Dataset Information

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.

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.

SUBMITTER: Fralick M

PROVIDER: S-EPMC6439654 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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.

Fralick Michael M Sacks Chana A CA Kesselheim Aaron S AS

JAMA internal medicine 20190201 2

<h4>Importance</h4>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).<h4>Objective</h4>To investigate the prescribing patterns of dextromethorphan-quinidine, including trends i ...[more]

PMID: 30615021

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Project description:Pseudobulbar affect (PBA) is a dysfunction of emotional expression characterized by involuntary outbursts of crying or laughing disproportionate or unrelated to mood, occurring in patients with various underlying neurologic disorders. This review describes the clinical data supporting dextromethorphan (DM) hydrobromide combined with quinidine sulfate (Q) as treatment of PBA and briefly surveys the ongoing debates concerning the terminology for dysfunction of emotional expression, as well as the ongoing searches for its brain substrates. Until recently, pharmacologic intervention consisted chiefly of off-label antidepressants. In October 2010, however, DM/Q at 20/10 mg twice daily received approval from the United States Food and Drug Administration for PBA in any setting, and in June 2013, dosages of 20/10 and 30/10 mg twice daily (labeled as 15/9 and 23/9 mg, respectively, DM/Q base) received approval from the European Medicines Agency. DM is an uncompetitive N-methyl-d-aspartate (NMDA) glutamate receptor antagonist, a sigma-1 receptor agonist, and a serotonin and norepinephrine reuptake inhibitor. To block DM hepatic metabolism, thereby increasing DM bioavailability, Quinidine, a cytochrome P450 2D6 inhibitor, is coadministered at a dosage well below those for treating cardiac arrhythmia. Three large-scale DM/Q trials have utilized PBA-episode counts and the Center for Neurologic Study-Lability Scale (CNS-LS), a validated PBA rating scale, to measure efficacy. In a 4-week study of patients with PBA in amyotrophic lateral sclerosis (ALS), DM/Q 30/30 mg was superior to its component drugs. A 12-week, double-blind, placebo-controlled study of DM/Q 30/30 mg showed similar efficacy in patients with PBA in multiple sclerosis (MS). A subsequent 12-week study of patients with PBA and ALS or MS showed superiority to placebo for the 20/10 and 30/10 mg doses. Efficacy was maintained during a 12-week, open-label extension (30/10 mg dose), with further improvement of mean CNS-LS scores. Across these studies, DM/Q was generally safe and well tolerated, with no evidence of clinically relevant cardiac or respiratory effects. DM/Q is being studied (currently unapproved) for conditions including agitation in autism and in dementia.

Project description:Phase 3 trials supporting dextromethorphan/quinidine (DM/Q) use as a treatment for pseudobulbar affect (PBA) were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). The PRISM II study provides additional DM/Q experience with PBA secondary to dementia, stroke, or traumatic brain injury (TBI).Participants in this open-label, multicenter, 90-day trial received DM/Q 20/10 mg twice daily. The primary outcome was the Center for Neurologic Study-Lability Scale (CNS-LS), assessing change in PBA episode frequency and severity. The CNS-LS final visit score was compared to baseline (primary analysis) and to the response in a previously conducted placebo-controlled trial with DM/Q in patients with ALS or MS. Secondary outcomes included change in PBA episode count and Clinical Global Impression of Change with respect to PBA as rated by a clinician (CGI-C) and by the patient or caregiver (PGI-C).The study enrolled 367 participants with PBA secondary to dementia, stroke, or TBI. Mean (standard deviation [SD]) CNS-LS score improved significantly from 20.4 (4.4) at baseline to 12.8 (5.0) at Day 90/Final Visit (change, -7.7 [6.1]; P?<?.001, 95 % CI: -8.4, -7.0). This magnitude of improvement was consistent with DM/Q improvement in the earlier phase-3, placebo-controlled trial (mean [95 % CI] change from baseline, -8.2 [-9.4, -7.0]) and numerically exceeds the improvement seen with placebo in that study (-5.7 [-6.8, -4.7]). Reduction in PBA episode count was 72.3 % at Day 90/Final Visit compared with baseline (P?<?.001). Scores on CGI-C and PGI-C showed that 76.6 and 72.4 % of participants, respectively, were "much" or "very much" improved with respect to PBA. The most frequently occurring adverse events (AEs) were diarrhea (5.4 %), headache (4.1 %), urinary tract infection (2.7 %), and dizziness (2.5 %); 9.8 % had AEs that led to discontinuation. Serious AEs were reported in 6.3 %; however, none were considered treatment related.DM/Q was shown to be an effective and well-tolerated treatment for PBA secondary to dementia, stroke, or TBI. The magnitude of PBA improvement was similar to that reported in patients with PBA secondary to ALS or MS, and the adverse event profile was consistent with the known safety profile of DM/Q.Clinicaltrials.gov, NCT01799941, registered on 25 February 2013.

