The FDA has approved NuedextaÃ’ (Avanir Pharmaceuticals Inc.), a drug that curbs involuntary and uncontrolled crying and laughing episodes (known as pseudobulbar affect (PBA)) that are experienced by patients with some neurological disorders. Nuedexta is the first drug to be approved to treat patients with these symptoms.
Nuedexta is a combination product containing dextromethorphan hydrobromide (an uncompetitive NMDA receptor antagonist and sigma-1 agonist) and quinidine sulfate (a CYP450 2D6 inhibitor) indicated for the treatment of PBA. Studies to support the effectiveness of Nuedexta were performed in patients with underlying amyotrophic lateral sclerosis (ALS) or multiple sclerosis (MS). 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.
Dextromethorphan hydrobromide is the pharmacologically active ingredient of Nuedexta that acts on the central nervous system (CNS). The mechanism by which dextromethorphan exerts therapeutic effects in patients with pseudobulbar affect is unknown. The quinidine component of NUEDEXTA is not expected to contribute to the effectiveness of Nuedexta, rather it increases the systemic bioavailability (BA) of dextromethorphan; it is intended to competitively inhibit the metabolism of dextromethorphan catalyzed by CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone. Following single and repeated combination doses of dextromethorphan hydrobromide 30 mg/quinidine sulfate 10 mg, dextromethorphan hydrobromide/quinidine sulfate-treated subjects had an approximately 20-fold increase in dextromethorphan exposure compared to dextromethorphan given without quinidine.
The FDA declined to approve the drug in 2006, citing concerns over heart rhythm safety. The agency’s chief concern was whether quinidine caused QT prolongation, a change in electrical rhythm that can increase heart attack risk. The company then reformulated the drug with a lower dose of quinidine and conducted new studies and then got approval.
Quinidine is a class Ia antiarrhythmic and anti-malarial agent. Quinidine (as gluconate or sulfate) is approved by FDA for malaria and various arrhythmias such atrial fibrillation/flutter and ventricular arrhythmias. It is known to have pharmacodynamic effects such as anticholinergic, vasodilating, proarrhythmic, and negative inotropic actions, and also various drug-drug interactions because of its effect on the cytochrome P system. Therefore, it is not surprising to see the long list of adverse events (AEs) associated with quinidine — diarrhea and other GIT distress, headache, lightheadedness, fatigue, palpitations, and angina-like pain being the commonest (incidence ranging from 6% – 35%).
A 12-week, placebo-controlled study evaluated Nuedexta and the commonest AEs observed were diarrhea, dizziness, and cough (incidence ranging from 5% – 13%). It makes sense that the AEs here are less than that known with the use of quinidine since the subjects in the trial had the daily intake of only 10 mg of quinidine, whereas the dose of quinidine in malaria and arrhythmia is usually 300 mg/day or more.
The concept used in Nuedexta — using one drug (quinidine) to increase the systemic BA of another (dextromethorphan) – is not a new one. StalevoÃ’, approved by FDA for Parkinson’s disease, contains levodopa, carbidopa, and entacapone. Whereas, levodopa relieves symptoms of Parkinson’s disease, carbidopa inhibits the decarboxylation of peripheral levodopa, making more levodopa available for transport to the brain. Entacapone is a selective and reversible inhibitor of catechol-O-methyltransferase (COMT), the major metabolizing enzyme for levodopa (when levodopa is given along with carbidopa). In this way, both carbidopa and entacapone increase the systemic BA of levodopa.
UnasynÃ’ contains ampicillin sodium and sulbactam sodium. Sulbactam is not bactericidal on its own but is a beta-lactamase inhibitor (beta-lactamase is an enzyme produced by bacteria to destroy the antibiotics). Hence, the presence of sulbactam in the Unasyn formulation effectively extends the antibiotic spectrum of ampicillin to include many bacteria normally resistant to it and to other beta-lactam antibiotics.
The approval of Nuedexta has taken the approach of developing combination products (where one ingredient is used to affect the pharmacology of another ingredient) to a higher level. A drug with not a very good safety profile (quinidine) was used in a low dose to increase the BA of another drug (dextromethorphan).
This post was prepared by Camargo researcher Shouryadeep Srivastava, MMBS, PhD.