Bupropion And Dextromethorphan

Introduction Overview

Generic Name

bupropion and dextromethorphan

Brand Name

Auvelity

Dosage Form

extended-release tablets

Drug Class

Miscellaneous antidepressants

Pharmacokinetics

Absorption

Auvelity is administered orally in the form of extended-release tablets containing fixed doses of bupropion hydrochloride and dextromethorphan hydrobromide. Bupropion is rapidly and well absorbed from the gastrointestinal tract with peak plasma concentrations occurring approximately 3 hours after administration. The extended-release formulation allows for gradual drug release, aiding in stable plasma levels and improved tolerability. Dextromethorphan is also well absorbed with peak plasma concentrations reached within approximately 4 hours. The concurrent presence of bupropion, a CYP2D6 inhibitor, inhibits the metabolism of dextromethorphan, resulting in increased plasma concentrations and prolonged elimination half-life. Food does not significantly impact the absorption of either component, allowing Auvelity to be taken with or without meals.

Distribution

Bupropion exhibits extensive tissue distribution with a volume of distribution ranging between 20 and 50 L/kg, indicative of wide peripheral tissue penetration. It is approximately 84% bound to plasma proteins. Dextromethorphan has a volume of distribution of approximately 2.8 L/kg and is about 65% bound to plasma proteins. The inhibition of CYP2D6 by bupropion increases systemic exposure to dextromethorphan, influencing its distribution and therapeutic effects. Both drugs cross the blood-brain barrier effectively, which is crucial for their central nervous system activity in treating depression.

Metabolism

Bupropion undergoes extensive hepatic metabolism primarily by cytochrome P450 2B6 (CYP2B6), forming three active metabolites: hydroxybupropion, threohydrobupropion, and erythrohydrobupropion, all contributing to its antidepressant effects. Dextromethorphan is metabolized predominantly by CYP2D6 to dextrorphan, its major active metabolite, which exerts NMDA receptor antagonist activity. Due to bupropion's CYP2D6 inhibitory effects, the metabolism of dextromethorphan is significantly reduced, enhancing its plasma concentration and prolonging its action. This metabolic interaction is fundamental to Auvelity’s pharmacological profile and clinical effectiveness.

Elimination

Bupropion and its metabolites are primarily eliminated via renal excretion, with approximately 87% of a dose excreted in urine. The elimination half-life of bupropion ranges from 12 to 30 hours, with active metabolites having longer half-lives contributing to sustained effects. Dextromethorphan is eliminated through renal excretion mainly as metabolites, with a half-life prolonged due to CYP2D6 inhibition by bupropion, averaging around 22 hours. The extended elimination half-life supports twice-daily dosing of Auvelity. Hepatic impairment may alter metabolism and clearance, necessitating careful patient monitoring.

Dosage Forms

Adults

Auvelity is formulated as an extended-release oral tablet containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride per tablet. The recommended adult dosing regimen begins with one tablet once daily in the morning for the first three days to enhance tolerability. Subsequently, the dose is increased to one tablet twice daily, with doses separated by at least 8 hours, reaching a maximum of two tablets per day. This dosing scheme facilitates a gradual adjustment to therapeutic plasma levels while minimizing adverse effects. Tablets must be swallowed whole and may be administered with or without food; crushing, chewing, or dividing tablets is contraindicated to preserve extended-release properties.

Adolescents

Auvelity is not indicated for use in children or adolescents under 18 years of age. Safety and efficacy have not been established in this population, and the risk of increased suicidal ideation in young patients necessitates avoidance of use in these groups.

Special Populations

In patients with renal or hepatic impairment, Auvelity should be used with caution due to altered metabolism and clearance, potentially leading to increased drug exposure and adverse effects. Specific dosage adjustments have not been firmly established, and clinical monitoring is advised. Elderly patients may have increased sensitivity to the drug’s side effects, such as dizziness and confusion, increasing fall risk; therefore, cautious dosing and monitoring are recommended. Pregnancy and lactation are contraindicated as Auvelity may harm the fetus and is excreted in breast milk; alternative treatments should be considered. Patients with a history of seizure disorders, eating disorders, or abrupt withdrawal from alcohol or sedatives should avoid Auvelity due to increased seizure risk.

Mechanism Of Action

Auvelity combines two active pharmaceutical ingredients—dextromethorphan and bupropion—that exhibit complementary and synergistic mechanisms to exert antidepressant effects. Dextromethorphan primarily functions as a noncompetitive antagonist of the N-methyl-D-aspartate (NMDA) receptor, a subtype of glutamate receptor involved in synaptic plasticity and neuroexcitatory signaling. By moderating NMDA receptor activity, dextromethorphan increases glutamatergic neurotransmission and enhances synaptic plasticity, which are believed to contribute to rapid antidepressant effects distinct from classical monoaminergic antidepressants.

