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    Antismoking Products
    Miscellaneous Antidepressants

    BOXED WARNING

    Children, suicidal ideation

    The safety and efficacy of bupropion for smoking cessation is not established in children or adolescents. Children 6 years and older with a major depressive episode or attention-deficit hyperactivity disorder (ADHD) have been studied in clinical trials of bupropion, but data regarding pediatric safety are limited. When bupropion is used for the treatment of ADHD in pediatrics, careful screening and monitoring is recommended by the American Heart Association. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events was 4% on drug and 2% for placebo; however, no suicides occurred. Pooled analysis of short-term clinical trials during early phase treatment with antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavioral changes. The clinical need for an antidepressant in pediatrics or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or behavioral changes, particularly within the first few months of starting therapy or during dose adjustments. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in any patient with depressive symptoms, whether these occur in a primary depressive episode or in association with another primary disorder such as OCD.  In patients who exhibit adverse changes in symptoms, worsening of depressive symptoms, or suicidality, a decision should be made to change or discontinue treatment. If discontinuing bupropion, the medication should be tapered as rapidly as possible, but with recognition that discontinuing treatment abruptly can also cause adverse symptoms. Bupropion should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    DEA CLASS

    Rx

    DESCRIPTION

    Oral antidepressant of the aminoketone class; unrelated to other antidepressants
    Brand-specific FDA approvals for major depression, seasonal affective disorder, and smoking cessation in adults
    Greater potential for causing seizures than many other antidepressants; a boxed warning exists for use in pediatric depression

    COMMON BRAND NAMES

    Aplenzin, Budeprion SR, Budeprion XL, Buproban, Forfivo XL, Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban

    HOW SUPPLIED

    Aplenzin/Budeprion SR/Budeprion XL/Buproban/Bupropion/Bupropion Hydrochloride/Forfivo XL/Wellbutrin SR/Wellbutrin XL/Zyban Oral Tab ER: 100mg, 150mg, 174mg, 200mg, 300mg, 348mg, 450mg, 522mg
    Bupropion/Bupropion Hydrochloride/Wellbutrin Oral Tab: 75mg, 100mg

    DOSAGE & INDICATIONS

    For the treatment of major depression.
    Oral dosage (immediate-release bupropion hydrochloride tablets; e.g., Wellbutrin)
    Adults

    Initially, 100 mg PO twice daily; titrate after no less than 3 days to 100 mg PO 3 times per day if needed; no single dose should exceed 150 mg. The onset of antidepressant effects takes 1 to 3 weeks, maximal effect may not be noted for 4 weeks. Generally, acute episodes of depression require several months of sustained pharmacologic Reassess the patient periodically to determine the individual need for continued treatment. Use the lowest dosage that maintains remission.

    Children† and Adolescents† 6 years and older

    Dosage not established. Suggested dosage ranges from 1.4 to 6 mg/kg/day PO, titrated upward slowly and administered in divided doses. In trials, the average effective dose is roughly 3 mg/kg/day PO; the maximum dosage is generally 250 to 300 mg/day PO. Safety data are not extensive; most patients have also been diagnosed with ADHD.

    Oral dosage (sustained-release bupropion hydrochloride tablets; e.g., Wellbutrin SR)
    Adults

    Initially, 150 mg PO once daily in the morning; titrate after no less than 4 days to 150 mg PO twice daily if needed. After several weeks, titrate to 200 mg PO twice daily if needed; administer doses at least 8 hours apart. The onset of antidepressant effects takes 1 to 3 weeks, maximal effect may not be noted for 4 weeks. Use the lowest dose that maintains remission.

