Dextromethorphan/quinidine
| Combination of | |
|---|---|
| Dextromethorphan | Sigma-1 receptor agonist, NMDA receptor antagonist |
| Quinidine | Antiarrhythmic agent |
| Clinical data | |
| Trade names | Nuedexta |
| Other names | AVP-786, AVP-923 |
| MedlinePlus | a611048 |
| Routes of administration | Oral |
| Legal status | |
| Legal status |
|
| Pharmacokinetic data | |
| Bioavailability | dextromethorphan 11%, quinidine 70-80%. Food has no effect on absorption. |
| Metabolism | Liver, extensive. Dextromethorphan is catalyzed by CYP2D6. Quinidine is metabolized by CYP3A4 and competitively inhibits the metabolism of dextromethorphan to increase and prolong plasma concentrations of dextromethorphan |
| Elimination half-life | dextromethorphan 13h, quinidine 7h |
| Excretion | quinidine 5-20% |
Dextromethorphan/quinidine (trade name Nuedexta) is a combination drug containing dextromethorphan and the class I antiarrhythmic agent quinidine. It is the first FDA-approved drug for the treatment of pseudobulbar affect (PBA).
Clinical studies
In a 12-week randomized, double-blind trial, amyotrophic lateral sclerosis and multiple sclerosis patients with significant PBA were given either Nuedexta 20/10 mg or placebo. In 326 randomized patients, the PBA-episode daily rate was 46.9% (p < 0.0001) lower for Nuedexta than for placebo.[1] The three deaths in each of the two drug treatment arms and the single death in the placebo arm of the study were believed to be due to the natural course of the disease.[2]
Nuedexta was approved in February 2011 and is marketed in the United States by Avanir Pharmaceuticals.
Those seemingly unrelated drugs became associated so that low-dose quinidine inhibits dextromethorphan's breakdown. The latter has shown marginal efficacy in pseudobulbar syndrome due to rapid first-pass metabolism that reduces its bioavailability.
Interactions
- Desipramine (CYP2D6 substrate)[2] levels increase 8-fold with co-administration
- Paroxetine (CYP2D6 inhibitor and substrate)[2]
- Memantine
Contraindications
- Atrioventricular (AV) block, complete, without implanted pacemaker or at high risk of complete AV block
- Concomitant use with drugs containing quinidine, quinine, or mefloquine
- Concomitant use with drugs that both prolong the QT interval and are metabolized by CYP2D6 (e.g., thioridazine, pimozide); effects on QT interval may be increased
- Concomitant use with MAOIs or use of MAOIs within 14 days; risk of serious, potentially fatal, drug interactions including serotonin syndrome
- Heart failure
- Hypersensitivity to dextromethorphan (e.g., rash, hives)
- Hypersensitivity to quinine, mefloquine, quinidine, or dextromethorphan/quinidine with a history of thrombocytopenia, hepatitis, bone marrow depression or lupus-like syndrome induced by these drugs
- QT interval, prolonged or congenital long QT syndrome or a history suggesting torsades de pointes
Adverse effects
Common risks and side effects include:[2][3][4]
- Abdominal pain
- Asthenia
- Cough
- Diarrhea (reported in 13% of patients)
- Dizziness
- Elevated gamma glutamyltransferase
- Flatulence
- Influenza
- Prolonged QT interval
- Muscle spasm
- Peripheral edema
- Urinary tract infection
- Vomiting
Other possible indications
In June 2012, drug discovery and development magazine reported that Avanir Pharmaceuticals plans to test the drug for the treatment of agitation associated with Alzheimer's disease.[5] The drug is also under investigation for the treatment of major depressive disorder.[3][6]
References
- ^ Pioro EP, Brooks BR, Cummings J, et al. (2010). "Dextromethorphan plus ultra low-dose quinidine reduces pseudobulbar affect". Ann Neurol. 68 (5): 693–702. doi:10.1002/ana.22093. PMID 20839238.
- ^ a b c d [1] Highlights of Prescribing Information. Retrieved 2014-01-07
- ^ NUEDEXTA. Avanir Pharmaceuticals. Retrieved 2013-10-28
- ^ [2] Nuedexta Official FDA information, side effects and uses. Retrieved 2014-01-07
- ^ "NNuedexta Testing New Indication". CDrug Discovery and Development Magazine. June 13, 2011.
- ^ Nguyen, Linda; Thomas, Kelan L.; Lucke-Wold, Brandon P.; Cavendish, John Z.; Crowe, Molly S.; Matsumoto, Rae R. (2016). "Dextromethorphan: An update on its utility for neurological and neuropsychiatric disorders". Pharmacology & Therapeutics. 159: 1–22. doi:10.1016/j.pharmthera.2016.01.016. ISSN 0163-7258.