Assessment of Use of Combined Dextromethorphan and Quinidine in Patients With Dementia or Parkinson Disease After US Food and Drug Administration Approval for Pseudobulbar Affect

Key Points

Question

After US Food and Drug Administration approval for treatment of pseudobulbar affect based on clinical trials conducted in patients with multiple sclerosis and amyotrophic lateral sclerosis, what patients received combined dextromethorphan hydrobromide and quinidine sulfate?

Findings

In this population-based cohort study of 12 858 patients in 2 commercial insurance databases who filled a prescription for the medication, most had a diagnosis of dementia and/or Parkinson disease. Reported Medicare spending on dextromethorphan-quinidine increased from $3.9 million in 2011 to $200.4 million in 2016; the number of patients receiving the medication increased from 3296 to 50 402 in the same period.

Meaning

Dextromethorphan-quinidine appears to be primarily prescribed for patients with dementia and/or Parkinson disease, although its preapproval studies of efficacy were performed in patients with other diagnoses.

This population-based cohort study investigates the prescribing patterns for combined dextromethorphan hydrobromide and quinidine sulfate after regulatory approval for treatment of pseudobulbar affect in patients with dementia and/or Parkinson disease.

Abstract

Importance

In 2010, the US Food and Drug Administration (FDA) approved a combination of dextromethorphan hydrobromide and quinidine sulfate for the treatment of pseudobulbar affect after studies in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This medication, however, may be commonly prescribed in patients with dementia and/or Parkinson disease (PD).

Objective

To investigate the prescribing patterns of dextromethorphan-quinidine, including trends in associated costs.

Design, Setting, and Participants

This population-based cohort study of patients prescribed dextromethorphan-quinidine used data from 2 commercial insurance databases, Optum Clinformatics Data Mart and Truven Health MarketScan. The Medicare Part D Prescription Drug Program data set was used to evaluate numbers of prescriptions and total reported spending by the Centers for Medicare & Medicaid Services. Patients were included if they were prescribed dextromethorphan-quinidine from October 29, 2010, when the drug was approved, through March 1, 2017, for Optum and December 31, 2015, for Truven. Data were analyzed from December 1, 2017, through August 1, 2018.

Main Outcomes and Measures

The proportion of patients prescribed dextromethorphan-quinidine with a diagnosis of MS, ALS, or dementia and/or PD, as well as the number of patients with a history of heart failure (a contraindication for the drug).

Results

In the commercial health care databases, 12 858 patients filled a prescription for dextromethorphan-quinidine during the study period. Mean (SD) age was 66.0 (18.5) years, 66.7% were women, and 13.3% had a history of heart failure. Combining results from both databases, few patients had a diagnosis of MS (8.4%) or ALS (6.8%); most (57.0%) had a diagnosis of dementia and/or PD. In the Medicare Part D database, the number of patients prescribed dextromethorphan-quinidine increased 15.3-fold, from 3296 in 2011 to 50 402 in 2016. Reported spending by Centers for Medicare & Medicaid Services on this medication increased from $3.9 million in 2011 to $200.4 million in 2016.

Conclusions and Relevance

Despite approval by the FDA for pseudobulbar affect based on studies of patients with ALS or MS, dextromethorphan-quinidine appears to be primarily prescribed for patients with dementia and/or PD.

Introduction

Pivotal clinical trials conducted to earn US Food and Drug Administration (FDA) approval of an investigational drug typically enroll a highly selected patient population.^1,2,3,4,5 Stringent selection criteria are necessary to achieve internal validity of trial results, but the trade-off is a lack of external generalizability.^1,3 Extrapolating a drug’s efficacy and safety to unstudied patients is commonplace but clinically challenging, especially when the preapproval studies demonstrate limited clinical benefit or important safety concerns. A 2017 report suggests that dextromethorphan hydrobromide and quinidine sulfate (Nuedexta; Avanir Pharmaceuticals, Inc) is an example of a medication studied in a narrow patient population in preapproval trials, which was then used in a broader population after its approval.⁶