    Adolescents†

    Limited data are available. Dosing may be weight based or may use a non-weight based titration similar to adults. One trial used initial doses up to 2 mg/kg (not to exceed 100 mg) PO once daily in the morning, followed by gradual titration to 3 mg/kg/dose every morning with 2 mg/kg/dose every evening at dinner. If needed, further titration to 3 mg/kg/dose PO twice daily occurred. Single doses of bupropion SR could not exceed 150 mg/dose. Max dose: 6 mg/kg/day PO, in divided doses. Other studies have used flat doses for titration. Initially, 150 mg PO once daily in the morning; titrate after no less than 4 days to 150 mg PO twice daily if needed. After several weeks, titrate to 200 mg PO twice daily if needed with doses at least 8 hours apart. In a small, 8-week open-label trial (n = 8), adolescents with major depression were given a mean dose of 362 mg/day PO of bupropion SR after titration; this regimen was effective as assessed by the expanded Hamilton Depression Rating Scale (SIGH-SAD). Insomnia and weight loss are common. Due to more rapid metabolism of bupropion SR in adolescents compared to adults, total daily doses in the adolescent age group should be given in 2 divided doses.

    Oral dosage (extended-release bupropion hydrochloride tablets; e.g., Wellbutrin XL)
    Adults

    Initially, 150 mg PO once daily in the morning. After no less than 4 days, titrate to the usual target dose of 300 mg PO once daily in the morning based upon patient response and tolerance. Due to a dose-related risk of seizures, gradually titrate.Max: 450 mg PO once daily. When discontinuing treatment, doses of 300 mg/day or more should be tapered to 150 mg PO once daily prior to discontinuation.

    Oral dosage (extended-release bupropion hydrobromide (HBr) tablets; e.g., Aplenzin)
    Adults

    174 mg PO once daily in the morning for initial dose. May be increased to the target dose of 348 mg PO once daily beginning on day 4 of treatment, if tolerated. If response is inadequate after several weeks at 348 mg/day, the dose may be increased to a maximum of 522 mg PO once daily in the morning. There should be a minimum interval of 24 hours between doses. As with many other antidepressants, the full therapeutic effect may not be evident for at least 4 weeks of treatment. For maintenance, use the lowest dosage that maintains remission. Periodically reassess to determine the need for continued treatment. When switching to Aplenzin from Wellbutrin, Wellbutrin SR, or Wellbutrin XL, use the equivalent total daily dose when possible (174 mg of bupropion HBr = 150 mg bupropion HCl; 348 mg of bupropion HBr = 300 mg bupropion HCl; 522 mg bupropion HBr = 450 mg bupropion HCl).

    Oral dosage (extended-release bupropion tablets; i.e., Forfivo XL)
    Adults

    Not for initial treatment, due to fixed high dosage. Give 450 mg PO once per day, after titration with another product. Forfivo XL may be implemented in patients who are currently receiving 300 mg/day of another bupropion formulation for at least 2 weeks and who require an increased dosage. May also switch patients who are receiving other bupropion products at a dose of 450 mg/day to Forfivo XL. Geriatric patients may have decreased renal function which may affect tolerability to the fixed high dosage; monitoring of renal function in geriatric patients is suggested.

    For the prevention of seasonal major depressive disorder episodes associated with seasonal affective disorder (SAD).
    Oral dosage (extended-release bupropion hydrochloride tablets; e.g., Wellbutrin XL):
    Adults

    Initiate in the autumn prior to the onset of depressive symptoms with 150 mg PO once daily in the morning. After 7 days, the dose may be increased to the target dose of 300 mg PO once daily in the morning if tolerated. Continue through the winter season. Taper and discontinue in early spring. For patients receiving 300 mg/day, taper to 150 mg/day prior to discontinuation. Total daily doses above 300 mg/day PO were not evaluated in seasonal affective disorder (SAD) trials. The start and duration of treatment should be individualized based on the patient's historical pattern of seasonal major depressive episodes. Patients whose seasonal depressive episodes are infrequent or not associated with significant impairment should not generally be treated prophylactically.

