FDA Approves Nuedexta to treat Pseudobulbar Affect (PBA)

On October 29, 2010, Avanir Pharmaceuticals, Inc. announced the approval of Nuedexta™ by the Food and Drug Administration (FDA) for the treatment of pseudobulbar affect (PBA) associated with certain neurological conditions, including multiple sclerosis (MS). PBA is characterized by uncontrolled, inappropriate, and/or exaggerated episodes of crying, laughing, or other emotional display. PBA occurs involuntarily with little or no stimulation to invoke such a response. It can greatly impact social situations and overall quality of life, both for the patient and his or her family.

Part I:

Introduction and Overview

Main Points:

• The FDA has approved Nuedexta for the treatment of pseudobulbar affect (PBA)
• PBA is characterized by uncontrolled, inappropriate, and/or exaggerated episodes of crying, laughing, or other emotional display
• Nuedexta is an oral drug in capsule form taken twice daily; it will be available by prescription in February 2011
• In studies with Nuedexta, episodes of excessive crying and laughing were significantly reduced in frequency and severity
• To reduce the risk of a serious side effect, patients need to discuss any heart issues as well as current medications with their physician

Nuedexta is an oral drug in capsule form and will be available by prescription in early 2011. Initially, a patient is given one capsule daily for the first seven days. Beginning on the eighth day, the medication is increased to the full dose of two capsules daily (one capsule every 12 hours). No one should take more than two capsules within a 24-hour period, and if a dose is missed, it will need to be skipped, as two doses should never be taken at the same time.

In studies with Nuedexta, episodes of excessive crying and laughing were significantly reduced in the treated group as compared to placebo, both in terms of frequency and severity. According to Avanir, the response to this drug is readily observable within a short time – often within the first week. In the most recent clinical trial (the STAR trial), about half of the patients with PBA experienced a complete remission of this symptom by the end of the study while taking Nuedexta. Scores on a scale measuring emotional lability (the Center for Neurologic Studies Lability Scale [CNS-LS]) were also significantly decreased. The approval of Nuedexta comes after 10 years of research and development.

MSAA Chief Medical Officer Dr. Jack Burks explains, "MS patients with PBA are often misdiagnosed, misunderstood, and embarrassed. Milder cases of PBA are frequently overlooked, even if these symptoms create social isolation. Patients who respond to Nuedexta can experience a new ‘lease on life,’ with the opportunity to enjoy activities that may have been impossible for them in the past. Although most patients tolerated the drug well, individuals need to discuss potential adverse events with their doctor before starting treatment with Nuedexta."

Nuedexta (formerly referred to as "Neurodex" and "Zenvia" while in studies) is the first and only FDA-approved treatment for PBA at this time. This medication is a combination of dextromethorphan hydrobromide, which is the ingredient that acts on the central nervous system (CNS), and quinidine sulfate, which is a metabolic inhibitor that controls the concentrations of dextromethorphan within the brain. This allows dextromethorphan to breakdown slowly and to provide higher active drug levels than if it was administered alone. Nuedexta acts on sigma-1 and NMDA receptors in the brain, although its therapeutic mechanism of action is not known.

The most common adverse events experienced with Nuedexta include diarrhea, dizziness, cough, vomiting, weakness, swelling of the feet and ankles, urinary tract infection, flu, elevated liver enzymes, and flatulence. Since dizziness may occur, care partners need to be especially careful to minimize the patient’s risk of falling.

Serious side effects include possible changes in heart rhythm, and the drug may be contraindicated for individuals with a history of certain heart conditions. The makers of Nuedexta note that this drug can interact with other medications, causing significant changes in blood levels of those medications and/or Nuedexta. Patients will need to discuss any heart issues as well as current medications with their physician.

Part II:

The Effects of PBA, Study Design and Participation, Study Results, and Safety Information

The Effects of PBA

As noted earlier, PBA is characterized by uncontrolled, inappropriate, and/or exaggerated episodes of crying, laughing, or other emotional display. It occurs involuntarily with little or no stimulation to invoke such a response. Other names for PBA include involuntary emotional expression disorder (IEED), emotional lability, emotional incontinence, and pathological laughing and crying.