In 2010, the FDA approved dextromethorphan-quinidine for the treatment of pseudobulbar affect. The pivotal trial at the approved dose was a 12-week placebo-controlled randomized clinical trial of 326 middle-aged patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS).^7,8 Pseudobulbar affect is characterized by sudden, uncontrollable, and often inappropriate episodes of crying or laughing. Pseudobulbar affect is diagnosed clinically, sometimes with the aid of a patient-reported questionnaire.^9,10 No specific laboratory markers, imaging findings, or pathologic results are available to confirm the diagnosis. Pseudobulbar affect is diagnosed in approximately 40% of patients with ALS and approximately 10% of patients with MS.^9,10 In the main placebo-controlled preapproval clinical trial, patients randomized to dextromethorphan-quinidine had modest reductions in episodes of crying or laughing, the study’s primary end point, and higher rates of dizziness, diarrhea, and urinary tract infection.¹¹ The mean age of patients in this trial was approximately 52 years.¹¹

The pharmacologic mechanism for why dextromethorphan-quinidine was found to help patients with pseudobulbar affect remains unclear. Dextromethorphan is the active ingredient in some over-the-counter cough syrups, has widely known sedative properties, and is metabolized by the cytochrome P450 2D6 isozyme (CYP2D6). Quinidine, known for its antiarrhythmic properties, is a potent CYP2D6 inhibitor, and its role in the combination is to increase plasma concentrations of dextromethorphan.⁸ In 2010, the medication was approved with an explicit warning: “Nuedexta has not been shown to be safe or effective in other types of emotional lability that can commonly occur, for example, in Alzheimer’s disease and other dementias.”⁸

In 2015, a 10-week phase 2 trial of dextromethorphan-quinidine in 220 patients with Alzheimer disease was published¹²; it was designed and funded by Avanir Pharmaceuticals. The study found that patients randomized to dextromethorphan-quinidine had a 1- to 2-point greater reduction in agitation scores (scale range, 0 [absence of symptoms] to 12 [daily severe symptoms]) compared with patients receiving placebo.¹² Patients randomized to dextromethorphan-quinidine also had higher rates of falls, urinary tract infection, and serious adverse events. In January 2015, the prescribing information was updated to remove the statement about patients with dementia. Because dextromethorphan-quinidine was primarily studied in patients with ALS or MS to earn FDA approval, we examined the prescribing patterns of dextromethorphan-quinidine to characterize the population of patients who received the drug after approval and to determine how its actual use changed over time.

Methods

We conducted a population-based cohort study using the following 2 US commercial insurance claims databases: Optum Clinformatics Data Mart¹³ and Truven Health MarketScan.¹⁴ Both databases include patient demographics and deidentified individual-level data on the use of health care services, including pharmacy dispensing of medications.¹⁵ Collectively, Optum and Truven provide data for approximately 60 million people. Data were collected for prescriptions from October 29, 2010 (date of drug approval), until December 31, 2015 (the most recent available data for the Truven database), and March 1, 2017 (the most recent available data for the Optum database). Data use agreements for the Truven and Optum databases were in place. The institutional review board of Brigham and Women’s Hospital, Boston, Massachusetts, provided ethics approval and waived the need for informed consent.

We identified all patients who filled a prescription for dextromethorphan-quinidine. When multiple prescriptions were filled for a single patient over time, we analyzed data from the time of the first prescription (index date). We excluded patients who did not have at least 180 days of baseline enrollment before the index date. We identified diagnoses from the baseline enrollment period using codes from the International Classification of Diseases, Ninth Revision, and International Statistical Classification of Diseases and Health Related Problems, 10th Revision (eTable 1 in the Supplement).

Although some patients with Medicare Advantage insurance are included (approximately 10% of patients in the Optum and <1% in the Truven databases), commercial insurance claims databases primarily include patients younger than 65 years and therefore likely underestimate the number of patients with dementia, who are often older. We also obtained data from the publicly available Medicare Part D Prescription Drug Program data set.¹⁶ This data set, developed by the Centers for Medicare & Medicaid Services (CMS), includes information for a subset of beneficiaries who are enrolled in Medicare Part D, which represents about 70% of Medicare beneficiaries.¹⁶ The Part D database differs from commercial claims databases, which typically include limited information on drug pricing and total spending for medications.

Baseline Covariates

Baseline demographics (ie, age and sex) and diagnoses related to chronic medical conditions were identified to 365 days before the index date. We determined claims for a prescription medication to 30 days before the index date (eTable 2 in the Supplement). We used information in the Optum database to identify the specialty of the prescribing health care professional; such an identifier was not consistently available in the Truven database.