    Oral dosage (extended-release bupropion hydrobromide; i.e., Aplenzin)
    Adults

    Initially, 174 mg PO once daily in the morning. After 7 days, the dose may be increased to the target dose of 348 mg PO once daily. Total daily doses above 348 mg/day PO were not evaluated in clinical trials for seasonal affective disorder (SAD). Treatment should be individualized based upon the patient's pattern of seasonal major depressive disorder (MDD) episodes. For prevention of seasonal MDD episodes associated with SAD, initiate therapy in the autumn prior to the onset of depressive symptoms. Continue through winter, then taper and discontinue in early spring. For patients receiving 348 mg/day, the dose should be tapered to 174 mg/day before discontinuation.

    For use as an adjunct to psychosocial interventions in the management of tobacco cessation (smoking cessation).
    For use alone to aide in tobacco cessation.
    Oral dosage (sustained-release bupropion HCl tablets; e.g., Zyban)
    Adults

    Initially, 150 mg PO once daily for the first 3 days, then 150 mg PO twice daily for the remainder of the treatment period; doses should be at least 8 hours apart. Do not exceed 300 mg/day PO. Initiate bupropion therapy 1 to 2 weeks before the patient's target smoking 'quit day'. The goal is complete abstinence. Bupropion should be continued for 7 to 12 weeks. Nicotine abstinence rates in clinical trials after 6 weeks of therapy were 44.2% for bupropion 300 mg/day versus 19% with placebo. At 1 year, the abstinence rate was superior to placebo for those patients receiving bupropion at 300 mg/day or 150 mg/day, but not for the 100 mg/day dosage.

    For aide with tobacco cessation using bupropion in combination with a nicotine transdermal system (NTS).
    Oral dosage (sustained-release bupropion HCl tablets; e.g., Zyban)
    Adults

    150 mg PO once daily for the first 3 days, then 150 mg PO twice daily for the remainder of the treatment period; doses should be at least 8 hours apart. Do not exceed 300 mg/day PO. Initiate bupropion 1 to 2 weeks before the target 'quit day'. The NTS should be initiated on the target 'quit date'. Continue bupropion for 7 to 12 weeks. Most NTS can be continued for 8 to 20 weeks. The goal is complete abstinence. One clinical trial indicates that the combination of bupropion with NTS results in abstinence rates of 51% at week 10 following a 4-week quit program, however, 1 year after the target quit-date, the bupropion and NTS combination is not significantly better at maintaining abstinence than the use of bupropion alone. Prior to use of combination therapy, review the complete prescribing information for both bupropion and the NTS. Monitor for treatment-induced hypertension.

    For the treatment of attention-deficit hyperactivity disorder (ADHD)†.
    For use as monotherapy of attention-deficit hyperactivity disorder (ADHD)† in adults.
    Oral dosage (sustained-release tablets; e.g., Wellbutrin SR)
    Adults

    150 mg PO once daily in the morning, then titrate over 2 weeks to 300 mg/day in divided doses (e.g., given as 200 mg PO at 8 AM and 100 mg PO at 4 PM). Doses of bupropion SR must be given at least 8 hours apart. In available clinical trials, bupropion was as effective as methylphenidate for adult ADHD patients, with comparable tolerability. Usually reserved as an option for adult patients who have failed FDA-approved treatments such as stimulants or atomoxetine. A systematic review of trials suggests bupropion may be an effective treatment in patients without comorbidities such as bipolar disorder, eating disorders, or epilepsy.

    Oral dosage (extended-release tablets; e.g., Wellbutrin XL)
    Adults

    150 mg PO once daily in the morning for at least 1 week, then titrate to 300 mg PO once daily during weeks 2 to 4. Further increase may be made at approximately 8 weeks, if needed and tolerated. Max: 450 mg PO once daily. In one clinical trial, the mean final effective dose of bupropion XL was 393 mg/day PO (63% at 450 mg/day, 35.8% at 300 mg/day, 1.2% at 150 mg/day). In available clinical trials, bupropion was as effective as methylphenidate for adult ADHD patients, with comparable tolerability. Usually reserved as an option for adult patients who have failed FDA-approved treatments such as stimulants or atomoxetine. A systematic review of trials suggests bupropion may be an effective treatment in patients without comorbidities such as bipolar disorder, eating disorders, or epilepsy.

