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Study Raises Questions on Nuedexta Prescribing

Dextromethorphan-quinidine (Nuedexta), approved by the FDA for pseudobulbar affect based on studies in patients with amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS), appeared to be prescribed primarily for patients with other underlying disorders, an analysis of insurance records found.

Few patients who received the drug had a diagnosis of MS (8.4%) or ALS (6.8%); most (57%) had a diagnosis of dementia or Parkinson’s disease, reported Aaron Kesselheim, MD, JD, MPH, of Brigham and Women’s Hospital in Boston, and co-authors in JAMA Internal Medicine.

“Our study identified that this medication is primarily prescribed to patients with dementia or Parkinson’s disease. This is concerning, since very few studies have evaluated the effectiveness or safety in this patient population,” said lead author Michael Fralick, MD, of the University of Toronto.

It is important physicians realize this medication was studied primarily in patients with ALS and MS, Fralick told MedPage Today: “There are very little data to support its use in patients who do not have either condition. The medication is associated with significant side effects including falls, urinary tract infection, and confusion.”

In 2010, the FDA approved the combination of dextromethorphan hydrobromide and quinidine sulfate to treat pseudobulbar affect — a condition marked by sudden, uncontrollable laughing or crying — based on studies of patients with ALS or MS. The drug’s pivotal trial was a 12-week study of 326 ALS and MS patients who were an average age of about 52.

Prescribing the drug for PBA associated with other conditions is not technically off-label, however, since the approval does not restrict the indications solely to MS/ALS patients.

After FDA approval, drugmaker Avanir Pharmaceuticals rolled out extensive ad campaigns, including television commercials featuring actor Danny Glover to generate awareness of pseudobulbar affect and subsequent ads calling on consumers to ask their doctor about possible treatment.

Pseudobulbar affect is diagnosed clinically, sometimes with the aid of a patient-reported questionnaire. Last June, CNN reported that Medicare asked insurance companies to monitor suspicious prescribing of dextromethorphan-quinidine after concerns that the drug was being marketed aggressively for dementia patients.

“Real pseudobulbar affect is rare,” said Adriane Fugh-Berman, MD, director of the Georgetown University Medical Center-based PharmedOut project, who was not involved with the study. “Financially, it makes sense that a company might try to expand the diagnosis to include populations for whom treatment is inappropriate, but such promotion is unethical,” she told MedPage Today.

Dextromethorphan, found in many cough syrups, is the active ingredient in the drug, noted Fugh-Berman. “Quinidine was added to prolong the effect. Unfortunately, quinidine, an anti-arrhythmic and anti-malarial drug, can also cause cardiac arrhythmias and other problems.”

In 2015, a 10-week phase II trial of 220 patients with Alzheimer’s disease showed the drug reduced agitation scores by 1 to 2 points over placebo on a 0 (no symptoms) to 12 (daily severe symptoms) scale. Patients who received dextromethorphan-quinidine also experienced higher rates of falls (8.6% vs 3.9%), urinary tract infections (5.3% vs 3.9%), and serious adverse events (7.9% vs 4.7%) than placebo. In 2015, the prescribing information was updated to remove a statement saying data in dementia patients were lacking.

In the new analysis, Kesselheim and his group looked at patients prescribed dextromethorphan-quinidine in two commercial insurance databases from October 2010 through March 2017 (Optum Clinformatics Data Mart records) or December 2015 (Truven Health MarketScan database). Because commercial health insurance records include mainly patients younger than age 65, the researchers also included an analysis of Medicare Part D data from 2011 to 2016.

In the commercial health care records, 12,858 patients filled a prescription for the drug. Their mean age was 66 years and 13.3% had a history of heart failure — a contraindication for dextromethorphan-quinidine. About 38% also filled a prescription for QT-prolonging medication within 30 days.

Combining results from both databases, 8.4% of patients had a diagnosis of MS, 6.8% had a diagnosis of ALS, and 57.0% had a diagnosis of dementia and/or Parkinson’s disease. The researchers found a similar pattern before the drug label update in 2015.

In the Medicare Part D database:

  • Prescriptions for dextromethorphan-quinidine jumped 51.2-fold, from 9,346 in 2011 to 478,481 in 2016
  • The number of patients prescribed the drug rose 15.3 times, from 3,296 in 2011 to 50,402 in 2016
  • Nearly three-quarters — 74.3%, or $102.2 million — of 2015 Part D spending for the drug was for patients 65 years and older

While behavioral symptoms are common in dementia patients, the cause often is not pseudobulbar affect, noted Kesselheim and co-authors. “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,” they wrote. “Yet the absence of data showing efficacy, coupled with the demonstrated risks of falls and possible cardiac effects, calls this strategy into question.”

Critics have likened this prescribing to an “uncontrolled experiment,” according to a CNN investigation that showed dozens of cases since 2013 in which state nursing home inspectors have questioned the use of the drug.

Further studies should be required to evaluate the safety and effectiveness of this medication as it is currently being used, Kesselheim and colleagues concluded.

The analysis has several limitations, they added. Reasons why dextromethorphan-quinidine was prescribed were unknown. Older adults and patients living in long-term care facilities typically are under-represented in commercial insurance claims databases, and the researchers therefore may have underestimated the extent of prescribing to dementia or Parkinson’s disease patients.

This study was supported by the Laura and John Arnold Foundation, the Harvard Program in Therapeutic Science, the Engelberg Foundation, and the University of Toronto Clinician Scientist Training Program.

Researchers reported relationships with the FDA Office of Generic Drugs and Division of Health Communication unrelated to the topic of this study.