Dextromethorphan and quiNIDine (Monograph)

Brand name: Nuedexta
Drug class: Central Nervous System Agents, Miscellaneous
- N-Methyl-Aspartate (NMDA) Receptor Antagonists
Chemical name: Morphinan, 3-methoxy-17-methyl-, (9α, 13α, 14α)- hydrobromide monohydrate
Molecular formula: C₁₈H₂₅NO•HBr•H₂O(C₂₀H₂₄N₂O₂)₂•H₂SO₄•2H₂O
CAS number: 6700-34-1

Introduction

Fixed combination of dextromethorphan (a sigma-1 [σ₁] receptor agonist and N-methyl-d-aspartate [NMDA] receptor antagonist) and quinidine (a class IA antiarrhythmic agent). Quinidine, a competitive inhibitor of CYP2D6, is used in the fixed combination to increase the systemic bioavailability of dextromethorphan.

Uses for Dextromethorphan and quiNIDine

Pseudobulbar Affect (PBA)

The fixed combination of dextromethorphan hydrobromide and quinidine sulfate (dextromethorphan/quinidine; Nuedexta) is used in the treatment of PBA.

PBA occurs secondary to various otherwise unrelated neurologic conditions (e.g., amyotrophic lateral sclerosis [ALS], multiple sclerosis [MS], dementia of the Alzheimer's type [Alzheimer's disease] or other dementia, parkinsonian syndrome, stroke, traumatic brain injury) and is characterized by involuntary, sudden, uncontrollable, and frequent episodes of laughing and/or crying. PBA episodes typically occur out of proportion or incongruent to the underlying emotional state.

Studies supporting efficacy in PBA were conducted in patients with underlying ALS or MS.

Safety and efficacy in the treatment of other common types of emotional lability (e.g., those occurring in patients with Alzheimer's disease and other dementias)^{† [off-label]} not established.

Dextromethorphan and quiNIDine Dosage and Administration

Administration

Oral Administration

Administer orally without regard to food.

Dosage

Available as fixed combination containing dextromethorphan hydrobromide and quinidine sulfate (dextromethorphan/quinidine; Nuedexta); dosage expressed in terms of the salts.

Adults

Pseudobulbar Affect (PBA)

Oral

Dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg given as fixed combination once daily for first 7 days. On day 8 and thereafter, dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg twice daily (every 12 hours).

Periodically reassess need for continued treatment since spontaneous improvement of PBA occurs in some patients.

Special Populations

Hepatic Impairment

Mild or moderate hepatic impairment: Dosage adjustment not necessary.

Severe hepatic impairment: Not studied; manufacturer makes no specific recommendations for dosage adjustment. Increases in dextromethorphan and/or quinidine concentrations likely. (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild or moderate renal impairment: Dosage adjustment not necessary.

Severe renal impairment: Not studied; manufacturer makes no specific recommendations for dosage adjustment. Increases in dextromethorphan and/or quinidine concentrations likely.

Geriatric Patients

Manufacturer makes no specific recommendations for dosage adjustment. (See Geriatric Use under Cautions.)

Cautions for Dextromethorphan and quiNIDine

Contraindications

• Concomitant use with other drugs containing quinidine, quinine, or mefloquine.

• History of dextromethorphan/quinidine-, quinine-, mefloquine-, or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression, or systemic lupus erythematosus-like syndrome. (See Thrombocytopenia and Other Hypersensitivity Reactions under Cautions.)

• Known hypersensitivity to dextromethorphan (e.g., rash, urticaria).

• During or within 14 days of discontinuing MAO inhibitor therapy because of risk of serotonin syndrome. (See Serotonin Syndrome under Cautions and also see Interactions.)

• Prolonged QT interval, congenital long QT syndrome, history suggestive of torsades de pointes, or heart failure.

• Complete AV block without implanted pacemaker or patients at high risk of complete AV block.

• Concomitant use with drugs that both prolong the QT interval and are metabolized by CYP2D6 (e.g., pimozide, thioridazine). (See Cardiac Effects under Cautions and also see Interactions.)

Warnings/Precautions

Thrombocytopenia and Other Hypersensitivity Reactions

Quinidine can cause immune-mediated thrombocytopenia, which can be severe or fatal. Nonspecific symptoms (e.g., lightheadedness, chills, fever, nausea, vomiting) may precede or occur with thrombocytopenia.

