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Dextromethorphan and Quinidine

Medically reviewed by Drugs.com. Last updated on Sep 5, 2020.

Pronunciation

(deks troe meth OR fan & KWIN i deen)

Index Terms

  • Dextromethorphan HBr/Quinidine
  • Dextromethorphan Hydrobromide and Quinidine Sulfate
  • Quinidine and Dextromethorphan

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Capsule, oral:

Nuedexta: Dextromethorphan hydrobromide 20 mg and quinidine sulfate 10 mg

Brand Names: U.S.

  • Nuedexta

Pharmacologic Category

  • N-Methyl-D-Aspartate (NMDA) Receptor Antagonist

Pharmacology

Dextromethorphan may relieve the symptoms of PBA by binding to sigma-1 receptors in the brain which may be involved in behavior, however the exact mechanism of action is not known. In the treatment of agitation and/or aggression in Alzheimer disease (off-label use), dextromethorphan may potentially relieve symptoms by several proposed mechanisms, including N-methyl-D-aspartase antagonism, sigma-1 receptor agonism, serotonin and norepinephrine reuptake inhibition, and nicotinic alpha-3-beta-4 receptor antagonism (Cummings 2015). However, the exact mechanism of action within this condition is not known.

Quinidine is used to block the rapid metabolism of dextromethorphan, thereby increasing serum concentrations. The dose of quinidine in this combination product provides serum concentrations 1% to 3% of those needed to treat cardiac arrhythmias.

Absorption

Bioavailability of dextromethorphan increased ~20-fold when administered with quinidine

Metabolism

Dextromethorphan: Hepatic via CYP2D6 to dextrorphan (active); Quinidine: Hepatic via CYP3A4 to 3-hydroxyquinidine (active) and other metabolites

Excretion

Urine (~20% as unchanged)

Time to Peak

Dextromethorphan: 3 to 4 hours; Quinidine: 1 to 2 hours

Half-Life Elimination

Dextromethorphan: 13 hours in extensive metabolizers; Quinidine: 7 hours in extensive metabolizers

Protein Binding

Dextromethorphan: 60% to 70%; Quinidine: 80% to 89%

Use: Labeled Indications

Pseudobulbar affect: Treatment of pseudobulbar affect (PBA)

Off Label Uses

Agitation and/or aggression in Alzheimer disease

Data from a 10-week, phase-2, randomized, double-blind controlled study suggests dextromethorphan and quinidine may be beneficial in the treatment of agitation and/or aggression in those with Alzheimer disease [Cummings 2015]. Of note, the patients in the trial were predominantly outpatients. Additional data may be necessary to further define the role of dextromethorphan and quinidine in this condition.

Contraindications

Hypersensitivity to dextromethorphan, quinidine, quinine, mefloquine, or any component of the formulation; concomitant use with quinidine or other medications containing quinidine, quinine, or mefloquine; history of quinine-, mefloquine-, or quinidine-induced thrombocytopenia, hepatitis, bone marrow depression, or lupus-like syndrome; concurrent administration with or within 2 weeks of discontinuing an MAO inhibitor; patients with prolonged QT interval, congenital QT syndrome, or history of torsade de pointes; patients with heart failure; concurrent use of drugs that prolong the QT interval and are metabolized by CYP2D6 (eg, pimozide, thioridazine); patients with complete atrioventricular (AV) block without an implanted pacemaker or patients at high risk of complete AV block

Dosing: Adult

Pseudobulbar affect: Oral: Dextromethorphan 20 mg/quinidine 10 mg once daily for 7 days, then increase to dextromethorphan 20 mg/quinidine 10 mg every 12 hours; reassess patient periodically to determine if continued use is necessary. Do not exceed dextromethorphan 40 mg/quinidine 20 mg in a 24-hour period.

Agitation/aggression in Alzheimer disease (off-label use): Oral: Dextromethorphan 20 mg/quinidine 10 mg once daily for 7 days, then increase to dextromethorphan 20 mg/quinidine 10 mg twice daily (Cummings 2015). Additional data may be necessary to further define the role of dextromethorphan and quinidine in this condition. Note: The trial further increased the dosage after 14 days to dextromethorphan 30 mg/quinidine 10 mg twice daily but that dosage form is not commercially available.

Administration

May be administered with or without food. Administer twice-daily doses every 12 hours.

Dietary Considerations

Avoid grapefruit juice.