PBA has been associated with various types of neurologic diseases and injuries, including MS, amyotrophic lateral sclerosis (ALS), stroke, and traumatic brain injury (TBI). These types of emotional episodes are thought to occur in 10 to 20 percent of individuals with these neurologic conditions, resulting from damage to certain nerves in the brain. Nerve impulses (or messages) traveling along injured nerves can "short circuit" and trigger these inappropriate emotional episodes. When not recognized as PBA, patients have been misdiagnosed with (and treated for) depression, bipolar disorder, generalized anxiety disorder, personality disorder, and sometimes even epilepsy.

The makers of Nuedexta have compiled a list of five key questions to serve as a self-assessment tool for individuals who may be suffering from PBA. These questions are as follows:

1. Do you have a neurologic condition such as multiple sclerosis? (Other potential conditions include ALS, stroke, and traumatic brain injury.)
2. Do you burst out crying or laughing for no apparent reason?
3. Do you cry or laugh at inappropriate times?
4. Do you have outbursts of emotion that are exaggerated or inappropriate to the situation?
5. Do you find that even when you try to control your crying or laughing, you are unable to do so?

Anyone who answers "yes" to the first question and "yes" to one or more of the other questions could be experiencing PBA. In such instances, individuals or their care partners should consider discussing such symptoms with their physician.

Family and friends need to recognize that such outbursts are not reflective of what the patient is truly feeling, but rather an uncontrolled and involuntary reaction to misdirected signals in the brain. This condition is both stressful and disruptive. Many individuals who suffer from PBA are frequently embarrassed by their outbursts, which can interfere with personal relationships and lead to social isolation. By reducing the frequency and severity of emotional episodes, one’s quality of life may be greatly improved, bringing about a return of positive social interaction and the ability to participate in more activities.

Study Design and Participation

Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) was studied for the treatment of pseudobulbar affect (PBA) in patients with either MS or ALS. To date, this is the largest and longest double-blind, randomized, placebo-controlled trial of this drug for the treatment of PBA. The 12-week study took place at 60 centers in the United States and South America between December 2007 and March 2009.

As noted, the 12-week study was randomized (participants were assigned to the different study arms randomly), double-blind (the sponsor, all patients, and all investigators did not know who was given the active drug [at either dose] and who was given placebo [the inactive treatment]). The study was also placebo-controlled, meaning that individuals in treated groups were compared to individuals taking an identical, but inactive treatment, sometimes referred to as a "sugar pill." Three treatment arms were studied: a high-dose group (given 30mg of dextromethorphan [DM] and 10mg of quinidine [q], abbreviated as DMq-30); a low-dose group (given 20mg of dextromethorphan [DM] and 10mg of quinidine [q], abbreviated as DMq-20); and the placebo group.

Participants included both men and women; they were required to be between the ages of 18 and 80; and all were diagnosed with clinically significant PBA. Study participants were also diagnosed with ALS (within the past 30 months), or diagnosed with either clinically definite MS or probable MS. Patients with a present or previous cardiac abnormality or major psychiatric disturbance were excluded from the study. Women who could become pregnant were required to use birth control; pregnant or nursing women were excluded from participating in the study.

The study enrolled 326 participants. A total of 283 patients (or roughly 87 percent) completed the study. The drop-out rate was approximately eight percent in the high-dose group, 18 percent in the lower-dose group, and 14 percent in the placebo group.

The primary efficacy outcome was the change in the number of daily PBA episodes. Secondary outcome measures included the proportion of patients with an improvement (i.e., reduction) in PBA rate; the number of days that were episode-free; and the number of individuals who experienced a complete remission (i.e., absence) of PBA episodes during the final two weeks of the 12-week study. All of these outcomes were determined through patient diaries.

Additional outcome measures were the changes from baseline to week 12 on certain health assessments. These included: the CNS-LS (a self-assessment of PBA severity); the BDI-II (a self-assessment of the symptoms of depression); the NPI (a questionnaire to evaluate neuropsychiatric symptoms); and the SF-36 (a health-status assessment covering physical, social, emotional, and mental health).