If thrombocytopenia occurs, unless clearly not drug related, immediately discontinue dextromethorphan/quinidine since continued use increases the risk of fatal hemorrhage. Thrombocytopenia usually, but not always, resolves within a few days. Do not reinitiate dextromethorphan/quinidine in sensitized patients.

Do not use dextromethorphan/quinidine if immune-mediated thrombocytopenia from structurally related drugs (e.g., mefloquine, quinine) is suspected since cross-sensitivity may occur.

A systemic lupus erythematosus-like syndrome involving polyarthritis reported with quinidine; in some cases, antinuclear antibodies (ANA) are present in blood. Other possible manifestations include rash, bronchospasm, lymphadenopathy, hemolytic anemia, vasculitis, uveitis, angioedema, agranulocytosis, the sicca syndrome, myalgia, elevated skeletal muscle enzyme concentrations, and pneumonitis. (See Contraindications under Cautions.)

Hepatotoxicity

Hepatitis, including granulomatous hepatitis, reported in quinidine-treated patients. Generally occurs during the first few weeks of therapy. Fever may be a presenting symptom; thrombocytopenia or other signs of hypersensitivity also may occur.

If hepatitis occurs, discontinue dextromethorphan/quinidine. In most cases, hepatitis resolves following discontinuance of quinidine. (See Contraindications and also see Thrombocytopenia and Other Hypersensitivity Reactions under Cautions.)

Cardiac Effects

Dextromethorphan/quinidine causes dose-dependent prolongation of the corrected QT (QT_c) interval. QT-interval prolongation can cause torsades de pointes-type ventricular tachycardia, with the risk increasing as the degree of QT-interval prolongation increases.

In patients at risk for QT-interval prolongation and torsades de pointes, perform ECG evaluation of the QT interval at baseline and 3–4 hours after the first dose of dextromethorphan/quinidine. Such patients include those concomitantly receiving other drugs that prolong the QT interval, patients receiving drugs that are potent or moderate inhibitors of CYP3A4 (see Interactions), and patients with left ventricular hypertrophy or left ventricular dysfunction. Left ventricular hypertrophy and left ventricular dysfunction are more likely to be present in patients with chronic hypertension, known CAD, or history of stroke.

If risk factors for cardiac arrhythmia change during treatment, reevaluate ECG. Risk factors for arrhythmia include concomitant use of drugs associated with QT-interval prolongation, electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia), bradycardia, and family history of QT-interval abnormalities.

Correct hypokalemia and hypomagnesemia before initiating dextromethorphan/quinidine, and monitor potassium and magnesium concentrations during treatment.

If symptoms indicating a possible cardiac arrhythmia (e.g., syncope, palpitations) occur, discontinue dextromethorphan/quinidine and further evaluate patient.

Concomitant Use of CYP2D6 Substrates

The quinidine in the fixed combination inhibits CYP2D6 in patients in whom the isoenzyme is not genetically absent or its activity otherwise pharmacologically inhibited. Because of this inhibitory effect on CYP2D6, accumulation of parent drug and/or failure of active metabolite formation may decrease the safety and/or efficacy of concomitantly used drugs that are metabolized by CYP2D6. (See Contraindications under Cautions and also see Drugs Metabolized by Hepatic Microsomal Enzymes under Interactions.)

Dizziness

May cause dizziness. Take precautions to reduce the risk of falls, especially in patients with motor impairment affecting gait or with a history of falls.

Serotonin Syndrome

Concomitant use of dextromethorphan/quinidine with SSRIs, tricyclic antidepressants (TCAs; e.g., clomipramine, imipramine), or MAO inhibitors may result in serotonin syndrome. Manifestations may include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor. (See Contraindications under Cautions and also see Interactions.)

Anticholinergic Effects of Quinidine

Quinidine may cause anticholinergic effects. Monitor patients with myasthenia gravis or other conditions that may be affected adversely by anticholinergic effects for possible worsening of their clinical condition.

Poor Metabolizers of CYP2D6

In poor metabolizers of CYP2D6 , the quinidine component of dextromethorphan/quinidine is not expected to contribute to the efficacy of the drug but still may result in adverse effects. Consider genotyping to determine metabolizer status prior to using dextromethorphan/quinidine in patients who may be at particular risk for quinidine toxicity.

Specific Populations

Pregnancy

Category C.

Effect of dextromethorphan/quinidine on labor and delivery unknown.

