Abstract
Background/Aim: A few case reports of central nervous system (CNS) symptoms caused by amantadine intoxication have been published, detailing various types of symptoms and differing times to onset. We encountered a patient who developed CNS symptoms with amantadine. This prompted us to investigate the types, time to onset, and outcome of CNS adverse reactions to amantadine by analyzing data from a pharmacovigilance database. Patients and Methods: The patient was evaluated at Chutoen General Hospital, Shizuoka, Japan. Analysis was performed using the Japanese Adverse Drug Event Report (JADER) database. Results: In our case, the amantadine blood concentration was 4,042 ng/ml, i.e., in the toxic range. The time to onset was 26 days for dyskinesia and 90 days for depressed level of consciousness. Symptoms resolved when amantadine was discontinued. The JADER database contained 974 cases of adverse reactions to amantadine. The most frequently reported CNS adverse reaction was hallucination, with a reporting odds ratio of 64.28 (95% confidence interval=52.67-78.46). Positive signals were detected for all CNS adverse reactions. For all CNS reactions, clinical outcomes were poor in a comparatively low percentage of cases. Most CNS reactions occurred soon after administration of amantadine, usually within approximately one month. Conclusion: Because most CNS adverse reactions to amantadine usually occur within approximately one month of initiating treatment, healthcare providers should exercise heightened vigilance in monitoring patients for such reactions during this period.
- Amantadine
- central nervous system
- adverse reactions
- Japanese Adverse Drug Event Report database
- time to onset
In Japan, amantadine is used to treat Parkinson’s disease and influenza A and also to relieve decreased spontaneity after cerebral infarction (1). Toxic adverse reactions to amantadine, mainly central nervous system (CNS) symptoms, such as myoclonus, hallucinations, and delirium, may occur as blood concentrations increase (2). Some case reports have reported on patients with amantadine toxicity and described varying types and times to onset of CNS symptoms (2-10). Furthermore, one review article described symptoms of myoclonus caused by amantadine (11).
Recently, various studies have used pharmacovigilance databases to analyze the risk and time to onset of adverse drug reactions (12-14). In Japan, the Pharmaceuticals and Medical Devices Agency (PMDA) publishes the Japanese Adverse Drug Event Report (JADER), a spontaneous reporting system of adverse drug reactions that is based on current, completely anonymized data submitted by health care professionals and pharmaceutical companies.
It is important to understand the types and time to onset of adverse reactions to a drug to support its proper use, but to our knowledge, no studies have evaluated CNS adverse reactions to amantadine in detail. Therefore, after we encountered a case of CNS adverse reactions due to amantadine intoxication in a 63-year-old woman with Parkinson’s disease, we decided to further investigate the types, time to onset, and outcomes of CNS adverse reactions to amantadine. To do so, we evaluated data from the JADER database and our own case.
Patients and Methods
Case experienced at our hospital. We collected data on CNS symptoms due to amantadine that occurred in a patient hospitalized at Chutoen General Medical Center, Shizuoka, Japan. Written informed consent was obtained from the patient’s family. Additionally, approval was obtained from the Ethics Committee of Chutoen Medical Center (approval no. 151). We used the Naranjo adverse drug reaction probability scale to determine the probability that the CNS symptoms represented an adverse reaction to amantadine treatment (15).
JADER data and survey content. We obtained data from the JADER database on the PMDA website (16). The database consists of four files, “Demo”, “DRUG”, “REAC”, and “HIST”: The “Demo” file contains patient information, such as age, sex, and reporting year; the “DRUG” file contains the drug name, route of administration, start and end dates of administration, and dosage; the “REAC” file contains adverse events, outcomes, and onset dates; and the “HIST” file contains information on the patient’s medical history.
In JADER, adverse events are defined according to the Medical Dictionary for Regulatory Activities (MedDRA). In this study, we extracted adverse events by using the preferred terms in MedDRA ver. 26.1. We downloaded data from April 2004 to September 2023 and excluded patients with unknown age and sex from the analysis. In the “DRUG” file, drug involvement in adverse events is categorized as “suspected”, “concomitant”, or “interacting”, and in the present study, we analyzed only “suspected” drug involvement. We extracted adverse events due to amantadine reported in 10 or more cases and analyzed the CNS adverse events.
JADER-based analysis of disproportionality and outcomes of CNS adverse reactions to amantadine. The PMDA and the Netherlands Pharmacovigilance Center use the reporting odds ratio (ROR) to detect signals of adverse events in spontaneous reporting systems and the ROR and 95% confidence interval (95%CI) to express the disproportionality in adverse event reporting between groups (17). ROR is a concept similar to the odds ratio in case-control studies and corresponds to the odds of exposure in reported cases over the odds of exposure in reported non-cases. We calculated the ROR and 95%CI for CNS adverse reactions in patients receiving amantadine; the signal of adverse reactions was considered to be positive when the lower limit of the 95%CI was greater than 1. We also studied the clinical outcomes of CNS adverse reactions and defined them as “good” in case of recovery and improvement and “bad” in case of non-recovery, sequelae, and death.
