dextromethorphan/quinidine (Rx)

>10%

Diarrhea (13%)

1-10%

Dizziness (10%)

Cough (5%)

Vomiting (5%)

Asthenia (5%)

Peripheral edema (5%)

Increased gamma-glutamyltransferase (3%)

Flatulence (3%)

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

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.

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/)

Oral Administration

May take with or without food