NUEDEXTA
Clinical safety rating: caution
Comprehensive clinical and safety monograph for NUEDEXTA (NUEDEXTA).
NUEDEXTA is a combination of dextromethorphan (an NMDA receptor antagonist and sigma-1 receptor agonist) and quinidine (a CYP2D6 inhibitor). The mechanism by which dextromethorphan exerts therapeutic effects in pseudobulbar affect is unknown, but it is thought to involve modulation of glutamatergic neurotransmission via NMDA receptor antagonism and sigma-1 receptor agonism. Quinidine increases dextromethorphan plasma concentrations by inhibiting its CYP2D6-mediated metabolism.
| Metabolism | Dextromethorphan is extensively metabolized by CYP2D6 to dextrorphan. Quinidine is a potent CYP2D6 inhibitor; coadministration increases dextromethorphan exposure. Quinidine is primarily metabolized by CYP3A4. |
| Excretion | Renal excretion of unchanged drug and metabolites: dextromethorphan and metabolites (including dextrorphan) undergo renal elimination; quinidine is primarily hepatically metabolized, with <20% excreted unchanged in urine. Fecal elimination is minor (<5%). |
| Half-life | Dextromethorphan: ~13 hours (range 9-19 hours) when co-administered with quinidine due to CYP2D6 inhibition; quinidine: ~6-8 hours. Clinical context: Steady-state achieved in approximately 3 days; half-life prolongation allows twice-daily dosing. |
| Protein binding | Dextromethorphan: ~60-70% bound to albumin; quinidine: ~80-90% bound mainly to albumin and alpha-1-acid glycoprotein. |
| Volume of Distribution | Dextromethorphan: approximately 5-7 L/kg; quinidine: approximately 2-4 L/kg. Large Vd indicates extensive tissue distribution, including CNS penetration. |
| Bioavailability | Oral: Dextromethorphan bioavailability is ~10-30% due to extensive first-pass metabolism; co-administration with quinidine (a CYP2D6 inhibitor) increases dextromethorphan bioavailability to >80% in extensive metabolizers. |
| Onset of Action | Oral: Clinical improvement (pseudobulbar affect symptoms) observed within 1-2 weeks of initiating therapy; peak plasma concentrations of dextromethorphan occur at ~3-4 hours post-dose. |
| Duration of Action | Oral: Duration of therapeutic effect is approximately 12 hours (twice-daily dosing); symptom control maintained with continuous administration. Clinical notes: May require up to 4 weeks to assess full response. |
NUEDEXTA (dextromethorphan hydrobromide 20 mg / quinidine sulfate 10 mg) is administered orally once daily in the morning for 7 days, then increased to twice daily (every 12 hours).
| Dosage form | CAPSULE |
| Renal impairment | Contraindicated in patients with severe renal impairment (eGFR <30 mL/min/1.73 m²). No dose adjustment recommended for mild to moderate impairment (eGFR 30-89 mL/min/1.73 m²) but monitor for quinidine toxicity. |
| Liver impairment | Contraindicated in patients with severe hepatic impairment (Child-Pugh Class C). No dose adjustment recommended for mild to moderate impairment (Child-Pugh Class A or B) but use with caution due to potential for increased exposure. |
| Pediatric use | Not indicated for use in pediatric patients; safety and efficacy not established. |
| Geriatric use | No specific dose adjustment recommended, but monitor renal function and QT interval more frequently due to age-related decline in renal function and increased susceptibility to quinidine's cardiac effects. |
| 1st trimester | Consult provider |
| 2nd trimester | Consult provider |
| 3rd trimester | Consult provider |
Clinical note
Comprehensive clinical and safety monograph for NUEDEXTA (NUEDEXTA).
| Breastfeeding | Excreted in breast milk; quinidine M/P ratio approximately 0.5–0.9. Dextromethorphan: limited data. Use caution due to potential for infant CNS effects and quinidine-related cardiotoxicity. Monitor infant for bradycardia, QT prolongation, and drowsiness. |
| Teratogenic Risk | Insufficient human data; animal studies with dextromethorphan/quinidine show developmental toxicity at maternal toxic doses. Avoid in first trimester due to theoretical risk of teratogenicity. Second and third trimester: limited data; use only if benefit outweighs potential fetal risks. Quinidine may cause uterine contractions and fetal arrhythmia at high doses. |
■ FDA Black Box Warning
None.
| Serious Effects |
["Concomitant use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing MAOIs.","Concomitant use with drugs that prolong the QT interval.","Heart failure (quinidine-related cardiotoxicity).","Atrioventricular block without pacemaker.","Hypersensitivity to dextromethorphan, quinidine, or any component of the formulation."]
| Precautions | ["Cardiovascular effects: Quinidine may cause QT prolongation and ventricular arrhythmias; avoid in patients with prolonged QT interval, atrioventricular block, or concurrent use of QT-prolonging drugs.","Serotonin syndrome: Dextromethorphan increases serotonin; avoid with MAOIs, SSRIs, SNRIs, and other serotonergic drugs.","Hepatotoxicity: Cases of elevated liver enzymes and hepatitis reported; monitor liver function.","CYP2D6 poor metabolizers: Increased risk of adverse effects due to higher dextromethorphan levels."] |
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| Fetal Monitoring | Maternal: Serial ECG monitoring for QT prolongation, electrolyte levels (K+, Mg2+), drug levels if signs of toxicity. Fetal: Ultrasound for growth, fetal heart rate monitoring in third trimester if used long-term. |
| Fertility Effects | No human data; animal studies show no impairment of fertility at clinically relevant doses. |