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: If combined, administer the P-gp inhibitor simultaneously with, or after, the dose of afatinib. Monitor closely for signs and symptoms of afatinib toxicity and if the combination is not tolerated, reduce the afatinib dose by 10 mg. Consider therapy modification

Ajmaline: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Ajmaline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Ajmaline. Monitor therapy

Aliskiren: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Aliskiren. Monitor therapy

Amitriptyline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Amitriptyline. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Amitriptyline. Monitor therapy

Amoxapine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Amoxapine. Monitor therapy

Amphetamines: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Amphetamines. Management: Monitor for amphetamine toxicities (including serotonin syndrome) if used with a strong CYP2D6 inhibitor. Initiate amphetamine therapy at lower doses, monitor frequently, and adjust doses as needed. Discontinue amphetamines if serotoinin syndrome occurs. Monitor therapy

ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions are required for indications other than major depressive disorder. Dose reductions vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. See full interaction monograph for details. Consider therapy modification

ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP2D6 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg) or if a CYP2D6 PM. Max dose is 441 mg if also taking strong CYP3A4 inhibitors. Consider therapy modification

AtoMOXetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of AtoMOXetine. Management: Initiate atomoxetine at a reduced dose (patients who weigh up to 70 kg: 0.5 mg/kg/day; adults or patients who weigh 70 kg or more: 40 mg/day) in patients receiving a strong CYP2D6 inhibitor. Increase to usual target dose after 4 weeks if needed. Consider therapy modification

Benzhydrocodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Benzhydrocodone. Monitor therapy

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-gp inhibitor. Avoid concomitant use of betrixaban and P-gp inhibitors in patients with severe renal impairment (CrCL less than 30 mL/min). Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Avoid combination

Brexpiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual with strong CYP2D6 inhibitors, reduce to 25% of usual if used with both a strong CYP2D6 inhibitor and a strong or moderate CYP3A4 inhibitor; these recommendations do not apply if treating major depressive disorder Consider therapy modification

Cardiac Glycosides: Quinidine (Non-Therapeutic) may increase the serum concentration of Cardiac Glycosides. Management: Measure cardiac glycoside serum concentrations before initiating treatment with quinidine. Reduce cardiac glycoside concentrations by either reducing the dose by 30% to 50% or by modifying the dosing frequency. Consider therapy modification

Carvedilol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Chlorpheniramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Chlorpheniramine. Monitor therapy

ClomiPRAMINE: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ClomiPRAMINE. CYP2D6 Inhibitors (Strong) may increase the serum concentration of ClomiPRAMINE. Monitor therapy

CloZAPine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Monitor therapy

Cobicistat: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Codeine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Codeine. These CYP2D6 inhibitors may prevent the metabolic conversion of codeine to its active metabolite morphine. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a P-gp inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See interaction monograph for details. Consider therapy modification

CycloSPORINE (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of CycloSPORINE (Systemic). Monitor therapy

CYP2D6 Inhibitors (Moderate): May increase the serum concentration of Dextromethorphan. Monitor therapy

CYP2D6 Inhibitors (Strong): May increase the serum concentration of Dextromethorphan. Monitor therapy

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Quinidine (Non-Therapeutic). Monitor therapy

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Quinidine (Non-Therapeutic). Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

Dapoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Monitor therapy

Desipramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Desipramine. Monitor therapy

Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg, and the maximum single dose of deutetrabenazine should not exceed 18 mg, with concurrent use of a strong CYP2D6 inhibitor. Consider therapy modification

Dextromethorphan: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Dextromethorphan. Monitor therapy

Digoxin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Digoxin. Management: Measure digoxin serum concentrations before initiating treatment with these P-glycoprotein (P-gp) inhibitors. Reduce digoxin concentrations by either reducing the digoxin dose by 15% to 30% or by modifying the dosing frequency. Consider therapy modification

Disulfiram: May enhance the adverse/toxic effect of Products Containing Ethanol. Management: Do not use disulfiram with dosage forms that contain ethanol. Avoid combination

Doxepin (Systemic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Doxepin (Systemic). Monitor therapy

Doxepin (Topical): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Doxepin (Topical). Monitor therapy

DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Avoid combination

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Avoid combination

DULoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Monitor therapy

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Monitor therapy

Eliglustat: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. Consider therapy modification

Etoposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide. Monitor therapy

Etoposide Phosphate: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Etoposide Phosphate. Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Fesoterodine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Monitor therapy

Flecainide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Flecainide. Monitor therapy

FluPHENAZine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of FluPHENAZine. Monitor therapy

FluvoxaMINE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of FluvoxaMINE. Monitor therapy

Galantamine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Galantamine. Monitor therapy

Gefitinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Monitor therapy

Glecaprevir and Pibrentasvir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Glecaprevir and Pibrentasvir. Monitor therapy

