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New Drugs Online Report for dextromethorphan + quinidine
Generic Name:
dextromethorphan + quinidine 
Trade Name: Nuedexta 
Synonym: AVP-923, Neurodex, Zeniva, Zenvia 
Entry Type: New formulation  
Development and Regulatory status
UK: Licence withdrawn 
EU: Licence withdrawn 
US: Launched 
UK launch Plans: Available only to registered users
Actual UK launch date:  
Feb 16: On the 15th Feb 2016 the European Commission withdrew the MA for Nuedexta in the EU. The withdrawal was at the request of the marketing authorisation holder, Jenson Pharmaceutical Services Ltd, which notified the European Commission of its decision not to market the product in the EU for commercial reasons [23]. 
20/06/2016 16:27:48
Jan 15: Avanir Pharmaceuticals acquired by Otsuka Pharmaceuticals [21]. 
08/06/2016 16:41:12
Sep 14: Launched in Czech Republic [21]. 
08/06/2016 16:40:39
Jun 13: Approved in the EU [20] 
26/06/2013 17:03:44
Apr 13: EU positive opinion for Nuedexta for treatment of pseudobulbar affect [19]. 
26/04/2013 12:20:23
Mar 13: Filed in EU October 2011. The company submitted responses addressing the EMA´s "Day-120" question, and anticipates receipt of an opinion on its MAA from the CHMP in the first quarter of 2013 [18] 
27/03/2013 14:42:51
Oct 11: EU MAA filed for Neudexta for the treatment of pseudobulbar affect, a neurologic condition which is characterised by frequent outbursts of involuntary crying or laughing [16]. 
09/05/2012 10:51:44
Jan 11: Launched in US [15]. 
03/02/2011 18:23:45
Oct 10: Approved in US for the treatment of pseudobulbar affect. It will be marketed under the trade name NUEDEXTA™[14] 
01/11/2010 11:11:59
May 10: Avanir has submitted its Complete Response to the October 2006 Approvable Letter from the FDA. Avanir expects the FDA to classify the response as a Class 2 resubmission, which would result in an expected review period of 180 days and potential approval of Zenvia in 4Q 2010 [13]. 
24/05/2010 18:02:05
FDA decision expected 2H 2010 (11). 
25/01/2010 17:13:40
Filed in US Jun 05(1). Approvable letter received from US Oct 06, a new NDA was submitted in Jan 06 (2). Positive top-line PIII results (3).  
Trial or other data
Jun 16: Open-label single arm study (n=367) found Nuedexta significantly reduced these PBA crying or laughing episodes in this patient population from an average of 12/week at baseline to two/week at the 90-day endpoint, and the treatment was well-tolerated overall [22]. 
13/06/2016 15:31:35
Jul 15: Top-line data from the PRISM II study showed that treatment with NUEDEXTA® was associated with a statistically significant reduction in symptoms of pseudobulbar affect (PBA) in pts with traumatic brain injury (TBI) or stroke. PRISM II is a nationwide, open-label, multicentre, study of 367 pts with PBA and baseline score 13 on the CNS-LS, an instrument originally validated as a measure of PBA episode frequency and severity in pts with ALS and MS. The objectives were to evaluate the safety, tolerability and effectiveness of NUEDEXTA capsules containing 20 mg dextromethorphan hydrobromide (DM) and 10 mg quinidine sulfate (Q) for these pts. Pts were treated with NUEDEXTA twice daily for 12 wks and the primary endpoint was change from baseline in PBA symptoms as measured by the CNS-LS. Additional outcomes measures included number of weekly PBA episodes (laughing and/or crying); Mini-Mental State Examination; PBA impact on quality of life; pts´ satisfaction with treatment and functional measures. Enrolment in PRISM II is now complete with 134 pts with PBA in the dementia/Alzheimer´s disease cohort, 120 pts with PBA in the TBI cohort, and 113 pts with PBA in the stroke cohort. Pts in the TBI cohort had a mean change in CNS-LS score from 20.5 to 11.9 (P<0.001 vs. baseline) and the number of PBA episodes decreased from 10 to 1 per week (P<0.001). Pts in the stroke cohort had a mean change in CNS-LS score from 20.8 to 13.1 (P<0.001 vs. baseline) and the number of PBA episodes decreased from 10 to 2 per week (P<0.001). Consistent improvement was observed in other effectiveness endpoints in both cohorts. Adverse events (AE) were reported by 43 pts; the most commonly reported ones were diarrhoea, headache and constipation [22]. 
01/07/2015 13:31:20
Apr 15: No further update 
01/04/2015 11:20:04
Apr 14: Post-hoc efficacy data from a phase III STAR trial in pseudobulbar affect released by Avanir Pharmaceuticals. New post-hoc analysis from the PIII STAR Trial comparing NUEDEXTA to placebo in the treatment of PBA showed that 19% of pts treated with NUEDEXTA achieved remission from their PBA symptoms after only one-week of treatment. This increased to approximately 50% by the end of the 12-week trial. Throughout the trial, sustained episode remission rates in patients treated with NUEDEXTA were significantly higher compared to placebo. Remission was defined as no episodes for the remainder of the study and a minimum of 14 days prior to completion or drop-out [21].  