JADER-based analysis of time to onset of CNS symptoms. When analyzing the time to onset of symptoms in the JADER data, we excluded cases with an unknown start date of amantadine or unknown date of adverse event onset. The time to onset of CNS adverse events was defined as the onset date of the adverse event minus the amantadine start date plus 1. Cases were excluded if the time to onset of the adverse event exceeded 1,095 days (i.e., 3 years).
Additionally, we evaluated the time to onset with the Weibull distribution in that we used the shape of the Weibull distribution, i.e., the Weibull shape parameter (WSP), to evaluate the pattern of adverse event onset. The WSP expresses the distribution of failure rates with respect to time, where failure rates correspond to the onset of adverse reactions. WSP α indicates the distribution, and a larger WSP α value indicates a wider distribution. WSP β indicates the hazard in the absence of a reference population: If WSP β is equal to 1, the occurrence of adverse events is considered to remain constant over time; if WSP β exceeds 1 and its 95%CI does not include 1, the frequency of adverse events is assumed to increase over time; and if WSP β is less than 1 and its 95%CI does not include 1, the frequency of adverse events is assumed to decrease over time.
Statistical analyses. All statistical analyses were performed with JMP pro 17.2 (SAS Institute Inc., Cary, NC, USA).
Results
Case presentation. The patient was a 63-year-old woman who had received continuous treatment for Parkinson’s disease for five years. She was admitted for aspiration pneumonia and started on intravenous ampicillin-sulbactam. At the time of admission, she was being treated for Parkinson’s disease with 500/125 mg/day of levodopa/benserazide, 16 mg/day of ropinirole, and 25 mg/day of opicapone. Her height was 154 cm; weight, 36.7 kg; blood urea nitrogen, 31.5 mg/dl; serum creatinine, 0.70 mg/dl; and estimated glomerular filtration rate, 64.6 ml/min/1.73 m2. On admission day 2, amantadine was started at a dose of 200 mg/day. Dyskinesia appeared on day 28, and depressed level of consciousness on day 92. On day 95, the amantadine dose was reduced from 200 mg/day to 100 mg/day, and on day 98, the dyskinesia and level of consciousness started to improve. On day 104, amantadine was discontinued.
The amantadine blood level on day 97 was 4,042 ng/ml, and the Naranjo scale score was 6 (Table I), suggesting a probable causal relationship between the CNS symptoms and amantadine treatment.
Naranjo adverse drug reaction probability scale score in a 63-year-old woman with adverse events during amantadine treatment.
JADER-based analysis of disproportionality and outcomes of CNS adverse reactions to amantadine. In the period from April 2004 to September 2023, JADER contained a total of 85,7168 cases. When cases of unknown age or sex were excluded, 757,332 cases remained. Of these, 974 were cases of suspected adverse reactions to amantadine and were included in the analysis. Characteristics of patients with adverse reactions to amantadine are shown in Table II. Two thirds of the patients were older than 70 years, and adverse reactions were most frequently reported in patients aged 70 to 79 years. Parkinson’s disease was the most common indication, accounting for one-third of the cases.
Characteristics of patients treated with amantadine and included in the Japanese Adverse Drug Event Report database.
Table III shows the adverse reactions that occurred in 10 or more patients. Among these adverse reactions, we calculated the ROR and 95%CI for CNS adverse reactions (Table IV). The most frequently reported CNS adverse event was hallucination, with a ROR (95% CI) of 64.28 (52.67-78.46). Positive signals were detected for all CNS adverse reactions, including hallucinations. For all CNS adverse reactions, the clinical outcomes were poor in a comparatively low percentage of cases (Figure 1).
Adverse events related to amantadine listed in the Japanese Adverse Drug Event Report database.
Reporting odds ratios of central nervous system adverse reactions to amantadine.
Outcomes of central nervous system adverse reactions to amantadine.
JADER-based analysis of time to onset of CNS adverse reactions. Table V shows the time to onset and WSP of CNS adverse reactions, and Figure 2 shows a box plot of CNS adverse reactions. The median time to the onset of delusions and restlessness was greater than 150 days, whereas the median time to the onset of other CNS adverse reactions was approximately 30 days or shorter. The onset pattern was random failure type for dyskinesia, delusions, restlessness, and confusion and early failure type for the other CNS adverse reactions.
Median and Weibull distribution of central nervous system adverse reactions to amantadine.
Box plot of central nervous system adverse reactions during treatment with amantadine.
Discussion
In this study, we reported on a patient with Parkinson’s disease who was started on amantadine after hospitalization and had CNS adverse reactions, i.e., dyskinesia and depressed level of consciousness, because of amantadine intoxication. We also analyzed the risk, clinical outcomes, and time to onset of CNS adverse reactions to amantadine by using pharmacovigilance data from Japan.