Study Outcomes

The primary outcome was the proportion of patients prescribed dextromethorphan-quinidine with diagnoses of MS, ALS, or dementia and/or PD. We included PD because it is a common cause of dementia. To identify the primary outcome diagnoses, we reviewed available data to 1000 days before or 30 days after the index date. This prolonged duration was used to limit undercounting of patients with the diagnoses. Using data from the Optum database, we assessed the days of medication supplied by the index prescription. We also identified patients with a history of heart failure, which is a contraindication for dextromethorphan-quinidine. Finally, because quinidine is known to prolong the QT interval, we assessed the number of patients with a concomitant prescription for another QT-prolonging medication, most commonly antibiotics or antipsychotics (eTable 2 in the Supplement).

We determined the estimated yearly aggregate payment for Part D claims for dextromethorphan-quinidine from 2011 (first available data) until 2016 (end of available data). The aggregated payment includes ingredient cost, dispensing fee, sales tax, and any applicable administration fees. The total drug cost was based on the amounts paid by the Part D plan, Medicare beneficiary, government subsidies, and any other third-party payers; the total cost did not include rebates or discounts from the drug’s manufacturer. Rebate amounts are usually proprietary and thus not publicly available.

Statistical Analysis

Data were analyzed from December 1, 2017, through August 1, 2018. We used descriptive statistics to characterize patient- and physician-level characteristics. Analyses were conducted using the Aetion platform,¹⁷ SAS statistical software (version 9.3; SAS Institute Inc), and R software (version 3.4.2; R Core Team, 2017).

Results

We identified 7923 individuals in the Optum database and 6633 in the Truven database who were prescribed dextromethorphan-quinidine. After excluding 1698 individuals who did not have 180 days of preceding baseline enrollment, the study cohort included 12 858 patients across the 2 databases. Mean (SD) age in the cohort was 66.0 (18.5) years; 66.7% were female and 33.3% were male.

In the Optum database, 365 patients (5.5%) had a diagnosis of ALS, 427 (6.4%) had a diagnosis of MS, and 4345 (65.3%) had a diagnosis of dementia and/or PD (Table). Similar findings were observed before the drug label update in 2015 (Figure 1). For example, in 2013 and 2014, 633 of 973 patients prescribed dextromethorphan-quinidine (65.1%) had a diagnosis of dementia and/or PD. The percentage of patients with a diagnosis of ALS or MS generally decreased over time, and the percentage of patients with dementia and/or PD generally increased over time (Figure 1).

Table. Baseline Characteristics of Patients Prescribed Dextromethorphan-Quinidine^a.

Characteristic	Study Database
	Optum (n = 6649)	Truven (n = 6209)
Date of cohort entry, No. (%)b
2010-2011	168 (2.5)	812 (13.1)
2011-2012	596 (9.0)	1150 (18.5)
2012-2013	833 (12.5)	1201 (19.3)
2013-2014	973 (14.6)	1310 (21.1)
2014-2015	1222 (18.4)	1736 (28.0)
2015-2016	1896 (28.5)	NA
2016-2017	961 (14.4)	NA
Age, mean (SD), y	69.2 (17.2)	62.7 (19.9)
Age group, No. (%)
<40 y	428 (6.4)	779 (12.5)
40-49 y	471 (7.1)	647 (10.4)
50-59 y	835 (12.6)	1182 (19.0)
60-69 y	1109 (16.7)	1113 (17.9)
≥70 y	3806 (57.2)	2488 (40.1)
Female, No. (%)	4621 (69.5)	3949 (63.6)
Presumed indication, No. (%)
Dementia and/or PD	4345 (65.3)	2978 (48.0)
ALS	365 (5.5)	514 (8.3)
MS	427 (6.4)	650 (10.5)
Unknown	1512 (22.7)	2067 (33.3)
Medical history, No. (%)
Stroke	1141 (17.2)	1408 (22.7)
Ischemic heart disease	1431 (21.5)	794 (12.8)
Hypertension	4492 (67.6)	3407 (54.9)
Heart failure	1096 (16.5)	617 (9.9)
Depression	3286 (49.4)	2684 (43.2)
Concomitant medications, No. (%)c
Dementia or PD associated	2092 (31.5)	1886 (30.4)
Antipsychotics	1868 (28.1)	1526 (24.6)
Anxiolytics or hypnotics	1219 (18.3)	722 (11.6)
Benzodiazepines	1882 (28.3)	1955 (31.5)
Antidepressants	3536 (53.2)	3494 (56.3)
QT-prolongation medication	2674 (40.2)	2254 (36.3)

Abbreviation: ALS, amyotrophic lateral sclerosis; MS, multiple sclerosis; NA, not available; PD, Parkinson disease.