Project description:BackgroundPseudobulbar affect (PBA) is associated with neurological disorders or injury affecting the brain, and characterized by frequent, uncontrollable episodes of crying and/or laughing that are exaggerated or unrelated to the patient's emotional state. Clinical trials establishing dextromethorphan and quinidine (DM/Q) as PBA treatment were conducted in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). This trial evaluated DM/Q safety in patients with PBA secondary to any neurological condition affecting the brain.ObjectiveTo evaluate the safety and tolerability of DM/Q during long-term administration to patients with PBA associated with multiple neurological conditions.MethodsFifty-two-week open-label study of DM/Q 30/30?mg twice daily. Safety measures included adverse events (AEs), laboratory tests, electrocardiograms (ECGs), vital signs, and physical examinations.Clinical trial registration#NCT00056524.ResultsA total of 553 PBA patients with >30 different neurological conditions enrolled; 296 (53.5%) completed. The most frequently reported treatment-related AEs (TRAEs) were nausea (11.8%), dizziness (10.5%), headache (9.9%), somnolence (7.2%), fatigue (7.1%), diarrhea (6.5%), and dry mouth (5.1%). TRAEs were mostly mild/moderate, generally transient, and consistent with previous controlled trials. Serious AEs (SAEs) were reported in 126 patients (22.8%), including 47 deaths, mostly due to ALS progression and respiratory failure. No SAEs were deemed related to DM/Q treatment by investigators. ECG results suggested no clinically meaningful effect of DM/Q on myocardial repolarization. Differences in AEs across neurological disease groups appeared consistent with the known morbidity of the primary neurological conditions. Study interpretation is limited by the small size of some disease groups, the lack of a specific efficacy measure and the use of a DM/Q dose higher than the eventually approved dose.ConclusionsDM/Q was generally well tolerated over this 52 week trial in patients with PBA associated with a wide range of neurological conditions.

Project description:ImportanceThe US Food and Drug Administration (FDA) grants accelerated approval according to surrogate measures of numerous drug indications for serious or life-threatening illnesses such as infectious diseases and cancer. Investigators, including the FDA, have evaluated the program's regulatory and clinical consequences in oncology, but evaluation of nononcology drugs is lacking.ObjectiveTo evaluate the accelerated approval program for nononcology drug indications over a period of 26 years.Design, setting, and participantsThis retrospective cohort study used publicly available data on FDA nononcology drug indications granted accelerated approval from June 1992 through May 2018, with preapproval and confirmatory trials for approved drugs. Data were analyzed from February to April 2022.Main outcomes and measuresThe study estimated the median time from accelerated approval to occurrence of regulatory outcomes such as regular approval conversion, postapproval boxed warning label changes, confirmatory trial completion, and confirmatory trial results publication.ResultsThe FDA granted accelerated approval of 48 drugs for 57 nononcology indications, including 23 (40%) HIV treatments, supported by 93 preapproval trials. Forty-three indications (75%) were converted to regular approval at a median time of 53.1 (95% CI, 38.7 to 70.2) months from accelerated approval. There were postapproval label modifications on boxed warnings in 27 indications (47%) with a median time of 248.6 (95% CI, 51.8 to not estimable) months from accelerated approval. Of the 86 required confirmatory trials, 17 (20%) had not fulfilled the postapproval requirements. The median time to confirmatory trial completion was 39.4 (95% CI, 30.7 to 47.9) months. Nine trials (10%) failed to verify clinical efficacy, but only 1 of 8 indications assessed (2%) was withdrawn owing to the failed confirmatory trial, which was 136 months after approval. Results were published in 56 completed confirmatory trials (65%), with the median time being 52.5 (95% CI, 35.6 to 82.2) months from accelerated approval to publication.Conclusions and relevanceAlthough the program expedited the approval of nononcology drug indications by a median (IQR) of 53.1 (26.8-133.2) months, safety-related label modifications were often added in boxed warnings after approval, and clinical efficacy was sometimes not confirmed. The study findings and long follow-up period suggest that comprehensive evaluation of such drugs may take more than a decade.