    As an alternative treatment of attention-deficit hyperactivity disorder (ADHD)† in children and adolescents.
    Oral dosage (immediate-release tablets; e.g., Wellbutrin)
    Children† and Adolescents† 6 years and older

    Not FDA-approved. Initial dose range: 1.4 to 3 mg/kg/day PO, titrated upward slowly and administered in divided doses. Average effective dose: 3 mg/kg/day PO. Max: 6 mg/kg/day PO or 150 to 300 mg/day PO, depending on age/weight. Compared to other treatments, there is currently only anecdotal evidence for safety or efficacy and thus guidelines do not recommend use of bupropion in pediatric patients. Bupropion has been considered an alternative for some patients when other FDA-approved treatments have failed. In a 6-week, multicenter trial, 109 children (age 6 to 12 years; mean 8.5 years) with ADHD received 3 mg/kg/day PO initially (in 2 divided doses at 7 AM and 7 PM). On days 15 to 28, the dose was escalated to 6 mg/kg/day PO. Max (based on weight): 20 to 30 kg: 150 mg/day PO; 31 to 40 kg: 200 mg/day PO; over 40 kg: 250 mg/day PO. A significant treatment effect was apparent by day 3 for symptoms of conduct problems and hyperactivity (assessed by teachers). Significant findings based on parent ratings were not evident until day 28. Bupropion was well tolerated without evidence of seizure activity; however, 4 children stopped bupropion treatment due to dermatologic reactions (urticaria, rash).

    For the symptomatic treatment of neuropathic pain† due to various causes, including pain associated with peripheral diabetic neuropathy† or postherpetic neuralgia†.
    Oral dosage (sustained-release bupropion HCl tablets; e.g., Wellbutrin SR)
    Adults

    In one trial, 150—300 mg/day PO was reported effective; 73% of patients receiving bupropion reported improvement in pain versus 10% with placebo. Patients began to experience pain relief at week 2 of treatment.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Immediate-release tablets: 450 mg/day PO, no single dose should exceed 150 mg.
    Wellbutrin SR: 400 mg/day PO; no single dose should exceed 200 mg.
    Zyban: 300 mg/day PO for smoking cessation; no single dose should exceed 150 mg.
    Wellbutrin XL: 450 mg/day PO.
    Aplenzin: 522 mg/day PO; no single dose should exceed 522 mg.
    Forfivo XL: 450 mg/day PO.

    Geriatric

    Immediate-release tablets: 450 mg/day PO, no single dose should exceed 150 mg.
    Wellbutrin SR: 400 mg/day PO; no single dose should exceed 200 mg.
    Zyban: 300 mg/day PO for smoking cessation; no single dose should exceed 150 mg.
    Wellbutrin XL: 450 mg/day PO.
    Aplenzin: 522 mg/day PO; no single dose should exceed 522 mg.
    Forfivo XL: 450 mg/day PO.

    Adolescents

    Safety and efficacy have not been established; however, a total daily dosage up to 300 mg/day PO for immediate-release tablets has been suggested for the treatment of attention-deficit hyperactivity disorder (ADHD); doses up to 6 mg/kg/day (not to exceed 300 or 400 mg/day) PO of the bupropion SR products have been used in studies for treatment of depression.

    Children

    6 to 12 years: Safety and efficacy have not been established; however, a total daily dosage up to 300 mg/day PO for immediate-release tablets has been suggested for the treatment of attention-deficit hyperactivity disorder (ADHD).
    5 years and younger: Safety and efficacy have not been established.

    Infants

    Safety and efficacy have not been established.

    Neonates

    Safety and efficacy have not been established.