Study Results

Overall, daily PBA episode rates were substantially reduced in all three treatment groups – including the placebo group -compared to baseline (the rates of episodes prior to the start of the study). While this finding reflects a strong placebo effect, the reductions in daily PBA episodes were significantly greater in the two treated groups versus the group given placebo.

Compared to the placebo group, the incremental reduction in the PBA episode rate was approximately 47 percent in the high-dose group (CMq-30) and 49 percent in the low-dose group. The mean change in daily episode rate at day 84 (end of week 12) was roughly four fewer episodes per day for the treated groups, and three less episodes per day for the placebo group. However, these rates varied substantially from day to day.

Versus the placebo group, the treated groups also experienced: a higher proportion of patients with an improvement from the baseline (starting) PBA rates; a significantly greater proportion of patients with episode-free days; and a significantly greater proportion of patients with a remission of PBA (experiencing no PBA episodes during the last two weeks of the study).

Improvements in CNS-LS scores (assessing PBA severity) were significantly greater in the treated groups versus the placebo group. Improvements on BDI-II (assessing symptoms of depression) were significantly greater for the high-dose group versus placebo. No difference between the groups was seen on the NPI questionnaire (evaluating neuropsychiatric symptoms). Compared to placebo, the high-dose group also showed a significant improvement on the Mental Summary score on SF-36 (assessing the status of several different health categories), and also on the Mental Summary’s sub-domains for social functioning and mental health.

Patients who completed the double-blind 12-week study were eligible to participate in a 12-week open-label extension (OLE) study, following two weeks without the drug. All patients were given the (higher) DMq-30 dose. The overall mean CNS-LS scores decreased from 13.8 at OLE baseline to 11.2 at week 12 – well below the CNS-LS threshold for PBA. (A lower score refers to less severe PBA episodes.)

Although the higher dose (DMq-30) used in the double-blind 12-week study provided some incremental advantages over the lower dose (DMq-20), the effectiveness of the drug was virtually the same for both groups in the primary analysis. Examples of these incremental advantages for the higher dose include a better and faster rate of effectiveness for individuals with more severe PBA episodes, as well as improvements on the secondary assessments for depression and mental health. However, the higher dose was associated with an increase in adverse events (i.e., an increased incidence of dizziness, nausea, and urinary tract infections versus the low-dose and placebo groups).

Since the lower dose provided virtually the same benefits in the primary analysis, and since it also had fewer adverse events, the low-dose (DMq-20) was submitted for and received FDA approval. The higher dose of Nuedexta may be considered for additional studies and possible submission for approval at a future time.

Safety Information

Dextromethorphan (DM) is either an antagonist or agonist to certain receptors in the central nervous system which appear to be involved with the symptoms of PBA. By modifying the action of these receptors, the emotional episodes seen with PBA occur less often – and in some cases, may go into remission while on treatment. However, as stated earlier, the exact mechanism of action is not known.

DM administered alone is quickly metabolized by the liver. In previous studies with some ALS patients, doses as large as 750mg per day (versus the presently approved 20mg twice daily) have been undetectable in the blood. To allow this drug to remain in the blood for a longer duration, a low-dose of quinidine (Q) – an inhibitor that helps to block the metabolism of the drug – is combined with DM.

Initial studies were conducted with 30mg of DM and 30mg of quinidine (DMQ 30/30mg) taken twice daily. To minimize the risk of side effects and adverse events, the most recent Phase III trials to treat PBA compared dose levels of DM at 30mg and 20mg. Additionally, a pharmacodynamic analysis predicted that an "ultra-low" dose of 10mg of quinidine (denoted with a lower-case "q") would achieve the same results while further reducing the risk of cardiac events.