Haloperidol: QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of Haloperidol. Monitor therapy

Haloperidol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Haloperidol. Monitor therapy

HYDROcodone: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of HYDROcodone. Specifically, concentrations of hydromorphone may be decreased. Monitor therapy

Iloperidone: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with a strong CYP2D6 inhibitor and monitor for increased iloperidone toxicities, including QTc interval prolongation and arrhythmias. Consider therapy modification

Imipramine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Imipramine. The concentrations of desipramine may be increased. CYP2D6 Inhibitors (Strong) may increase the serum concentration of Imipramine. Monitor therapy

Indoramin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Indoramin. Monitor therapy

Lapatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lapatinib. Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy

Lefamulin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Lefamulin. Management: Avoid concomitant use of lefamulin tablets with P-glycoprotein/ABCB1 inhibitors. If concomitant use is required, monitor for lefamulin adverse effects. Consider therapy modification

Lofepramine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Lofepramine. The active metabolite of lofepramine is desipramine. Monitor therapy

Lofexidine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Lofexidine. Monitor therapy

Lumefantrine: May increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Maprotiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Maprotiline. Monitor therapy

Mefloquine: Quinidine (Non-Therapeutic) may enhance the adverse/toxic effect of Mefloquine. Avoid combination

Memantine: NMDA Receptor Antagonists may enhance the adverse/toxic effect of Memantine. Monitor therapy

Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Avoid combination

Methotrimeprazine: Products Containing Ethanol may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, CNS depressant effects may be increased. Management: Avoid products containing alcohol in patients treated with methotrimeprazine. Avoid combination

Metoclopramide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoclopramide. Management: For gastroparesis: reduce metoclopramide dose to 5mg 4 times/day and limit to 20mg/day; nasal spray not recommended. For GERD: reduce metoclopramide dose to 5mg 4 times/day or to 10mg 3 times/day and limit to 30mg/day. Monitor for EPS when combined. Consider therapy modification

Metoprolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoprolol. Monitor therapy

Mexiletine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mexiletine. Monitor therapy

Monoamine Oxidase Inhibitors: May enhance the serotonergic effect of Dextromethorphan. This may cause serotonin syndrome. Avoid combination

Morphine (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Morphine (Systemic). Monitor therapy

Nadolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Nadolol. Monitor therapy

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Monitor therapy

Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Monitor therapy

Nortriptyline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nortriptyline. Monitor therapy

Oliceridine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Oliceridine. Monitor therapy

Olmutinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Olmutinib. Monitor therapy

Parecoxib: May increase the serum concentration of Dextromethorphan. Monitor therapy

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Peginterferon Alfa-2b: May decrease the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Peginterferon Alfa-2b may increase the serum concentration of CYP2D6 Substrates (High risk with Inhibitors). Monitor therapy

Perhexiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perhexiline. Monitor therapy

Perphenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perphenazine. Monitor therapy

Pimozide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pimozide. Avoid combination

Pitolisant: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Consider therapy modification

Primaquine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Primaquine. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Primaquine. Monitor therapy

Propafenone: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propafenone. Monitor therapy

Propranolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propranolol. Monitor therapy

Protriptyline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Protriptyline. Monitor therapy

QT-prolonging Agents (Highest Risk): QT-prolonging Agents (Indeterminate Risk - Caution) may enhance the QTc-prolonging effect of QT-prolonging Agents (Highest Risk). Management: Monitor for QTc interval prolongation and ventricular arrhythmias when these agents are combined. Patients with additional risk factors for QTc prolongation may be at even higher risk. Monitor therapy

QuiNIDine: (Non-Therapeutic) may enhance the adverse/toxic effect of QuiNIDine. Avoid combination

QuiNINE: Quinidine (Non-Therapeutic) may enhance the adverse/toxic effect of QuiNINE. Avoid combination

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

Rimegepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Rimegepant. Avoid combination

RisperiDONE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of RisperiDONE. Management: Careful monitoring for risperidone toxicities and possible dose adjustment are recommended when combined with strong CYP2D6 inhibitors. See full interaction monograph for details. Consider therapy modification

RomiDEPsin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RomiDEPsin. Monitor therapy

Saquinavir: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Saquinavir. Monitor therapy

Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors): Dextromethorphan may enhance the serotonergic effect of Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors). This could result in serotonin syndrome. Selective Serotonin Reuptake Inhibitors (Strong CYP2D6 Inhibitors) may increase the serum concentration of Dextromethorphan. Management: Consider alternatives to this drug combination. If combined, monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes). Consider therapy modification