Project description:ImportanceNumerous cancer drugs have received accelerated approval from the US Food and Drug Administration (FDA) based on clinical trial outcomes that are otherwise not acceptable for traditional FDA approval; the accelerated approval process allows outcomes based on surrogate measures that are only reasonably likely to estimate clinical benefits. In England, the National Institute for Health and Care Excellence (NICE) evaluates the clinical benefits and cost-effectiveness of drugs after they have received regulatory approval and issues recommendations regarding their coverage in the National Health Service (NHS). However, the level of concordance between European and FDA decision-making in the context of drugs qualifying for FDA accelerated approval is unknown.ObjectiveTo compare FDA accelerated approval decisions for cancer drugs with NICE coverage decisions.Design, setting, and participantsThis retrospective cohort study compared cancer drug indications that received FDA accelerated approval from December 11, 1992, to May 31, 2017, with the same set of drug indication pairs in England until August 31, 2019. Data from European Public Assessment Reports developed by the European Medicines Agency (EMA) and public appraisal documents from NICE were used to determine NHS coverage recommendations. National Institute for Health and Care Excellence (NICE) public appraisal documents were analyzed for drug indications, characteristics of clinical evidence, cost-effectiveness, and coverage decisions. Data were analyzed from September 1 to December 31, 2019.Main outcomes and measuresCancer drug indication coverage decision by NICE.ResultsFrom 1992 to 2017, 93 cancer drug indications received FDA accelerated approval, 6 of which were subsequently withdrawn, leaving 87 cancer drug indications on the market. As of August 2019, 5 of these indications had been withdrawn or denied market authorization for the European Union by the EMA. From the cohort of EMA-approved drugs, an additional 7 drug indications were not recommended by NICE and were not deemed to have sufficient clinical benefits or cost-effectiveness to warrant mandatory public coverage in England; 5 drugs were not recommended based on clinical benefit and cost-effectiveness criteria, and 2 drugs were not recommended based on cost-effectiveness criteria alone. In total, 12 drug indications were not recommended for public coverage in the NHS, and an additional 30 drug indications were not reviewed by either the EMA (14 drug indications) or NICE (16 drug indications) by the study end date. Most drug indications recommended by NICE were conditional on the negotiation of additional confidential discounts, the imposition of restricted indications that limited prescribing to specific patient subgroups, or the collection of additional data. Among the 9 drug indications with evidence of overall survival benefit at the time of NICE review, 2 were not recommended for public funding based on cost-effectiveness criteria.Conclusions and relevanceIn this cohort study, 30 cancer drug indications that were granted accelerated approval by the FDA were not subsequently reviewed by either European regulators or NICE, and 12 drugs were denied authorization or coverage owing to insufficient safety, clinical efficacy, or cost-effectiveness. National Health Service coverage of cancer drugs given FDA accelerated approval commonly required additional price concessions, restrictions to approved indications, or review of additional data.

Project description:ImportanceState Medicaid programs have reported concerns about rising drug prices and spending, particularly regarding drugs entering the market through the accelerated approval program under the US Food and Drug Administration (FDA). The accelerated approval program enables the FDA to approve drugs on the basis of unverified surrogate end points, meaning that clinical benefits for these products are uncertain at the time of approval. However, state Medicaid programs are legally required to cover these drugs. Little is known about the set of products with accelerated approval over time, their use among Medicaid beneficiaries, or the magnitude of their financial influence on state Medicaid programs.ObjectiveTo identify the number and class of drugs approved through the FDA's accelerated approval pathway and analyze state Medicaid programs' use and spending on these drugs from 2015 through 2019.Design setting and participantsIn this cross-sectional study, biannual FDA reports were used to identify products granted accelerated approval and their associated indications approved between December 1992 and December 2020. State Medicaid Drug Utilization Data files available for 1992 through 2019 were used to estimate national totals for spending and use of outpatient drugs.Main outcomes and measuresNational Medicaid use and gross and net spending on drugs with accelerated approval from 2015 through 2019.ResultsSince the inception of the FDA's accelerated approval pathway in 1992 through 2020, 216 product-indication pairs granted accelerated approval were identified, comprising 149 unique products. The composition of drugs approved through the pathway has changed over time, with 28 of 30 (93.3%) product-indication pairs receiving accelerated approval in 2020 being indicated for cancer. Relative to all outpatient prescription drugs paid for by Medicaid, products with accelerated approval ranged from 0.2% to 0.4% of use (1.3-2.4 million prescriptions annually). Despite their infrequent use, drugs with accelerated approval represented a minimum annual net spending on all drugs covered by Medicaid of 6.4% ($2.2 billion of $34.6 billion) in 2015 and a maximum of 9.1% ($2.5 billion of $27.6 billion) in 2018. Estimated annual gross spending on drugs with accelerated approval ranged from $4.2 billion to $4.9 billion over 2015 through 2019, and estimated net spending from $2.2 billion to $2.6 billion.Conclusions and relevanceIn this cross-sectional study of 216 drugs granted accelerated approval, state spending on drugs approved through the FDA's growing accelerated approval program represented an outsized amount of spending relative to use. Because drugs with accelerated approval have come to market on the basis of trials using surrogate end points, considerable amounts of this spending may have been attributable to products with unproven clinical benefits.

Dataset Information

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.

Importance

Objective

Design, setting, and participants

Main outcomes and measures

Results

Conclusions and relevance

Publications

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.

Similar Datasets

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