    DOSING CONSIDERATIONS

    Hepatic Impairment

    In patients with moderate to severe hepatic impairment (Child-Pugh Score 7—15), initiate therapy at a lower dosage and do not exceed 75 mg/day PO of immediate-release Wellbutrin, 100 mg/day or 150 mg every other day of Wellbutrin SR, 150 mg every other day of Zyban or Wellbutrin XL, or 174 mg every other day of Aplenzin. Consider reduced dosage or dosage frequency in patients with mild hepatic impairment (Child-Pugh Score 5—6); however, no guidelines are available. Use of Forfivo XL, a 450 mg extended-release tablet formulation, is not recommended in patients with hepatic impairment since there is no lower dose strength.

    Renal Impairment

    Consider reduced dosage and/or dosage frequency in patients with a CrCl < 90 mL/min; specific recommendations are not available. Bupropion and its metabolites are renally eliminated and may accumulate in patients with renal impairment. Use of Forfivo XL, a 450 mg extended-release tablet formulation, is not recommended in patients with renal impairment because there is no lower dose strength.

    ADMINISTRATION

    A MedGuide is available which informs patients about the increased risk of suicidal thoughts and behaviors in children and young adults during early phase treatment with antidepressants.

    Oral Administration

    May administer with food, if needed to minimize gastric upset.
    To avoid or limit the risk of insomnia, do not administer doses at bedtime.
    Given that there are multiple dosing regimens and 2 salt forms of bupropion available, it is important to be familiar with each product's name and dosing schedule to avoid dosing errors.
    It is advisable to follow the dosing instructions provided by each manufacturer to limit the risk of seizures or other adverse effects.

    Oral Solid Formulations

    Wellbutrin immediate-release bupropion hydrochloride tablets: It is advisable to separate doses by at least 6 hours. The total daily dose is usually administered in three divided doses.
    Wellbutrin SR sustained-release bupropion hydrochloride tablets: It has been suggested that the tablets may be cut in half once, if needed, just prior to administration ; however, the manufacturer states that the tablets should be swallowed whole and should not be cut, chewed, or crushed since this may lead to an increased risk of adverse effects including seizures. If multiple doses are administered daily, each dose should be given at least 8 hours apart.
    Wellbutrin XL extended-release bupropion hydrochloride tablets: Do not chew, cut, or crush tablets since this may lead to an increased risk of adverse effects including seizures. Administer once daily, preferably in the morning.
    Zyban sustained-release bupropion hydrochloride tablets: Do not crush, divide, or chew tablets. The total daily dose is usually administered in two divided doses. Each dose should be given at least 8 hours apart.
    Aplenzin extended-release bupropion hydrobromide tablets: Do not chew, cut, or crush tablets. Administer once daily in the morning. It should be noted that the molecular weight of the hydrobromide salt is higher than the hydrochloride salt; therefore, a larger total mg dose of Aplenzin is needed to provide the same amount of active drug.
    Forfivo XL, extended-release high dose bupropion hydrochloride tablets: Tablets should be swallowed whole. Do not crush, divide, or chew. Administer once daily, preferably in the morning.

    STORAGE

    Aplenzin:
    - Store at 77 degrees F; excursions permitted to 59-86 degrees F
    Budeprion SR :
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Budeprion XL :
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Buproban:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Forfivo XL:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Wellbutrin:
    - Protect from light
    - Protect from moisture
    - Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F
    Wellbutrin SR:
    - Protect from light
    - Protect from moisture
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Wellbutrin XL:
    - Store at controlled room temperature (between 68 and 77 degrees F)
    Zyban:
    - Store at controlled room temperature (between 68 and 77 degrees F)

    CONTRAINDICATIONS / PRECAUTIONS

    General Information

    NOTE: Given that there are multiple dosage forms of bupropion available, it is important to be familiar with each product name, dosage form, and dosing schedule to avoid dosing errors.
     
