severe), phlebitis, and pulmonary embolism Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, pancreatitis, and stomach ulcer Endocrine: Hyperglycemia, hypoglycemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia Metabolic and nutritional: Glycosuria Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness Nervous system: Abnormal electroencephalogram (EEG), aggression, agitation, akinesia, aphasia, coma, completed suicide, delirium, delusions, depression, dysarthria, euphoria, extrapyramidal syndrome (dyskinesia, dystonia, hypokinesia, parkinsonism), hallucinations, homicidal ideation, hostility, increased libido, manic reaction, neuralgia, neuropathy, panic, paranoid ideation, psychosis, restlessness, suicide ideation, suicide attempt, and unmasking tardive dyskinesia Respiratory: Pneumonia Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome Special senses: Deafness, increased intraocular pressure, and mydriasis Black Box Warnings Antidepressants increased 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 Not approved for use in pediatric patientsContraindications Seizure disorders Current or prior diagnosis of bulimia or anorexia nervosa (higher incidence of seizures with immediate-release bupropion) Abrupt discontinuance of alcohol, benzodiazepine, barbiturates, or antiepileptic drugs Taking, or within 14 days of stopping, MAOIs; starting dextromethorphan/bupropion in patients treated with reversible MAOIs (eg, linezolid, IV methylene blue) Known hypersensitivity to bupropion, dextromethorphan, or other components Cautions Serotonin syndrome reported; if concomitant use of this medication with other serotonergic drugs clinically warranted, inform patients of increased risk for serotonin syndrome and monitor for symptoms; discontinue treatment and/or concomitant serotonergic drug immediately if above symptoms occur, and initiate supportive symptomatic treatment Bupropion may elevated blood pressure; risk of hypertension increased if coadministered with MAOIs or other drugs that increase dopaminergic or noradrenergic activity Caution with angle-closure glaucoma; pupillary dilation that occurs following use of many antidepressant drugs, including bupropion, may trigger an angle-closure attack in patients with anatomically narrow angles who do not have a patent iridectomy May cause dizziness; take precautions to reduce falls and caution patients regarding operating hazardous machinery, including motor vehicles, until they are reasonably certain that therapy does not affect them adversely May cause fetal harm; use alternate treatment for females planning to become pregnant Suicidality In short-term studies, antidepressants increased the risk of suicidal thinking and behavior in children, adolescents, and young adults (aged <24 years) taking antidepressants for major depressive disorders and other psychiatric illnesses; this increase was not seen in patients aged >24 years Closely monitor all antidepressant-treated patients for clinical worsening and for emergence of suicidal thoughts and behaviors, especially during the initial few months of drug therapy, as well as at times of dosage changes Counsel family members or caregivers of patients to monitor for changes in behavior and to alert healthcare provider; consider changing therapeutic regimen, including possibly discontinuing therapy, in patients whose depression is persistently worse, or who are experiencing emergent suicidal thoughts or behaviors Psychosis/neuropsychiatric reactions Bupropion: Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion; symptoms may abate with dose reduction and/or treatment withdrawal Dextromethorphan: Overdose can cause toxic psychosis, stupor, coma, and hyperexcitability Antidepressants can precipitate manic, mixed, or hypomanic manic episode; risk increased in patients who have bipolar disorder or have risk factors for bipolar disorder Screen patients for bipolar disorder and use of other bupropion- or dextromethorphan-containing products before initiating Seizures Bupropion can cause seizure; risk of seizure with bupropion is dose-related; use contraindicated in patients with seizures If concomitant use of this medication with other bupropion-containing products is clinically warranted, inform patients of the risk; discontinue therapy, and do not restart treatment if the patient experiences a seizure Drug interaction overview Bupropion (and metabolites): CYP2D6 inhibitor; CYP2B6 substrate Dextromethorphan: CYP2D6 substrate (major) MAOIs Contraindicated Coadministration (or within 14 days) increases risk of hypertensive crisis and serotonin syndrome Serotonin syndrome Monitor for symptoms of serotonin syndrome Coadministration with other serotonergic drugs (eg, SSRIs, TCAs) increases risk of serotonin syndrome, a potentially life-threatening condition with changes that include altered mental status, hypertension, restlessness, myoclonus, hyperthermia, hyperreflexia, diaphoresis, shivering, and tremor Drugs that lower seizure threshold Caution Bupropion can cause seizure; coadministration with other drugs that lower seizure threshold may increase risk If seizure occurs, discontinue dextromethorphan/bupropion and do not restart Strong CYP2D6 inhibitor Modify (decrease) dextromethorphan/bupropion dose Strong CYP2D6 inhibitors increase dextromethorphan plasma concentrations, which may result in somnolence and dizziness Strong CYP2B5 inducers Avoid Strong CYP2B6 inducers decrease plasma concentrations of bupropion CYP2D6 substrates May need to modify dose of