^aPatients were prescribed the combination drug dextromethorphan hydrobromide and quinidine sulfate. Databases included Optum Clinformatics Data Mart and Truven Health MarketScan. Percentages have been rounded and may not total 100.

^bExact start and end dates for each study year and database are given in Figures 1 and 2.

^cIndicates in the preceding 30 days. Truven and Optum are different US insurance claims databases. Further details are given in the Methods section.

Figure 1. Changes Over Time in Main Associated Diagnoses Among Study Patients in the Optum Database.

Includes patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or dementia and/or Parkinson disease (PD) who received a prescription for dextromethorphan hydrobromide and quinidine sulfate from 2011 through 2017. The diagnoses were identified before and within 30 days after a prescription claim for the combination drug dextromethorphan-quinidine in the Optum Clinformatics Data Mart database. The exact periods represented by each year were October 29, 2010, through September 30, 2011 (2011); October 1, 2011, through September 30, 2012 (2012); October 1, 2012, through September 30, 2013 (2013); October 1, 2013, through September 30, 2014 (2014); October 1, 2014, through September 30, 2015 (2015); October 1, 2015, through September 30, 2016 (2016); and October 1, 2016, through March 1, 2017 (2017).

In the Truven database, 514 patients (8.3%) had a diagnosis of ALS, 650 (10.5%) had a diagnosis of MS, and 2978 (48.0%) had a diagnosis of dementia and/or PD (Table). Similar findings were observed before the drug label update in 2015; over time the percentage of patients with a diagnosis of ALS or MS decreased and the percentage of patients with a diagnosis of dementia and/or PD generally increased (Figure 2). When we combined results from both databases, few patients prescribed dextromethorphan-quinidine had diagnoses of MS (1077 [8.4%]) or ALS (879 [6.8%]). Most patients (7323 [57.0%]) had a diagnosis of dementia and/or PD. In addition, 1713 patients in our study (13.3%) had a diagnosis of heart failure and 4928 (38.3%) filled a prescription for a QT-prolonging medication within 30 days of receiving dextromethorphan-quinidine (Table).

Figure 2. Changes Over Time in Main Associated Diagnoses Among Study Patients in the Truven Database.

Includes patients with amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), or dementia and/or Parkinson disease (PD) who received a prescription for dextromethorphan hydrobromide and quinidine sulfate from 2011 through 2015. The diagnoses were identified before and within 30 days after a prescription claim for the combination drug dextromethorphan-quinidine in the Truven Health MarketScan database (IBM Corp). The exact periods represented by each year were October 29, 2010, through September 30, 2011 (2011); October 1, 2011, through September 30, 2012 (2012); October 1, 2012, through September 30, 2013 (2013); October 1, 2013, through September 30, 2014 (2014); and October 1, 2014, through December 31, 2015 (2015).

Using the Optum database, we identified 3864 distinct prescribers. The most common prescribers included general internists (982 [25.4%]), neurologists (880 [22.8%]), family practitioners (676 [17.5%]), psychiatrists (380 [9.8%]), geriatricians (195 [5.1%]), nurse practitioners (187 [4.8%]), and physician assistants (97 [2.5%]). The mean (SD) supply of the prescriptions was for 22.0 (16.4) days (range, 1-180 days).

Using the Medicare Part D database, the number of prescriptions for dextromethorphan-quinidine increased 51.2-fold, from 9346 in 2011 to 478 481 in 2016; the number of patients receiving these prescriptions increased 15.3-fold, from 3296 in 2011 to 50 402 in 2016. Estimated Part D spending on dextromethorphan-quinidine in the database increased from $3.9 million in 2011 to $200.4 million in 2016 (Figure 3). Of the 2015 spending, $102.2 million (74.3%) was for patients 65 years and older (2016 data for patients 65 years and older were not available).