    Some reports suggest that a false positive urine drug screen may occur for amphetamines in patients who have received bupropion. Caution should be exercised when interpreting positive urine drug screens for these medications, and confirmation by alternative tests such as gas chromatography/mass spectrometry should be considered.
     
    Bupropion is contraindicated in patients with a history of hypersensitivity to bupropion or any inactive ingredients in the formulations. Delayed hypersensitivity reactions, consisting of arthralgia, myalgia, fever and rash have been reported in association with bupropion and may resemble serum sickness. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have also been reported.

    Alcoholism, anorexia nervosa, benzodiazepine withdrawal, brain tumor, bulimia nervosa, diabetes mellitus, head trauma, hypoglycemia, hyponatremia, hypoxemia, intracranial mass, obesity treatment, seizure disorder, seizures, stroke, substance abuse

    Bupropion is contraindicated in patients with a pre-existing seizure disorder or conditions that increase the risk of seizures (e.g., severe head trauma, arteriovenous malformation, CNS tumor (e.g., brain tumor or intracranial mass), CNS infection, severe stroke, anorexia nervosa, bulimia nervosa, and in cases of abrupt benzodiazepine withdrawal as well as abrupt withdrawal from alcohol, barbiturates, or anti-epileptic drugs, because bupropion can cause seizures. Other predisposing factors that may increase the risk of seizures include alcoholism, substance abuse (e.g., cocaine or prescription abuse of stimulants such as amphetamines), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, hypoxemia), diabetes mellitus treated with oral hypoglycemic agents or insulin, excessive use of benzodiazepines, sedative/hypnotics, or opiates, use of anorectic drugs for obesity treatment, or use of concomitant medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, tramadol, systemic corticosteroids). Bupropion should be discontinued and not re-initiated in patients who experience a seizure during treatment. The incidence of seizures with bupropion is dose-dependent. In studies using bupropion hydrochloride sustained-release up to 300 mg/day, the incidence of seizures was about 0.1%. The incidence of seizures in patients taking bupropion hydrochloride immediate-release 300 mg/day to 450 mg/day was about 0.4%. At higher immediate-release dosages between 450 mg/day and 600 mg/day, the estimated risk of seizures increases 10-fold compared to the seizure risk at 450 mg/day. The incidence of seizures has not been formally evaluated for the use of Aplenzin, Forfivo XL, or Wellbutrin XL. Do not exceed maximum recommended single or total daily dosages of any bupropion product. Patients who are taking bupropion for smoking cessation (e.g., Zyban) should not also take bupropion for depressive disorders (e.g., Wellbutrin, Aplenzin), and vice-versa. Healthcare professionals should be aware that bupropion is available under several brand names for various indications in order to avoid duplicative administration. During controlled trial evaluation of immediate-release bupropion, an increase in motor activity and agitation/excitement was demonstrated in normal volunteers, subjects with a history of multiple drug abuse, and depressed patients. Results from single-dose studies suggest that the recommended daily dose of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, because clinical trial results may not reliably predict the abuse potential of drugs, the benefits of treatment should be weighed against the potential for abuse prior to administering bupropion to patients with a history of substance abuse. It should be noted that bupropion extended-release formulations are intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has resulted in seizures and/or cases of death.