The therapeutic blood level range for amantadine is reported to be 100 to 2,000 ng/ml (18), although older adults are reported to have a higher incidence of CNS symptoms at a blood level range of 1,000 to 2,000 ng/ml (19, 20). CNS adverse reactions are likely to occur at blood levels of 3,000 ng/ml or higher (4, 6, 7, 9, 10). In our case, the amantadine blood level was also at a toxic level (4,042 ng/ml), and the CNS symptoms resolved with dose reduction and discontinuation of amantadine. These results correspond to a score of 6 on the Naranjo scale, indicating that CNS symptoms are probable adverse reactions of amantadine treatment. The JADER analysis showed that the clinical outcome of CNS adverse reactions is relatively good.
In the case presented here, time to onset of adverse reactions was 26 days for dyskinesia and 90 days for depressed level of consciousness. Several reports of amantadine intoxication have been published, but the time to onset of CNS reactions differed between reports, with some reporting a relatively early onset (6-10) and others a later onset (2-5).
In our analysis of pharmacovigilance data, the median time to onset of delusions and restlessness was approximately 6 and 16 months, respectively, whereas the median time to onset of other CNS adverse reactions was approximately one month or less. In the Weibull distribution analysis, dyskinesia, delusions, restlessness, and confusional state were considered as random failures, whereas other CNS adverse reactions were considered as early-onset types. The analysis may have found that these CNS adverse reactions were random failures because of the small number of cases with these reaction types.
Our results suggest that most amantadine-related CNS adverse reactions occur within one month and decrease over time. However, the finding that dyskinesia, delusion, restlessness, and confusional state are random failures suggests that health care providers may need to remain vigilant regarding the occurrence of adverse reactions even in patients undergoing long-term treatment with amantadine. This topic warrants further study.
In the JADER database analysis, more than 65% of patients were aged 70 years older. Amantadine is mainly excreted by the kidneys, thus its dosage should be reduced in patients with impaired renal function (21). Older patients may be more susceptible to adverse reactions than younger ones because they more often have impaired renal function. In the patient treated at our hospital, creatinine clearance was 47.7 ml/min, as calculated by the Cockcroft-Gault formula (22), and renal function was impaired, suggesting that the amantadine dose should have been reduced to 100 mg/day. However, the metabolism of amantadine is not yet fully understood because 5% to 15% of oral doses are acetylated and the acetylator phenotype may influence toxicity (23). Furthermore, CNS adverse reactions due to amantadine have been reported also in patients with normal renal function (11). Therefore, health care providers must be aware that CNS adverse reactions can occur regardless of age or renal function. Continuous use of amantadine may cause acute kidney injury, resulting in increased blood levels of amantadine and CNS symptoms (4, 5). Such amantadine-induced acute kidney injury may also be related to the time to onset and random failure found in the Weibull distribution in this study.
In the United States and other countries, amantadine extended-release capsules are used to treat the adverse effects of levodopa-induced dyskinesia (24). Although one review suggested that patients who take amantadine are not at risk of developing dyskinesia as an adverse reaction (25), our analysis of pharmacovigilance data on amantadine detected a positive signal for dyskinesia, indicating that it may occur as an adverse event associated with amantadine.
Study limitations. First, we used the JADER database, a spontaneous report database, to analyze RORs, clinical outcomes, and time to onset. Therefore, as in other studies that used a similar approach, we were unable to calculate the incidence of adverse events and inaccuracies in the registration data (13). Second, we did not investigate the influence of concomitant medications. The basic drugs used for Parkinson’s disease, such as pergolide and ropinirole, may cause hallucinations and dyskinesia (26). Although this study analyzed reports in which the involvement of amantadine was categorized as “suspected”, it is possible that the CNS adverse reactions may have been caused by concomitant medications. To address these issues, prospective clinical trials or case-control studies with more refined study designs are needed.
Conclusion
This study suggests that most CNS adverse reactions with amantadine occur early after administration of treatment and within approximately one month and that outcomes are comparatively good. Health care providers should be particularly careful about the development of CNS adverse reactions for approximately one month after patients start amantadine treatment.
Acknowledgements
The Authors are grateful to Professor Masahiro Nagai at the Department of Clinical Pharmacology and Therapeutics, Ehime University Graduate School of Medicine, Ehime, Japan, and his staff for measuring the blood concentration of amantadine.
Footnotes
Authors’ Contributions
NI and MY designed the study. NI wrote the manuscript. NI and YH analyzed the data. MY, AS, MO, KA, and SM acquired the patient data. All Authors read and approved the final manuscript.
Conflicts of Interest
The Authors have no conflicts of interest to disclose in relation to this study.
Funding
The Authors declare that no funds, grants, or other support were received for this study.
- Received April 19, 2024.
- Revision received May 18, 2024.
- Accepted May 20, 2024.
- Copyright © 2024 The Author(s). Published by the International Institute of Anticancer Research.
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).