Lactation

Manufacturer states that it is not known whether dextromethorphan and/or quinidine is distributed into milk. Use with caution.

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age. (See Special Populations under Pharmacokinetics.)

Geriatric Use

Insufficient experience in patients ≥65 years of age to determine whether geriatric patients respond differently than younger adults. (See Special Populations under Pharmacokinetics.)

Hepatic Impairment

Not studied in patients with severe hepatic impairment. Adverse effects reported more frequently in patients with moderate hepatic impairment; consider additional monitoring for adverse reactions in such patients. (See Special Populations under Pharmacokinetics.)

Renal Impairment

Not studied in patients with severe renal impairment. (See Special Populations under Pharmacokinetics.)

Common Adverse Effects

Diarrhea, dizziness, cough, vomiting, asthenia, peripheral edema, urinary tract infection, influenza, increased serum γ-glutamyltransferase (γ-glutamyltranspeptidase, GT, GGTP) concentrations, flatulence.

Drug Interactions

Dextromethorphan is metabolized by CYP2D6. Quinidine is metabolized by CYP3A4. Quinidine inhibits CYP2D6 in patients in whom CYP2D6 is not genetically absent or its activity otherwise pharmacologically inhibited.

Dextromethorphan does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2D6, 2E1, or 3A4 in vitro. Quinidine does not inhibit CYP isoenzymes 1A2, 2A6, 2B6, 2C8, 2C9, 2C19, 2E1, or 3A4 in vitro. Neither dextromethorphan nor quinidine induces CYP1A2, CYP2B6, or CYP3A4 in vitro.

Drugs Metabolized by Hepatic Microsomal Enzymes

CYP2D6 substrates: Concomitant use of drugs that are extensively metabolized by CYP2D6 may result in altered drug effects because of accumulation of the parent drug and/or failure of active metabolite formation.

Initiate therapy with drugs that are principally metabolized by CYP2D6 and have a relatively narrow therapeutic index at a low dosage. If dextromethorphan/quinidine is initiated in a patient already receiving a drug metabolized principally by CYP2D6, consider dosage adjustment of the original drug metabolized by CYP2D6.

For prodrugs dependent on CYP2D6 for activation, consider the use of alternative drugs when clinically indicated.

Concomitant use of dextromethorphan/quinidine with drugs that both prolong the QT interval and are metabolized by CYP2D6 is contraindicated.

Drugs Affecting Hepatic Microsomal Enzymes

Moderate or potent CYP3A4 inhibitors: Because of the increased risk of QT-interval prolongation and torsades de pointes, perform ECG evaluation of the QT interval at baseline and 3–4 hours after the first dose of dextromethorphan/quinidine. (See Cardiac Effects under Cautions.)

Drugs Associated with Serotonin Syndrome

Potential pharmacologic interaction (potentially serious, sometimes fatal serotonin syndrome) with serotonergic agents. (See Serotonin Syndrome under Cautions.)

Drugs that Prolong the QT Interval

Monitor ECG at baseline and 3–4 hours after the first dose of dextromethorphan/quinidine in patients concurrently receiving other drugs that prolong the QT interval. (See Cardiac Effects under Cautions.)

Dextromethorphan/quinidine is contraindicated in patients receiving drugs that both prolong the QT interval and are metabolized by CYP2D6; effects on the QT interval may be increased in such patients.

Specific Drugs and Foods

Dextromethorphan and quiNIDine Pharmacokinetics

Absorption

Bioavailability

Quinidine, a CYP2D6 inhibitor, increases systemic bioavailability of dextromethorphan. Following single and repeated combination doses of dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg, individuals receiving dextromethorphan and quinidine had an approximately 20-fold increase in dextromethorphan exposure compared with dextromethorphan given without quinidine.

Following repeated doses of dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg and dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg (Nuedexta), peak plasma concentrations of dextromethorphan and quinidine are reached in approximately 3–4 and 1–2 hours, respectively.

Food

Food does not substantially affect dextromethorphan and quinidine exposure.

Plasma Concentrations

Following administration of dextromethorphan hydrobromide 30 mg and quinidine sulfate 10 mg twice daily in patients with PBA, mean peak plasma concentration of quinidine was within 1–3% of the concentrations required for antiarrhythmic efficacy (2–5 mcg/mL).

Distribution

Extent

Manufacturer states not known whether dextromethorphan and/or quinidine distributes into milk.

