Dosing & Uses
Dosing Forms & Strengths
dextromethorphan/quinidine
capsule
- 20mg/10mg
Pseudobulbar Affect
Indicated for PBA and symptoms associated with a variety of neurological conditions (eg, MS, ALS) that result in involuntary, sudden, and frequent episodes of laughing and/or crying
PBA occurs secondary to a variety of otherwise unrelated neurologic conditions, and is characterized by involuntary, sudden, and frequent episodes of laughing and/or crying; episodes typically occur out of proportion or incongruent to the underlying emotional state
PBA is a specific condition, distinct from other types of emotional lability that may occur in patients with neurological disease or injury
1 capsule PO qDay for 7days, THEN 1 capsule q12h
Dosage Modifications
Renal impairment
- Mild or moderate: No dose adjustment required
- Severe: Safety and effaicacy not established
Hepatic impairment
- Mild or moderate: No dosage adjustment required; increase in adverse reactions possible with moderate impairment
- Severe: Safety and efficacy not established
Amyotrophic Lateral Sclerosis (Orphan)
Orphan designation for treatment of amyotrophic lateral sclerosis (ALS)
Sponsor
- Avanir Pharmaceuticals; 30 Enterprise, Suite 400; Aliso Viejo, California 92656
Safety and efficacy not established
Dose selection for elderly should be cautious, usually starting at low end of dosing range, reflecting greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy
Interactions
Interaction Checker
No Results
Contraindicated
Serious - Use Alternative
Significant - Monitor Closely
Minor
Adverse Effects
>10%
Diarrhea (13%)
1-10%
Dizziness (10%)
Cough (5%)
Vomiting (5%)
Asthenia (5%)
Peripheral edema (5%)
Increased gamma-glutamyltransferase (3%)
Flatulence (3%)
Warnings
Contraindications
Hypersensitivity
History of quinine, mefloquine, or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression, or lupus-like syndrome
Concomitant use with drugs containing quinidine, quinine, or mefloquine
Coadministration of MAOIs or use within 14 d
Drugs that both prolong QT interval and are metabolized by CYP2D6 (eg, thioridazine, pimozide)
Complete AV block (without implanted pacemakers)
Prolonged QT interval, congenital long QT syndrome, or history of torsades de pointes or heart failure
Cautions
Quinidine can cause immune-mediated thrombocytopenia (discontinue if thrombocytopenia occurs)
Hepatotoxicity reported within first few weeks following initiation of quinidine
Monitor for QTc prolongation if concomitant use of drugs taht prolong QT interval cannot be avoided or concomitant CYP3A4 used
Quinidine may cause anticholinergic effects and exacerbate certain conditions (eg, myasthenia gravis)
Monitor ECG in patients with left ventricular hypertrophy or left ventricular dysfunction
Dextromethorphan may cause serotonergic effects; monitor for worsening in myasthenia gravis and other sensitive conditions
Use caution with CYP2D6 poor metabolizers
CYP3A4 inhibitors may increase quinidine serum levels and risk for QT prolongation
Coadministration with CYP2D6 substrates other than dextromethorphan that cause accumulation of parent drug and/or failure of metabolite formation may decrease safety and/or efficacy of concomitant CYPD6 metabolized drugs; adjust dose of CYPD6 substrate or use alternative therapy when indicated
Concomitant use of dextromethorphan with serotonergic drugs (eg, SSRIs, TCAs) may increase risk for serotonin syndrome
Quinidine may increase digoxin levels (as much as double) by inhibiting P-glycoprotein
Coadministration with alcohol or other CNS depressants may cause additive effects
May cause dizziness; use precautions to reduce falls
Pregnancy & Lactation
Pregnancy
There are no adequate data on the developmental risk associated with use in pregnant women
Animal studies
- In oral studies conducted in rats and rabbits, a combination of dextromethorphan/quinidine demonstrated developmental toxicity, including teratogenicity (rabbits) and embryolethality, when given to pregnant animals
- When administered to female rats during pregnancy and lactation, pup survival and pup weight were decreased at all doses, and developmental delay was observed in offspring at the mid and high doses
Lactation
Quinidine is excreted in human milk; unknown whether dextromethorphan is excreted in human milk
There are no data on the effects of quinidine or dextromethorphan on the breastfed infant or the effects on milk production
There are no data on effects of quinidine or dextromethorphan on breastfed infant or on milk production
Developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for therapy and any potential adverse effects on breastfed infant from therapy or from underlying maternal condition
Pregnancy Categories
A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.
B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available.Pharmacology
Mechanism of Action
The mechanism by which dextromethorphan exerts therapeutic effects in patients with pseudobulbar affect is unknown
Dextromethorphan (DM) is a sigma-1 receptor agonist and an uncompetitive NMDA receptor antagonist
Quinidine increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P4502D6, which catalyzes a major biotransformation pathway for dextromethorphan
Pharmacokinetics
Half-Life: 13 hr (dextromethorphan); 7 hr (quinidine)
Peak Plasma Time: 3-4 hr (dextromethorphan); 1-2 hr (quinidine)
Protein Bound: 60-70% ((dextromethorphan); 80-89% (quinidine)
Metabolism: dextromethorphan by CYP2D6; quinidine’s primary pharmacological action in is to competitively inhibit the metabolism of dextromethorphan catalyzed by CYP2D6 in order to increase and prolong plasma concentrations of dextromethorphan; quinidine metabolized by CYP3A4
Excretion: Urine
Pharmacogenomics
The quinidine component is intended to inhibit CYP2D6 so that higher exposure to dextromethorphan can be achieved compared to when dextromethorphan is given alone
Approximately 7-10% of Caucasians and 3-8% of African Americans lack the capacity to metabolize CYP2D6 substrates and are classified as poor metabolizers (PMs)
The quinidine component is not expected to contribute to effectiveness in PMs, but adverse events of the quinidine are still possible
In those patients who may be at risk of significant toxicity due to quinidine, genotyping to determine if they are PMs should be considered prior to making the decision to treat
Genetic testing laboratories
- Genotyping tests for CYP2D6 variants are commercially available through the following companies
- Applied Biosystems (http://www.appliedbiosystems.com/)
- GenPath Diagnostics (http://www.genpathdiagnostics.com/)
Administration
Oral Administration
May take with or without food
Images
Patient Handout
Formulary
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