Figure 3. Estimates on Spending and the Number of Prescriptions Among Medicare Part D Beneficiaries.

Includes patients who received a prescription for the combination drug dextromethorphan hydrobromide and quinidine sulfate from 2011 through 2016.

Discussion

In our study, fewer than 20% of patients prescribed dextromethorphan-quinidine had a diagnosis of ALS or MS. This finding was consistent across 2 national commercial claims databases; it was more pronounced in the Optum database, which has a greater proportion of patients with Medicare Advantage coverage, than in the Truven database. Despite FDA approval for treatment of pseudobulbar affect based on studies of patients with ALS or MS, our findings suggest that dextromethorphan-quinidine was primarily prescribed for patients with dementia and/or PD.

Pseudobulbar affect is a clinical diagnosis, which might partly explain why the drug was used in a broader population after approval than in the preapproval trials. Although behavioral symptoms are common in patients with dementia, the cause is often not pseudobulbar affect.^18,19 Current therapies to treat behavioral symptoms of dementia are largely ineffective, and thus clinicians may want to prescribe dextromethorphan-quinidine to see if it helps their patients, despite the dearth of trial evidence on its efficacy in this context.^18,19 Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.

The use of dextromethorphan-quinidine in broader populations than those included in the pivotal studies leading to FDA approval has some parallels with the prescribing of antipsychotics.^20,21 A population-based cohort study of 51 881 adults in Ontario, Canada, with intellectual and developmental disabilities found that 39% were prescribed an antipsychotic.²² Of these patients, only 40% had a documented major mental illness (ie, psychotic disorder, bipolar disorder, major depressive disorder). Although broader use of medications in understudied patient populations may be clinically justifiable, drugs may also have previously unrecognized adverse effects when used in broader populations.²³

Clinical trials of antipsychotics typically enrolled young to middle-aged patients with major mental illnesses, but with few medical comorbidities.²⁴ After FDA approval, these medications were prescribed to patients who were older, had a greater burden of chronic medical conditions, and often did not have a major mental illness.²⁵ Multiple studies have since demonstrated that antipsychotics increase the risk of mortality in elderly patients.^25,26 As a result, these medications now carry a boxed warning about this risk, the most prominent safety warning the FDA can issue. In the case of dextromethorphan-quinidine, we found that it is being used in a population that is approximately 15 years older than those included in the main preapproval clinical trial (mean ages, 66.0 years compared with 52.0 years). Age is one of the strongest risk factors across all drugs for adverse drug events.²⁷

Other important commonalities between past experiences with antipsychotics and prescribing of dextromethorphan-quinidine may exist. For example, for patients with intellectual and developmental disabilities, prescribing of antipsychotics was more common for patients in group homes (56.4%) compared with 39.2% not in group homes.²² Prior studies have also shown that the use of antipsychotics is more common for patients with dementia living in nursing homes than those living in their own home.²⁸ What proportion of patients in our study were institutionalized is unknown, because insurance claims data rarely include institutionalized patients. However, according to the 2017 CNN report, which used data from Quintiles and IMS Health (currently IQVIA),⁶ approximately half of all prescriptions for dextromethorphan-quinidine from 2012 to 2016 were for patients in long-term care facilities. Because patients in long-term care are generally not included in insurance claims databases, this finding may explain why we identified more patients prescribed dextromethorphan-quinidine using data from CMS compared with patients in the Optum and Truven databases. According to the report,⁶ nearly half of the CMS claims for this medication were from physicians who had received money, gifts, or meals from Avanir Pharmaceuticals or its parent company, Otsuka Pharmaceutical. Because the Optum and Truven claims databases use encrypted physician identifiers, we were unable to link these physician identifiers with the federal Open Payments database that records payments from pharmaceutical companies to physicians.