01/04/2015 11:19:50
Sep 10: The PIII STAR trial has been e-published in the Annals of Neurology (http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1531-8249/earlyview)  
16/09/2010 18:27:32
Apr 10: Cardiac safety data from the PIII STAR trial were presented in two posters at the American Academy of Neurology Annual Meeting. 283 patients completed a 12-week double-blind phase and 253 patients entered the open-label extension. At baseline, the treatment groups had similar demographics, similar PBA severity and similar QTc interval length. At the end of the double-blind phase, mean changes in QTcB and QTcF were <5 msec in all treatment groups. No patients had QTc intervals >500 msec at day 84, and no patients had increases >60 msec in either QTcB or QTcF. No new cardiac safety signals emerged in the extension study and there were no reports of pro-arrhythmic events or cardiovascular serious adverse events [12]. 
18/04/2010 19:02:15
Dec 09: Further results from the STAR study. In Amyotrophic Lateral Scleroris (ALS) subset of pts (n=197), Zenvia (30/10mg and 20/10mg) achieved main efficacy outcome by significantly reducing pseudobulbar affect (PBA) episode rates vs. placebo (62.9% and 63.4% incremental reductions in PBA vs. placebo over study course). Reported that 90.8%, 77.9% and 85.9% of ALS patients completed the 12-week double-blind study phase in the Zenvia (30/10 mg), Zenvia (20/10 mg) and placebo groups, respectively. (10) 
11/12/2009 08:40:39
Nov 09: Company report results from the 12-week open-label extension phase of the PIII STAR. Of 283 patients who completed the double-blind phase, 253 enrolled in the extension all of whom received Zenvia 30/10 mg twice daily. Efficacy was assessed at baseline and during subsequent clinic visits using the CNS-LS score. There was a significant incremental improvement in CNS-LS scores irrespective of treatment received in the first 12 weeks, and the drug was generally safe and well tolerated with 92.9% of patients completing the extension study. There were 3 deaths in the open-label study in patients with ALS; they were attributed to respiratory failure. The company say that they will file a complete response early in 2Q 10, with an FDA approval decision expected 6 months later [9].  
10/11/2009 21:47:23
Oct 09: Detailed results from PIII STAR study reported by the company. Both the Zenvia 30/10mg and 20/10mg groups met the primary endpoint by demonstrating a significant reduction in daily PBA episode rates vs. placebo group. In addition, in the Zenvia groups there was a greater proportion of patients with complete remission of PBA episodes, a higher % of days that were episode-free, a greater proportion of patients who achieved response thresholds of 50%, 75% and 90% improvement and a greater mean reduction from baseline in CNS-LS score vs placebo. Zenvia 30/10mg demonstrated statistical superiority in time to onset of clinically meaningful effect, greater mean improvement in SF-36 Mental Health Summary scores and greater mean improvement in Beck Depression Inventory scores vs placebo. In an additional analysis of the primary endpoint pre-specified in the protocol, the % of patients who achieved and maintained complete episode remission during the last 14 days of the study was 76% in the Zenvia 30/10mg group, 80% in the 20/10mg group and 61% in the placebo group (p=0.0024 and p=0.0001) [8]. 
26/10/2009 19:19:49
Oct 09: Additional results reported from the PIII STAR trial evaluating two doses of Zenvia vs placebo in the MS patient subset (n=129). Zenvia 30/10mg reduced PBA episode rates by 11.9% over placebo (p=0.028). The lower dose Zenvia 20/10mg was not significantly different vs placebo. Zenvia 30/10mg demonstrated relief of MS-related pain in patients with moderate-to-severe pain. There was no significant difference between groups on the Center for Neurologic Studies Lability Scale (CNS-LS) [7]. 
10/10/2009 17:31:30
Oct 09: Avanir has obtained a new patent on Zenvia that will extends its commercial exclusivity period to 2025 [6]. 
07/10/2009 21:07:12
Aug 09: Company announced that the 12 week double-bline phase of the PIII STAR study met the primary endpoint (reduction in self-reported in crying/laughing episode rates): Zenvia 30/10 mg provided a 47.2% incremental reduction in episode rates vs placebo (p<0.0001). Zenvia 20/10 mg also provided a statistically significant incremental reduction of episode rates vs placebo (p<0.0001) [5].  
24/08/2009 10:21:29
Confirmatory PIII STAR trial - enrolling pts with emotional lability secondary to multiple sclerosis or amyotrophic lateral sclerosis. Double-blind phase will be followed by a three month open-label extension study. The primary efficacy endpoint will be the change in crying/laughing episodes per day (4) 
23/07/2008 12:01:07
(1) Company looking for partners for EU. PIII resulst published Neurology 2006;59(5):780-87;  
Evidence Based Evaluations
EPAR  http://www.ema.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/002560/human_med_001652.jsp&mid=WC0b01ac058001d124 
Available only to registered users
BNF Category:
Central nervous system (04)
Pharmacology: Dextromethorphan (NMDA antagonist/sigma agonist) +quinidine (CYP2D6 inhibitor)  
Epidemiology: Prevalence of pathological emotions (pseudobulbar affect) following stroke is 14.9% [7].  
Indication: Pseudobulbar affect  
Method(s) of Administration
Company Information
Name: Jenson 
US Name: Avanir 
Further Information
Anticipated commissioning route (England) CCG 
High cost drug list? Awaiting Update
Tariff Likely HRG included.
Implications Available only to registered users