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Dextromethorphan Hydrobromide / Quinidine Sulfate

Pronunciation: DEX-troe-meth-OR-fan HYE-droe-BROE-mide/KWIN-i-deen SUL-fate
Class: Psychotherapeutic combination

Trade Names

Nuedexta
- Capsules, oral dextromethorphan 20 mg/quinidine 10 mg

Pharmacology

Dextromethorphan

Dextromethorphan is a sigma-1 receptor agonist and an uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. The mechanism by which dextromethorphan exerts therapeutic effects in patients with pseudobulbar affect is unknown.

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Quinidine

Increases plasma levels of dextromethorphan by competitively inhibiting CYP-450 2D6, which catalyzes a major biotransformation pathway for dextromethorphan.

Indications and Usage

For the treatment of pseudobulbar affect.

Contraindications

Prolonged QT interval; congenital long QT syndrome or a history suggestive of torsades de pointes; heart failure; concurrent use with drugs that both prolong QT interval and are metabolized by CYP2D6 (eg, thioridazine, pimozide); complete AV block without implanted pacemaker, or in patients who are at high risk of complete AV block; history of dextromethorphan/quinidine, quinine, mefloquine or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression, or lupus-like syndrome; hypersensitivity to dextromethorphan (eg, rash, hives); concurrent MAOI use or MAOI use within the preceding 14 days; concurrent use with other drugs containing quinidine, quinine, or mefloquine.

Dosage and Administration

Pseudobulbar Affect
Adults

PO 1 capsule daily for the first 7 days of therapy, then 2 capsules daily, given as 1 capsule every 12 h.

General Advice

  • Administer orally with or without food.
  • Periodically reassess the need for continued treatment because spontaneous improvement of pseudobulbar affect occurs in some patients.

Storage/Stability

Store between 59° and 86°F.

Drug Interactions

Alcohol

CNS effects may be increased. Use with caution.

CYP2D6 substrates (eg, codeine, desipramine, hydrocodone, paroxetine)

Quinidine may elevate plasma concentrations of the CYP2D6 substrate (eg, desipramine, paroxetine) and increase the risk of adverse reactions. In this instance, a lower dose of the substrate may be needed. A dosage of more than desipramine 40 mg/day or paroxetine 35 mg/day is not recommended. Monitor the clinical response of the patient. By inhibiting CYP2D6, quinidine may also reduce metabolism of a substrate (eg, codeine, hydrocodone) to its active metabolite (eg, morphine, hydromorphone [respectively]), decreasing the pharmacologic effects (eg, analgesia, antitussive). In this instance, alternative treatment may be necessary.

Digoxin

Digoxin levels may be increased. Closely monitor digoxin plasma concentrations and adjust the dose as needed.

Drugs that both prolong the QT interval and are CYP2D6 substrates (eg, pimozide, thioridazine)

The risk of QT prolongation may be increased, increasing the risk of torsades de pointes–type ventricular tachycardia. Concomitant use is contraindicated.

Drugs that prolong the QT interval, moderate CYP3A inhibitors (eg, aprepitant, diltiazem, erythromycin, fluconazole, fosamprenavir, grapefruit juice, verapamil), strong CYP3A inhibitors (eg, atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin)

The risk of QT prolongation may be increased, increasing the risk of torsades de pointes–type ventricular tachycardia. Conduct an ECG evaluation of the QT interval at baseline and 3 to 4 h after the first dose of dextromethorphan/quinidine in patients taking drugs that prolong the QT interval or are strong or moderate CYP3A inhibitors. If patients experience symptoms of cardiac arrhythmias, discontinue dextromethorphan/quinidine.

MAOIs (eg, phenelzine)

Concomitant use is contraindicated in patients taking MAOIs or who have taken MAOIs within the preceding 14 days. Allow at least 14 days after stopping dextromethorphan/quinidine before starting an MAOI.

Mefloquine, quinidine, quinine

Concomitant use is contraindicated. The risk of adverse reactions may be increased.

NMDA receptor antagonists (eg, memantine)

Both memantine and dextromethorphan are NMDA antagonists; coadministration could theoretically result in an additive effect at NMDA receptors and, potentially, an increased incidence of adverse reactions.

SSRIs (eg, fluoxetine), tricyclic antidepressants (eg, clomipramine, imipramine)

The risk of serotonin syndrome may be increased. Closely monitor the patient. Serotonin syndrome requires immediate medical attention, including withdrawal of the serotonergic agent and supportive care.

Adverse Reactions

CNS

Dizziness (10%); asthenia (5%).

