (0.18-2.95) | 6 | 0.27 (0.12-0.6) | 3 | 1.29 (0.42-4.01) | 3 | 0.32 (0.1-0.98) |
| Sluggishness | 3 | 0.67 (0.22-2.08) | 9 | 2 (1.04-3.86) | 1 | 1.46 (0.21-10.37) | 5 | 0.89 (0.37-2.15) | 0 | - | 0 | - |
| Somnolence | 221 | 1.38 (1.21-1.57) | 108 | 0.66 (0.55-0.8) | 40 | 1.63 (1.19-2.23) | 285 | 1.42 (1.27-1.6) | 26 | 1.23 (0.84-1.81) | 131 | 1.53 (1.29-1.82) |
| Speech disorder | 34 | 1.24 (0.89-1.74) | 45 | 1.64 (1.22-2.19) | 4 | 0.95 (0.36-2.54) | 41 | 1.2 (0.88-1.63) | 6 | 1.67 (0.75-3.72) | 34 | 2.33 (1.66-3.26) |
| Suicide attempt | 10 | 0.43 (0.23-0.79) | 4 | 0.17 (0.06-0.45) | 2 | 0.56 (0.14-2.23) | 7 | 0.24 (0.11-0.5) | 8 | 2.61 (1.3-5.23) | 4 | 0.32 (0.12-0.85) |
| Suspected suicide | 3 | 5.14 (1.65-15.96) | 0 | - | 0 | - | 0 | - | 0 | - | 0 | - |
| Thinking abnormal | 21 | 1.79 (1.17-2.75) | 13 | 1.1 (0.64-1.9) | 2 | 1.11 (0.28-4.45) | 14 | 0.95 (0.56-1.61) | 0 | - | 7 | 1.11 (0.53-2.34) |
| Vision blurred | 258 | 3.39 (2.99-3.83) | 355 | 4.67 (4.21-5.19) | 90 | 7.89 (6.39-9.74) | 829 | 8.99 (8.39-9.65) | 75 | 7.66 (6.08-9.65) | 216 | 5.35 (4.68-6.13) |
| Visual acuity reduced | 11 | 0.82 (0.45-1.48) | 29 | 2.15 (1.49-3.1) | 8 | 3.89 (1.94-7.8) | 24 | 1.43 (0.96-2.13) | 4 | 2.27 (0.85-6.05) | 14 | 1.95 (1.15-3.29) |
| Visual impairment | 132 | 1.72 (1.45-2.05) | 135 | 1.75 (1.48-2.08) | 15 | 1.27 (0.77-2.12) | 131 | 1.37 (1.15-1.62) | 45 | 4.54 (3.38-6.1) | 55 | 1.34 (1.03-1.75) |
| Vitreous floaters | 3 | 0.76 (0.24-2.35) | 11 | 2.77 (1.53-5) | 0 | - | 4 | 0.81 (0.3-2.15) | 0 | - | 2 | 0.94 (0.24-3.78) |
| Walking aid user | 2 | 0.77 (0.19-3.09) | 6 | 2.31 (1.04-5.15) | 1 | 2.52 (0.36-17.93) | 2 | 0.62 (0.15-2.47) | 0 | - | 4 | 2.89 (1.08-7.71) |
| Xerophthalmia | 13 | 10.57 (6.13-18.23) | 8 | 6.46 (3.22-12.93) | 0 | - | 9 | 5.84 (3.03-11.24) | 0 | - | 4 | 6.05 (2.27-16.15) |
| Abbreviations: ROR, reporting odds ratio; CI, confidence interval. aSignificant RORs are in bold. |
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In the second-pass, 8 ADRs were identified. Drugs which exhibited most significant RORs were tolterodine (amnesia: 2.77, 95% CI 2.27-3.37), fesoterodine (cognitive disorder: 2.87, 95% CI 1.95-4.21), trospium (confusional state: 4.64, 95% CI: 3.54-6.08; disorientation: 3.36, 95% CI 1.75-6.47; visual hallucination: 7.65, 95% CI 3.97-14.73), solifenacin (dementia: 3.52, 95% CI 1.32-9.4), oxybutynin (hallucination: 5.89, 95% CI 5.2-6.67), and darifenacin (somnolence: 1.63, 95% CI 1.19-2.23; Figure). Disproportionality signals were observed in darifenacin (cognitive disorder and disorientation), fesoterodine (amnesia, disorientation, hallucination, and visual hallucination), tolterodine (somnolence), and trospium (amnesia and somnolence) but were not statistically significant.
This VigiBase pharmacovigilance analysis reveals that anticholinergic agents are at least 2 times more likely compared to other drugs to have adverse neurologic, delirium-promoting effects. Fesoterodine was noted to have the highest likelihood of reporting for dementia, while trospium and oxybutynin were found to have increased reporting odds for visual hallucination. Mouse studies have shown that oxybutynin, solifenacin, and tolterodine have high brain penetration while darifenacin and trospium exhibited lower brain penetration.9 However, according to the results of this VigiBase analysis, the relative reporting risk of clinical ADRs between these agents don’t fully correlate with their brain penetration tendency as shown in animal studies. A meta-analysis exhibited consistent results with this VigiBase analysis regarding a statistically significant decrease in Mini Mental Status Exam–measured cognitive function associated with darifenacin and tolterodine, matched with cognitive disorder/disorientation and amnesia ADRs, respectively.10
Limitations in this study particularly stem from ADR classification; resulting sequelae of cognitive impairment (eg, falls) were not categorized as cognitive and were not included. This likely underestimates the cumulative cognitive burden these medications may pose. Further, we could not investigate dose-response due to deficient dosing data. Since the data in this disproportionality analysis are taken from patients, physicians, and pharmacists, this mix of sources may impact the data quality. Furthermore, only approximately 25% of ADRs are reported from low- and middle-income countries, with the US making up 36.2% of the reports so the population studied may not be representative of the globe.11 Finally, despite the overall large number of ADR reports, cognitive-classified reports were lower in number, limiting our sample size and comparison between drugs.
These international longitudinal data support existing studies on the cognitive effects of anticholinergic medications and should prompt future study, particularly of those thought to have fewer cognitive effects (eg, trospium). This may allow for improved prescription patterns and decrease the risk of cognitive side effects in high-risk populations (eg, the elderly).
Funding Source: No funding.
Data Source: https://who-umc.org/vigibase/
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