Dextromethorphan

AUVELITY is a combination of dextromethorphan, an uncompetitive N -methyl D -aspartate (NMDA) receptor antagonist and sigma-1 receptor agonist, and bupropion, an aminoketone and CYP450 2D6 inhibitor, indicated for the treatment of major depressive disorder (MDD) in adults the treatment of agitation associated with dementia due to Alzheimer’s disease. Limitations of Use: AUVELITY is not indicated as an as needed (“prn”) treatment for agitation associated with dementia due to Alzheimer’s disease.

Dextromethorphan is an uncompetitive antagonist of the NMDA receptor (an ionotropic glutamate receptor) and a sigma-1 receptor agonist. The mechanism of dextromethorphan in the treatment of MDD and agitation associated with dementia due to Alzheimer’s disease is unclear. Bupropion increases plasma levels of dextromethorphan by competitively inhibiting cytochrome P450 2D6, which catalyzes a major biotransformation pathway for dextromethorphan. The mechanism of action of bupropion in the treatment of MDD is unclear, however, it may be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine and does not inhibit monoamine oxidase or the reuptake of serotonin.

Prior to initiating treatment with AUVELITY: assess blood pressure, screen patients for history of bipolar disorder, mania, or hypomania, and determine if patients are receiving any other medications that contain bupropion or dextromethorphan. For MDD, the starting dosage is AUVELITY 45 mg/105 mg once daily in the morning. On day 4, increase to the maximum recommended dosage of AUVELITY 45 mg/105 mg twice daily, separated by at least 8 hours. Do not exceed two doses within the same day. For agitation associated with dementia due to Alzheimer’s disease, the starting dosage is AUVELITY 30 mg/105 mg once daily in the morning. On day 8, increase to AUVELITY 30 mg/105 mg twice daily, separated by at least 8 hours, based on tolerability. On day 15, increase to the maximum recommended dosage of AUVELITY 45 mg/105 mg twice daily, separated by at least 8 hours, based on tolerability.

AUVELITY is contraindicated in patients: with a seizure disorder. with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with the immediate-release formulation of bupropion. undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. taking, or within 14 days of stopping, MAOIs due to the risk of serious and possibly fatal drug interactions, including hypertensive crisis and serotonin syndrome.

Boxed warning (suicidal thoughts and behaviors): Antidepressants increased the risk of suicidal thoughts and behaviors in pediatric and young adult patients in short-term studies. Closely monitor all antidepressant-treated patients for clinical worsening, and emergence of suicidal thoughts and behaviors. AUVELITY is not approved for use in pediatric patients. Seizure: Risk is dose-related. Discontinue if seizure occurs. Increased Blood Pressure and Hypertension: AUVELITY can increase blood pressure and cause hypertension. Assess blood pressure before initiating treatment and monitor periodically during treatment. Activation of Mania or Hypomania: Screen patients for bipolar disorder. Psychosis and Other Neuropsychiatric Reactions: Instruct patients to contact a healthcare provider if such reactions occur.

The following adverse reactions are discussed in more detail in other sections of the labeling: Suicidal Thoughts and Behaviors in Adolescents and Young Adults Seizure Increased Blood Pressure and Hypertension Activation of Mania or Hypomania Psychosis and Other Neuropsychiatric Reactions Angle-closure Glaucoma Dizziness Serotonin Syndrome Embryo-fetal Toxicity Hyponatremia MDD: Most common adverse reactions (≥5% and more than twice as frequently as placebo): dizziness, headache, diarrhea, somnolence, dry mouth, sexual dysfunction, and hyperhidrosis. Agitation associated with dementia due to Alzheimer’s disease: Most common adverse reactions (≥5% and more than twice as frequently as placebo): dizziness and dyspepsia.

Strong CYP2D6 inhibitors: For patients with MDD or agitation associated with dementia due to Alzheimer’s disease, maximum recommended dosage is one tablet of 45 mg dextromethorphan hydrobromide/105 mg bupropion hydrochloride by mouth once daily in the morning. Strong CYP2B6 inducers: Avoid use. CYP2D6 Substrates: Increases the exposures of drugs that are substrates of CYP2D6. Digoxin: May decrease plasma digoxin levels. Monitor digoxin levels. Drugs that lower seizure threshold: Coadministration may increase risk of seizure. Dopaminergic drugs: Central Nervous System (CNS) toxicity can occur with concomitant use. Drug-laboratory test interactions: AUVELITY can cause false-positive urine test results for amphetamines.

Store AUVELITY in original bottle at 20°C to 25°C (68°F to 77°F), excursions permitted to 15°C to 30°C (59°F to 86°F).