Serotonergic Agents (High Risk): Dextromethorphan may enhance the serotonergic effect of Serotonergic Agents (High Risk). This could result in serotonin syndrome. Management: Monitor for signs and symptoms of serotonin syndrome/serotonin toxicity (eg, hyperreflexia, clonus, hyperthermia, diaphoresis, tremor, autonomic instability, mental status changes) when these agents are combined. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy

Sirolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Sirolimus. Management: Avoid concurrent use of sirolimus with P-glycoprotein (P-gp) inhibitors when possible and alternative agents with lesser interaction potential with sirolimus should be considered. Monitor for increased sirolimus concentrations/toxicity if combined. Consider therapy modification

Tacrolimus (Systemic): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tacrolimus (Systemic). Monitor therapy

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Monitor therapy

Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with a reduced clinical effectiveness of tamoxifen. Consider therapy modification

Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Monitor therapy

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Teniposide: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Teniposide. Monitor therapy

Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Limit the tetrabenazine dose to 50 mg per day (25 mg per single dose) in patients taking strong CYP2D6 inhibitors. Consider therapy modification

Thioridazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Thioridazine. Avoid combination

Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Monitor therapy

Timolol (Systemic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Systemic). Monitor therapy

Tolterodine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Monitor therapy

Tolvaptan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tolvaptan. Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

TraMADol: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of TraMADol. CYP2D6 Inhibitors (Strong) may increase the serum concentration of TraMADol. Monitor therapy

Trimipramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Trimipramine. Monitor therapy

Tropisetron: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tropisetron. Monitor therapy

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (at least 2 hours later if needed) of 50 mg when used with a P-gp inhibitor. Consider therapy modification

Valbenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. Management: Reduce valbenazine dose to 40 mg once daily when combined with a strong CYP2D6 inhibitor. Monitor for increased valbenazine effects/toxicities. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Reduce the venetoclax dose by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Resume the previous venetoclax dose 2 to 3 days after discontinuation of a P-gp inhibitor. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Vortioxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with a strong CYP2D6 inhibitor. Following cessation of the strong CYP2D6 inhibitor, the vortioxetine dose should be returned to the normal level. Consider therapy modification

Zuclopenthixol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Zuclopenthixol. Monitor therapy

Test Interactions

See individual agents.

Adverse Reactions

The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.

>10%: Gastrointestinal: Diarrhea (13%)

1% to 10%:

Cardiovascular: Peripheral edema (5%)

Central nervous system: Dizziness (10%)

Endocrine & metabolic: Increased gamma-glutamyl transferase (3%)

Gastrointestinal: Vomiting (5%), flatulence (3%)

Genitourinary: Urinary tract infection (4%)

Infection: Influenza (4%)

Neuromuscular & skeletal: Weakness (5%)

Respiratory: Cough (5%)

Warnings/Precautions

Concerns related to adverse effects:

• Anticholinergic effects: May cause anticholinergic effects; use caution in patients with myasthenia gravis or other conditions which may be affected.

• Dizziness: May cause dizziness; use caution in patients with motor impairment or history of falls.

• Hepatotoxicity: Quinidine has been associated with hepatitis, including granulomatous hepatitis, occurring generally during the first few weeks of therapy. Most cases resolve when quinidine is discontinued.

• Hypersensitivity reactions: Agranulocytosis, angioedema, bronchospasm, hemolytic anemia, increased skeletal muscle enzymes, lymphadenopathy, myalgia, pneumonitis, rash, sicca syndrome, uveitis, vasculitis may be associated with use.

• Lupus-like syndrome: Lupus-like syndrome, with polyarthritis and sometimes a positive antinuclear antibody test, may occur with quinidine. Use is contraindicated in patients with quinidine-, quinine-, or mefloquine-induced lupus-like syndrome.

• Thrombocytopenia: Immune-mediated thrombocytopenia (severe or fatal) may be associated with quinidine use. Unless clearly not drug related, discontinue immediately; continued use may be associated with an increase in fatal hemorrhage. Thrombocytopenia generally resolves within a few days of discontinuation. Therapy should not be restarted in sensitized patients. Use is contraindicated in patients with prior history of immune-mediated thrombocytopenia associated with structurally related drugs (eg, quinine, mefloquine).

Concurrent drug therapy issues:

• High potential for interactions: Concomitant use of moderate or strong CYP3A4 inhibitors may increase quinidine levels and prolong the QTc interval. Quinidine inhibits CYP2D6; concomitant use with CYP2D6 substrates may cause an accumulation of concomitantly administered drug and/or reduce active metabolite formation, decreasing their safety and/or efficacy.