CYP2D6 substrate Bupropion may increase systemic exposure of CYP2D6 substrates; dose modification of CYP2D6 substrates with narrow therapeutic indexes may be necessary Conversely, drugs requiring metabolic activation by CYP2D6 may have reduced efficacy and require an increased dose Digoxin Monitor digoxin levels Coadministration may decrease plasma digoxin levels Digoxin exposure was decreased when a single oral dose of 0.5-mg digoxin was administered 24 hr after a single oral dose of extended-release 150 mg bupropion in healthy volunteers Dopaminergic drugs Caution Coadministration of levodopa or amantadine with bupropion may cause CNS toxicity, including restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness Alcohol Avoid alcohol during treatment Bupropion can increase adverse neuropsychiatric events or reduce alcohol tolerance Pregnancy Not recommended during pregnancy Based on animal studies, may cause fetal harm when administered during pregnancy Encourage patients to register for the National Pregnancy Registry for Antidepressants at 1-866-961-2388 or online at womensmentalhealth.org/research/pregnancyregistry/antidepressants/ Clinical considerations A prospective, longitudinal study followed 201 pregnant women with history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy Women who discontinued antidepressants during pregnancy were more likely to experience relapse of major depression than women who continued antidepressants Consider maternal risks of untreated depression and potential effects on fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum Lactation Owing to potential for neurotoxicity, advise patients that breastfeeding is not recommended during treatment and for 5 days after final dose Dextromethorphan Neurotoxicity observed in juvenile rats treated with dextromethorphan/quinidine on postnatal day 7, which corresponds to third trimester of gestation through the first few months of life and may extend through the first 3 years of human life Unknown if dextromethorphan is present in human milk; data are not available regarding effects on breastfed infant or on milk production Bupropion There are no data on the effects of bupropion or its metabolites on milk production Data from postmarketing reports are limited; use in lactating patients has not identified a clear association of adverse reactions in the breastfed infant Pregnancy Categories A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk. B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk. C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done. D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk. X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist. NA: Information not available. Mechanism of Action Dextromethorphan: Uncompetitive N-methyl-D-aspartate receptor (NMDA) receptor antagonist (glutamate receptor modulator) with multimodal activity; also is an agonist of sigma-1 receptor Bupropion: Serves to increase bioavailability of dextromethorphan; also inhibits norepinephrine and dopamine reuptake Absorption Peak plasma time: 3 hr (dextromethorphan); 2 hr (bupropion) Steady state achieved within 8 days Distribution Protein bound Dextromethorphan: 60-70% Bupropion and hydroxybupropion metabolite: 84% Threohydroxybupropion metabolite: ~42% Metabolism Dextromethorphan primarily metabolized by CYP2D6 to dextrorphan Bupropion extensively metabolized to 3 active metabolites via hydroxylation CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion Elimination Half-life CYP2D6 extensive metabolizers: Dextromethorphan increased ~3-fold to 22 hr, compared with dextromethorphan given without bupropion Bupropion: 15 hr Bupropion active metabolites: Hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion were ~35, 44 and 33 hr, respectively Excretion Dextromethorphan CYP2D6 extensive metabolizers: 37-52% recovered in urine (<2% unchanged) CYP2D6 poor metabolizers: 45-83% recovered in urine (~26% unchanged) Oral Administration May administer with or without food Swallow tablets whole; do not crush, divide, or chew Storage Store in original bottle at 20-25ºC (68-77ºF), excursions permitted to 15-30ºC (59-86ºF) No images available for this drug. No images available for this drug.A Patient Handout is not currently available for this monograph.Print FormularyPatient DiscountsAdding plans allows you to compare formulary status to other drugs in the same class.To view formulary information first create a list of plans. Your list will be saved and can be edited at any time.Create Your List of PlansAdding plans allows you to:View the formulary and any restrictions for each plan.Manage and view all your plans together – even plans in different states.Compare formulary status to other drugs in the same class.Access your plan list on any device – mobile or desktop. The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information. View explanations for tiers and restrictions Tier Description 1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs. 2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs. 3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs. 4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. 6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products. NC NOT COVERED – Drugs that are not covered by the plan. Code Definition PA Prior Authorization Drugs that require prior authorization. This restriction requires that specific clinical criteria be met prior to the approval of the prescription. 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