Additionally, dextromethorphan acts as an agonist at the sigma-1 receptor, a chaperone protein modulating multiple neurotransmitter pathways and neuroprotective processes. Activation of the sigma-1 receptor further supports neuroplasticity and may reduce neuroinflammation, contributing to mood regulation. Dextromethorphan also weakly inhibits the serotonin and norepinephrine transporters, modulating their synaptic levels.

Bupropion, the second component, is classified as a norepinephrine-dopamine reuptake inhibitor (NDRI). It inhibits the presynaptic reuptake of norepinephrine and dopamine, increasing their synaptic concentrations, which enhances neurotransmission along these pathways and leads to improved mood and motivation. Bupropion's inhibition of cytochrome P450 2D6 (CYP2D6) concurrently increases systemic levels of dextromethorphan by reducing its hepatic metabolism, thereby potentiating dextromethorphan’s NMDA receptor antagonism and sigma-1 receptor agonism.

The unique combination of monoaminergic modulation through bupropion and glutamatergic signaling modulation through dextromethorphan provides a novel, rapid-acting antidepressant effect. This multi-modal action has been demonstrated in clinical trials to improve depressive symptoms more quickly than traditional antidepressants, marking a significant advancement in MDD treatment paradigms.

Pharmacological Actions

Noncompetitive antagonist of NMDA receptors by dextromethorphan, modulating glutamatergic neurotransmission.
Agonist activity at sigma-1 receptors, enhancing neuroplasticity and neuroprotection.
Norepinephrine and dopamine reuptake inhibition by bupropion, increasing synaptic levels of these neurotransmitters.
CYP2D6 inhibition by bupropion, leading to increased plasma concentrations and prolonged activity of dextromethorphan.
Modulation of serotonin transporter (SERT) and norepinephrine transporter (NET) by dextromethorphan, affecting monoaminergic pathways.
Rapid antidepressant effects due to combined glutamatergic and monoaminergic mechanisms.
Improvement in mood by enhancing neurochemical signaling in key brain regions involved in depression.
Reduction of depressive symptoms with observed onset as early as one week of therapy.

Therapeutic Clinical Uses

Treatment of major depressive disorder (MDD) in adults.
Rapid relief of depressive symptoms with earlier onset compared to traditional antidepressants.
Alternative therapy for patients who have inadequate response to conventional antidepressants.
Potential off-label use in depressive disorders with neuropathic components (research ongoing).
Treatment consideration in patients where combination modulation of glutamate and monoamines is desired.
Use in patients without significant risk factors for seizures or contraindications to components.
Management of depressive episodes presenting with anhedonia, low energy, and motivational deficits.
Therapeutic option for patients seeking medications with a potentially favorable sexual side effect profile compared to SSRIs and SNRIs.

Side Or Adverse Effects

Dizziness, occurring in a significant proportion of patients, which may increase fall risk especially in the elderly.
Diarrhea, generally mild to moderate in severity.
Dry mouth (xerostomia), common and often transient.
Excessive sweating (hyperhidrosis), which may impact compliance.
Headache, reported as a frequent complaint among users.
Somnolence or feeling sleepy, potentially affecting activities requiring alertness.
Sexual dysfunction, including decreased libido or other disturbances.
Risk of seizures, especially with higher doses or in patients with predispositions such as history of seizures or eating disorders.
Elevation in blood pressure (hypertension), necessitating monitoring during therapy.
Manic episodes in patients with bipolar disorder or family history of mania.
Unusual thoughts or behavioral changes, including delusions, hallucinations, paranoia, or confusion linked to bupropion component.
Potential for serotonin syndrome if combined with serotonergic agents.
Eye problems such as angle-closure glaucoma in susceptible individuals.
Nausea and vomiting possible with initiation or dose escalation.
Potential for drug screening interference causing false-positive results in urine drug tests.