Quinidine is used at much larger doses (1,000 to 1,600mg per day) when treating a heart arrhythmia (atrial fibrillation and flutter), to return heart function back to its normal rhythm. This drug may affect the heart’s electrical cycle, causing a "prolonged QT interval." This is the time between when the Q wave begins and the T wave ends. A prolonged QT interval increases the risk of a ventricular arrhythmia, and this change in heart rhythm can degenerate into ventricular fibrillation, which can lead to sudden death without emergency treatment.

Nuedexta may not be appropriate for individuals who have an existing prolonged QT interval, a history suggestive of torsades de pointes (a rare ventricular arrhythmia), heart failure, atrioventricular (AV) block, or certain other cardiac conditions. Anyone with such risk factors should undergo an electrocardiographic (ECG) evaluation of their QT interval prior to starting Nuedexta. If the condition does not appear to present a risk when taking Nuedexta, then another ECG evaluation should be conducted three to four hours after the first dose. Other drugs can also prolong the QT interval, so all medications should be discussed with one’s physician in advance.

Individuals considering Nuedexta may be reminded that the doses of quinidine used to treat heart rhythm problems are 1,000 to 1,600mg per day, while Nuedexta uses an "ultra-low dose" of 10mg twice daily (equaling 20mg total per day), which is 1.25 to 2 percent of the large doses mentioned. During the study, cardiovascular safety was considered satisfactory with only mild QTc prolongation ("c" after "QT" takes into account a person’s heart rate and refers to a "corrected" figure). No cardiac events occurred during the study.

The proportion of patients with PBA reporting serious adverse events were roughly the same across the three different treatment arms. Two of these events may have been treatment related: one patient experienced respiratory depression and ALS progression; the other patient experienced worsening muscle spasticity. Both were in the DMq-20 group. Seven deaths were reported – all were individuals with ALS. Of the seven fatalities, three were in the high-dose group, three were in the low-dose group, and one was in the placebo group. These deaths were determined to be caused by respiratory issues resulting from the progression of their underlying disease (ALS) and not related to the treatment for PBA.

As mentioned earlier, the most common adverse events experienced with Nuedexta include diarrhea, dizziness, cough, vomiting, weakness, swelling of the feet and ankles, urinary tract infection, flu, elevated liver enzymes, and flatulence. According to a published list of adverse events (appearing in the November 2010 issue of the Annals of Neurology ), the events that were reported most frequently in the treated groups versus placebo were dizziness, nausea, diarrhea, and urinary tract infection. Interestingly, depression was significantly more common in the placebo group. Combined with the significant improvement in the mental-health measures within the high-dose group, researchers speculate that Nuedexta could potentially have an antidepressant effect, but this would require additional studies to determine.

Anyone considering Nuedexta, or anyone who suspects that he or she (or a loved one) may suffer from PBA, should contact his or her physician. Women who could become pregnant may be advised to use birth control if taking Nuedexta, and those who are already pregnant or are nursing may be advised against the drug until their situation changes. While this study was limited to individuals with MS and ALS, individuals who have other conditions (such as Alzheimer’s disease, stroke, or traumatic brain injury) and suffer from PBA may benefit from Nuedexta. However, no controlled studies were performed with these populations, so the effectiveness of this drug for these patients is not known. The labeling allows doctors to prescribe Nuedexta for individuals with these other conditions if appropriate.

For More Information

Anyone interested in learning more about PBA may visit www.PBAinfo.org. For more information about Nuedexta, readers may visit www.nuedexta.com or call 855-4NUEDEX (855-468-3339). Once the drug is available in February 2011, Avanir will provide support services; these will include a reimbursement counseling hotline and co-pay assistance (certain restrictions may apply). Individuals may also call MSAA’s Helpline at (800) 532-7667 to speak with one of our trained Helpline consultants.

Resources for this article include "Dextromethorphan Plus Ultra Low-Dose Quinidine Reduces Pseudobulbar Affect," by EP Pioro, et al, Annals of Neurology (November 2010, Vol. 68, No.5; 693-702). Several scientific poster presentations from recent neurological conferences were also referenced.

Written by Susan Wells Courtney, MSAA Senior Writer

Reviewed by Jack Burks, MD, MSAA Chief Medical Officer