GI

Diarrhea (13%); vomiting (5%); flatulence (3%).

Genitourinary

UTI (4%).

Respiratory

Cough (5%)

Miscellaneous

Peripheral edema (5%); influenza (4%); increased GGT (3%).

Precautions

Monitor

When initiating therapy in patients at risk of QT prolongation and torsades de pointes, conduct an ECG of QT interval at baseline and 3 to 4 h after the first dose. Reevaluate ECG if risk factors for arrhythmia change during the course of treatment. Correct hypokalemia and hypomagnesemia prior to initiation of therapy and monitor during treatment. Monitor for worsening clinical condition in myasthenia gravis and other conditions that may be adversely affected by anticholinergic effects. Monitor for adverse reactions in patients with mild or moderate hepatic impairment.


Pregnancy

Category C .

Lactation

Dextromethorphan

Undetermined.

Quinidine

Excreted.

Children

Safety and efficacy not established.

Renal Function

Increases in dextromethorphan and/or quinidine levels are likely to be observed in patients with severe renal impairment. Use with caution.

Hepatic Function

Increases in dextromethorphan and/or quinidine levels are likely to be observed in patients with severe hepatic impairment. Use with caution.

Cardiac effects

Can cause dose-dependent QTc prolongation.

CYP2D6 poor metabolizers

In those patients who may be at risk of significant toxicity due to quinidine, consider genotyping to determine if they are poor metabolizers prior to making the decision to treat with dextromethorphan/quinidine.

Dizziness

May occur. Take precautions to reduce the risk of falls, particularly for patients with motor impairment affecting gait or with a history of falls.

Drug abuse

Cases of dextromethorphan abuse have been reported, predominantly in adolescents. Closely observe patients with a history of drug abuse for signs of dextromethorphan/quinidine misuse or abuse.

Hepatotoxicity

Hepatitis, including granulomatous hepatitis, has been reported in patients receiving quinidine, generally during the first few weeks of therapy. Fever may be a presenting symptom, and thrombocytopenia or other signs of hypersensitivity may also occur.

Lupus-like syndrome

Quinidine has been associated with a lupus-like syndrome involving polyarthritis, sometimes with a positive antinuclear antibody test. Other associations include rash, bronchospasm, lymphadenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, the sicca syndrome, myalgia, elevation in serum levels of skeletal-muscle enzymes, and pneumonitis.

Thrombocytopenia

Quinidine can cause immune-mediated thrombocytopenia that can be severe or fatal. This drug should not be used if immune-mediated thrombocytopenia from structurally related drugs, including quinine and mefloquine, is suspected because cross-sensitivity can occur.

Overdosage

Symptoms

Dizziness, headache, mild to moderate nausea.

Dextromethorphan

Ataxia, blurred vision, changes in muscle reflexes, coma, dystonia, hyperexcitability, nausea, nystagmus, respiratory depression, seizures, serotonin syndrome, stupor, tachycardia, toxic psychosis, vomiting.

Quinidine

Blurred vision, confusion, delirium, diarrhea, diplopia, headache, high-frequency hearing loss, hypotension, photophobia, potentially fatal cardiac arrhythmia (including torsades de pointes), tinnitus, ventricular arrhythmias, vertigo, vomiting.

Patient Information

  • Advise patients that a hypersensitivity reaction to dextromethorphan/quinidine could occur and to seek medical attention immediately if they experience symptoms indicative of hypersensitivity after taking dextromethorphan/quinidine.
  • Advise patients to consult their health care provider immediately if they feel faint or lose consciousness.
  • Counsel patients to inform their health care provider if they have any personal or family history of QTc prolongation.
  • Advise patients that dextromethorphan/quinidine may cause dizziness. Precautions to reduce the risk of falls should be taken, particularly for patients with motor impairment affecting gait or a history of falls.
  • Inform patients that dextromethorphan/quinidine increases the risk of adverse drug interactions. Instruct patients to inform their health care provider about all the medications that they are taking.
  • Summarize for patients the risks of treatment with dextromethorphan/quinidine. Advise patients to tell their health care provider if they have side effects that bother them or do not go away.
  • Instruct patients to take dextromethorphan/quinidine exactly as prescribed. Instruct patients not to take more than 2 capsules in a 24-hour period and to make sure that there is an approximate 12-hour interval between doses, and not to take a double dose if they miss a dose.
  • Advise patients to contact their health care provider if their pseudobulbar affect symptoms persist or worsen.

Copyright © 2009 Wolters Kluwer Health.

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