Plasma Protein Binding

Dextromethorphan: Approximately 60–70%.

Quinidine: Approximately 80–89%.

Elimination

Metabolism

Both dextromethorphan and quinidine are metabolized principally by liver enzymes.

Dextromethorphan is extensively metabolized by CYP2D6 to dextrorphan, which is rapidly glucuronidated and unable to cross the blood-brain barrier.

Quinidine is metabolized by CYP3A4 to several hydroxylated metabolites. The major metabolite, 3-hydroxyquinidine, is at least half as active as quinidine with respect to cardiac effects (e.g., QT-interval prolongation).

Elimination Route

About 20% of administered quinidine appears unchanged in the urine when urine pH is <7; when the urine is more alkaline, amount excreted unchanged in the urine decreases to as low as 5%. Renal clearance involves both glomerular filtration and active tubular secretion, moderated by pH-dependent tubular reabsorption.

Half-life

Following administration of dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg in extensive metabolizers of CYP2D6 substrates, the elimination half-lives of dextromethorphan and quinidine were approximately 13 and 7 hours, respectively.

Special Populations

Mild or moderate hepatic impairment: AUC, peak plasma concentrations, and clearance of dextromethorphan similar to those observed in healthy individuals. Little effect on quinidine pharmacokinetics.

Severe hepatic impairment. Not studied; however, increases in dextromethorphan and/or quinidine concentrations likely.

Hepatic cirrhosis: Clearance of quinidine not affected; however, volume of distribution is increased, resulting in an increased elimination half-life of the drug.

Mild or moderate renal impairment: Little difference in the pharmacokinetics of quinidine or dextromethorphan compared with healthy individuals.

Severe renal impairment: Not studied; however, increases in dextromethorphan and/or quinidine concentrations likely.

Pharmacokinetics of dextromethorphan/quinidine not systematically evaluated in individuals >65 years of age. In a population pharmacokinetic analysis of patients receiving dextromethorphan hydrobromide 30 mg and quinidine sulfate 30 mg, similar pharmacokinetics were observed in individuals <65 years of age and those ≥65 years of age.

Pharmacokinetics of dextromethorphan/quinidine not studied in pediatric patients.

No apparent gender or racial differences in the pharmacokinetics of dextromethorphan/quinidine.

Stability

Storage

Oral

Capsules

25°C (may be exposed to 15–30°C); protect from light and moisture.

Actions

• Dextromethorphan is the pharmacologically active ingredient in dextromethorphan/quinidine (Nuedexta).

• Dextromethorphan acts on the CNS as a potent σ₁ receptor agonist and a noncompetitive NMDA receptor antagonist.

• Quinidine's main pharmacologic action in the fixed combination is to competitively inhibit CYP2D6, which increases and prolongs plasma concentrations of dextromethorphan.

• Dextromethorphan also has serotonergic activity. (See Serotonin Syndrome under Cautions.)

• Dextromethorphan's mechanism of action in the treatment of PBA is unknown, but may involve σ₁-mediated inhibition of neurotransmission of glutamate, which has an excitatory effect on neurons. σ₁ Receptors are expressed principally in the brainstem and cerebellum, brain regions thought to be associated with emotional expression disorders.

Advice to Patients

• Risk of hypersensitivity reactions. Importance of advising patients to seek immediate medical attention if they experience symptoms suggestive of a hypersensitivity reaction. (See Contraindications and Thrombocytopenia and Other Hypersensitivity Reactions under Cautions.)

• Risk of cardiac effects. Importance of patients informing their clinician of any personal or family history of QT_c-interval prolongation. Importance of advising patients to immediately contact their clinician if they feel faint or lose consciousness. (See Contraindications and Cardiac Effects under Cautions.)

• Risk of dizziness. Importance of advising patients to take precautions to reduce the risk of falls, especially if they have motor impairment affecting gait or a history of falls.

• Importance of advising patients to take dextromethorphan/quinidine exactly as prescribed, with an interval of approximately 12 hours between doses and no more than 2 capsules (each containing dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg) in a 24-hour period. Importance of advising patients not to take a double dose if they miss a dose.

• Importance of advising patients to contact clinician if symptoms of PBA persist or worsen.

• Importance of women informing their clinician if they are or plan to become pregnant or plan to breast-feed.

• Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses (e.g., QT_c-interval prolongation or other cardiac disease).

• Importance of informing patients of other important precautionary information. (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

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