The phase 2 trial comparing dextromethorphan-quinidine with placebo for the treatment of agitation in patients with Alzheimer disease¹² used a patented sequential parallel comparison design method. This design, according to the study report, enhanced “the ability to detect a treatment signal even in the context of a robust placebo response.”^12(p1243) Although the study concluded that these “preliminary findings require confirmation in additional clinical trials with longer treatment duration,”^12(p1252) a letter to the editor noted that the proprietary study design functionally precluded replication without obtaining a license from the patent holders.²⁹

The adverse effects of dextromethorphan-quinidine, as reported in the trial in patients with Alzheimer disease,¹² also warrant attention. Two of the more common adverse effects were falls and urinary tract infection, both likely the result of the sedating effects of dextromethorphan. Other concerns include QT prolongation and a risk of precipitating heart failure.⁸ In our study, 13.3% of patients prescribed dextromethorphan-quinidine had a history of heart failure, a contraindication, and 38.3% were recently prescribed another medication known to prolong the QT interval. We were not able to calculate the risk of urinary tract infection or fall because our study lacked an active comparator.

Our study found that CMS reported spending approximately $520 million on dextromethorphan-quinidine from 2011 to 2016 (Figure 3). A recent study³⁰ comparing the cost of combination medications with the cost of their individual generic constituents found that CMS reported spending $12.30 per dose of dextromethorphan-quinidine, whereas the cost of the generic constituents was $0.69 total. Notably, to determine the cost of the generic constituents, the study³⁰ used the price of a 200-mg dose of quinidine rather than the 10-mg dose used in Nuedexta because quinidine is not available in the United States at that lower dose as an individual product. If the lower dose of quinidine was available at a similar cost, that study estimated that the potential reduction in reported spending by the Medicare drug benefit program in 2016 could have been $189 million had the generic products been prescribed instead. The same study³⁰ also found that the cost of dextromethorphan-quinidine increased by 42% from 2011 to 2016.

Limitations

Our study has several limitations. First, we were unable to contact physicians and other health care professionals and determine why dextromethorphan-quinidine was prescribed and thus inferred the reason based on patient diagnoses from the approximate time of the initial prescription. For patients without recent claims connected to ALS or MS, we were unable to determine whether the dextromethorphan-quinidine was for the treatment of agitation or whether those patients displayed signs of pseudobulbar affect, which has been reported to occur in about 18% of patients with dementia and about 7% of patients with PD.^31,32,33 The exact prevalence of pseudobulbar affect for patients with dementia or PD, however, is hard to estimate. A prior study by the manufacturer of dextromethorphan-quinidine suggests that prevalence may range from 9% to 39% for patients with dementia and from 4% to 24% for patients with PD.³⁴ One might argue that extrapolation of available data and prescription of dextromethorphan-quinidine to patients similar to those identified in our data would be reasonable; however, until January 2015, the drug’s labeling explicitly stated that the medication was not shown to be safe or effective in patients with Alzheimer disease and other dementias who do not have pseudobulbar affect.⁸ Second, some patients had a diagnosis of dementia and/or PD with ALS (1.0%) or MS (1.8%), but these percentages are small, and such dual diagnoses do not meaningfully affect our overall findings. Also, some overlap occurred between patients captured in the Truven and Optum databases, and we may have double-counted some patients. This degree of overlap is small (likely <15%) and is unlikely to change our findings.^35,36 Third, because older patients and patients living in long-term care facilities are underrepresented in commercial insurance claims databases, we may have underestimated the extent of prescribing to patients with dementia or PD. Fourth, the cost data from CMS does not include rebates or discounts; thus, the actual figures for CMS spending on dextromethorphan-quinidine are likely somewhat smaller than the published data indicate.

Conclusions

In response to findings such as ours, further attention should be paid to educating prescribers about the actual benefits and risks of this costly drug combination. In addition, the FDA could consider more closely monitoring the characteristics of the populations of patients using medication after their approval, as well as their adverse drug-related clinical outcomes. Through the Sentinel Initiative, the FDA already collects near real-time anonymized prescribing data for more than 100 million people.^37,38 The agency launched the Sentinel Initiative in 2008 with the goal of monitoring the use and safety of drugs and other medical products. Data from the Sentinel Initiative could be used to identify and quantify how medications are being prescribed following their approval. When medications are identified as being prescribed widely among patient populations that have not been studied in clinical trials, further investigation would be warranted to understand why this is occurring and to conduct studies directly assessing the safety and effectiveness of the medications in these patients.

In the case of dextromethorphan-quinidine, our findings show that this medication was quickly used after approval primarily in elderly patients with dementia and/or PD. Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used.

Supplement.

eTable 1. Covariate Definitions: Diagnosis Codes

eTable 2. Covariate Definitions: Medications Used and Indications