• QT prolonging agents: Use caution with medications which may further prolong the QT interval or cause cardiac arrhythmias. Dose-dependent QTc prolongation may occur. Monitor patients at risk following the first dose. Discontinue if arrhythmia occurs.

• Serotonin syndrome: Symptoms associated with serotonin syndrome such as agitation, confusion, hallucinations, hyper-reflexia, myoclonus, shivering, and tachycardia may occur with concomitant proserotonergic drugs (ie, SSRIs/SNRIs or triptans); especially with higher dextromethorphan doses. Discontinue if such reaction occurs.

Disease-related concerns:

• Cardiovascular disease: Use caution in patients with left ventricular hypertrophy or left ventricular dysfunction which are more common in patients with chronic hypertension, coronary artery disease or history of stroke; risk of QTc prolongation may be increased. Use is contraindicated in patients with prolonged QT interval, congenital QT syndrome, or history of torsade de pointes, patients with heart failure, complete AV block without an implanted pacemaker or patients at high risk of complete AV block. Correct hypokalemia or hypomagnesemia prior to therapy.

• Hepatic impairment: Safety and efficacy have not been established with severe hepatic impairment; increased serum concentrations may occur.

• Renal impairment: Safety and efficacy have not been established with severe renal impairment; increased serum concentrations may occur.

Special populations:

• CYP2D6 poor metabolizers: Dextromethorphan is metabolized by hepatic CYP2D6. Poor metabolizers of CYP2D6 may have exaggerated or prolonged effects of dextromethorphan. Increased risk may be seen with concomitant use of potent CYP2D6 inhibitors; use with caution (Abduljalil 2010; Jurica 2012; Sager 2014; Zhou 2009).

• Dementia: Has not shown to be safe or effective in other types of commonly occurring emotional labilities (eg, neurological disease or injury).

Other warnings/precautions:

• Appropriate use: Periodically reassess the need for treatment; spontaneous improvement of PBA may occur.

• Abuse/misuse: Patients with a history of drug abuse should be monitored closely for signs of abuse/misuse (eg, development of tolerance, increase in dose, drug-seeking behavior). Abuse of dextromethorphan may cause brain damage, cardiac arrhythmia, loss of consciousness, or death.

Monitoring Parameters

QT interval at baseline and 3 to 4 hours after the first dose in patients at risk for QTc prolongation; potassium and magnesium prior to and during therapy; CBC, liver and renal function tests; periodically assess risk factors for arrhythmias during treatment; periodically reassess the need for treatment (spontaneous improvement of PBA may occur); worsening myasthenia gravis or other sensitive conditions due to anticholinergic effects.

Pregnancy Considerations

Adverse events were observed in animal reproduction studies using this combination. See individual agents.

Patient Education

What is this drug used for?

• It is used to treat sudden laughing and/or crying that happens without your control.

All drugs may cause side effects. However, many people have no side effects or only have minor side effects. Call your doctor or get medical help if any of these side effects or any other side effects bother you or do not go away:

• Diarrhea

• Cough

• Dizziness

WARNING/CAUTION: Even though it may be rare, some people may have very bad and sometimes deadly side effects when taking a drug. Tell your doctor or get medical help right away if you have any of the following signs or symptoms that may be related to a very bad side effect:

• Bleeding like vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding

• Lupus like rash on the cheeks or other body parts, sunburn easy, muscle or joint pain, chest pain or shortness of breath, or swelling in the arms or legs

• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.

• Abnormal heartbeat

• Fast heartbeat

• Passing out

• Severe loss of strength and energy

• Severe nausea

• Severe vomiting

• Chills

• Swollen glands

• Swelling of arms or legs

• Depression

• Vision changes

• Serotonin syndrome like dizziness, severe headache, agitation, sensing things that seem real but are not, fast heartbeat, abnormal heartbeat, flushing, tremors, sweating a lot, change in balance, severe nausea, or severe diarrhea

• Signs of an allergic reaction, like rash; hives; itching; red, swollen, blistered, or peeling skin with or without fever; wheezing; tightness in the chest or throat; trouble breathing, swallowing, or talking; unusual hoarseness; or swelling of the mouth, face, lips, tongue, or throat.

Note: This is not a comprehensive list of all side effects. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a limited summary of general information about the medicine's uses from the patient education leaflet and is not intended to be comprehensive. This limited summary does NOT include all information available about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not intended to provide medical advice, diagnosis or treatment and does not replace information you receive from the healthcare provider. For a more detailed summary of information about the risks and benefits of using this medicine, please speak with your healthcare provider and review the entire patient education leaflet.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.