Precautions

Avoid use in patients with a history of seizure disorder or conditions predisposing to seizures such as eating disorders or abrupt alcohol or sedative withdrawal.
Screen patients for bipolar disorder or history of mania before initiating to prevent induction of manic episodes.
Monitor blood pressure at baseline and regularly during treatment due to risk of hypertension.
Exercise caution in elderly patients due to increased risk of falls secondary to dizziness or sedation.
Avoid abrupt discontinuation to prevent withdrawal symptoms and relapse of depression.
Advise patients to avoid alcohol due to increased seizure risk and potential CNS effects.
Monitor for new or worsening depression or emergence of suicidal ideation, especially in young adults.
Inform patients about the possibility of serotonin syndrome if combined with serotonergic drugs and educate on symptoms.
Assess patients for glaucoma risk prior to initiation, particularly angle-closure glaucoma.
Caution with concomitant medications that influence CYP2D6 or CYP3A4 metabolism to avoid altered drug levels.
Advise patients not to operate heavy machinery until they understand individual responses to the drug.
In pregnancy, Auvelity is not recommended; counsel women of childbearing potential accordingly.
Advise breastfeeding patients to discontinue breast-feeding during and for 5 days after therapy due to drug excretion in milk.
Evaluate history of substance abuse as bupropion may lower seizure threshold and impact CNS.
Review all concomitant medications for potential interactions prior to prescribing Auvelity.

Warnings

Increased risk of suicidal thoughts and behaviors in children, adolescents, and young adults; not approved for pediatric use.
Seizure risk, which increases with higher doses and in susceptible individuals; do not exceed recommended dose.
Potential hypertensive episodes; blood pressure should be monitored before and during treatment.
Manic episodes in patients with bipolar disorder risk exacerbation leading to mood destabilization.
Serious hypersensitivity reactions including angioedema and anaphylaxis reported rarely.
Angle-closure glaucoma risk; patients with narrow-angle glaucoma should be evaluated prior to use.
Potential for serotonin syndrome when used concomitantly with serotonergic agents; emergency management may be required.
CNS depression or impairment causing dizziness or somnolence, increasing accident risk.
Use caution in patients with history of drug or alcohol abuse due to bupropion component.
Interference with urine drug screening tests leading to false positives.
Not for use with monoamine oxidase inhibitors (MAOIs) or within 14 days of discontinuing MAOIs due to hypertensive crisis risk.
Use during pregnancy may cause harm to the fetus; not recommended.
Breastfeeding not recommended during treatment and for 5 days after final dose due to drug excretion.

Contraindications

History of seizure disorder or conditions that predispose to seizures such as anorexia nervosa or bulimia.
Concurrent use or recent (within 14 days) use of monoamine oxidase inhibitors (MAOIs).
Use with linezolid or intravenous methylene blue, both known MAO inhibitors.
Hypersensitivity to bupropion, dextromethorphan, or any excipients in the formulation.
Abrupt discontinuation of alcohol or sedatives (benzodiazepines, barbiturates, antiseizure medications).
Known angle-closure glaucoma or patients at risk not properly evaluated before use.
Pediatric patients and adolescents due to increased risk of suicidal ideation.
Concomitant use with other bupropion-containing medications leading to risk of overdose and seizures.
Patients with uncontrolled hypertension due to risk of exacerbation.
Pregnant or breastfeeding women due to fetal and neonatal risk.

Drug Interactions

Inhibitors or inducers of CYP2D6 may alter plasma levels of dextromethorphan, affecting efficacy and toxicity.
Concomitant use with other bupropion-containing products increases seizure risk and should be avoided.
Serotonergic agents including selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and triptans increase risk of serotonin syndrome when combined with Auvelity.
Use with monoamine oxidase inhibitors (MAOIs), linezolid, or intravenous methylene blue is contraindicated due to risk of hypertensive crisis and serotonin syndrome.
Co-administration with CNS depressants such as benzodiazepines, opioids, or alcohol can potentiate sedation and respiratory depression.
Drugs lowering seizure threshold (e.g., antipsychotics, systemic corticosteroids, theophylline) require caution when used concomitantly.
Co-treatment with nicotine replacement therapies or stimulants may increase neuropsychiatric side effects.
Interactions with oral antidiabetic agents or insulin necessitate monitoring of blood glucose due to potential pharmacodynamic effects.
Potential interference with drug screening tests, necessitating communication with laboratory personnel.
Concomitant use of appetite suppressants or anorectics may increase cardiovascular risks.
Enzymatic induction or inhibition affecting bupropion metabolism (e.g., CYP2B6 inhibitors or inducers) may alter drug exposure.

Preparations Of The Drug

Extended-release oral tablets containing 45 mg dextromethorphan hydrobromide and 105 mg bupropion hydrochloride per tablet.
Packaged in blister packs or bottles for oral administration.
Supplied as film-coated tablets designed for once or twice daily dosing.
Formulated as a fixed-dose combination to ensure consistent dosing and pharmacokinetic interaction.
Packaged at room temperature storage conditions between 20°C to 25°C (68°F to 77°F).