    Children, suicidal ideation

    The safety and efficacy of bupropion for smoking cessation is not established in children or adolescents. Children 6 years and older with a major depressive episode or attention-deficit hyperactivity disorder (ADHD) have been studied in clinical trials of bupropion, but data regarding pediatric safety are limited. When bupropion is used for the treatment of ADHD in pediatrics, careful screening and monitoring is recommended by the American Heart Association. In October 2004, the FDA directed manufacturers of all antidepressants to include a boxed warning detailing the risk of suicide in pediatric patients. The risk of suicidality for these drugs was identified in a pooled analysis of 24 placebo-controlled trials (n = 4400) lasting up to 16 weeks in pediatric patients with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events was 4% on drug and 2% for placebo; however, no suicides occurred. Pooled analysis of short-term clinical trials during early phase treatment with antidepressants in young adults (18 to 24 years) also showed an increased risk of suicidal thinking and behavioral changes. The clinical need for an antidepressant in pediatrics or young adults for any use must be weighed against the risk of increased suicidality; patients who are started on therapy should be observed closely for clinical worsening, suicidality, or behavioral changes, particularly within the first few months of starting therapy or during dose adjustments. It is unknown if the suicidality risk in children and young adults extends to longer-term therapy. The possibility of a suicide attempt is inherent in any patient with depressive symptoms, whether these occur in a primary depressive episode or in association with another primary disorder such as OCD.  In patients who exhibit adverse changes in symptoms, worsening of depressive symptoms, or suicidality, a decision should be made to change or discontinue treatment. If discontinuing bupropion, the medication should be tapered as rapidly as possible, but with recognition that discontinuing treatment abruptly can also cause adverse symptoms. Bupropion should be prescribed in the smallest quantity consistent with good patient management in order to reduce the risk of overdose.

    Tics, Tourette's syndrome

    Patients with Tourette's syndrome or tics should be closely monitored for emerging or worsening tics during treatment with bupropion. Like other stimulant medications, bupropion may precipitate motor or phonetic tics in those with Tourette's syndrome or a tic disorder.

    Behavioral changes, bipolar disorder, depression, mania, psychiatric event, schizophrenia

    The use of antidepressants, such as bupropion, has been associated with the development of mania or hypomania in susceptible individuals. Patients should be adequately screened for bipolar disorder prior to initiating an antidepressant, including a detailed personal and family history of bipolar disorder, depression, and suicidal thoughts or actions. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of therapy and during dose adjustments. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in behavior, or emergence of suicidality. If a patient develops manic symptoms, bupropion should be held, and appropriate therapy initiated to treat the manic symptoms. Patients should be observed for a potential psychiatric event or worsening of pre-existing psychiatric illness (e.g., schizophrenia, depression, bipolar disorder) during treatment with bupropion, including smoking cessation products (e.g., Zyban), due to serious neuropsychiatric symptoms reported during postmarketing use of bupropion products for smoking cessation. If neuropsychiatric symptoms develop, evaluate the patient for symptom severity and the extent of benefit from treatment, and consider dose reduction or discontinuation, or continued treatment with closer monitoring. In many cases, resolution of symptoms has occurred after discontinuation, although the symptoms can persist; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. Postmarketing reports during use of bupropion smoking cessation products have included neuropsychiatric adverse events such as mood or behavioral changes (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, panic, suicidal ideation, suicide attempt, and completed suicide in patients with and without a psychiatric history. Some reported cases may have been complicated by symptoms of nicotine withdrawal, such as depressed mood, in patients who stopped smoking. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. Some reported neuropsychiatric events, including unusual and sometimes aggressive behavior directed to oneself or others, may have been worsened by concomitant use of alcohol. Advise patients and caregivers that the patient should stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood, suicidal ideation, suicidal behavior, or other behavioral changes that are not typical for the patient are observed. The boxed warning in the bupropion smoking cessation product labeling regarding serious neuropsychiatric effects was removed in December 2016 following results from the Evaluating Adverse Events in a& Global Smoking Cessation Study (EAGLES), which was a large, randomized, double-blind, active- and placebo-controlled smoking cessation clinical trial assessing varenicline, bupropion, and nicotine replacement therapy in patients with (n = 4,003) and without (n = 3,912) a history of a psychiatric disorder. The results showed that the benefits of taking smoking cessation products outweigh the risks, which are less frequent and severe than previously suspected.

    MAOI therapy

    Bupropion is contraindicated with concurrent use of MAOI therapy intended to treat psychiatric disorders because of an increased risk of hypertensive reactions. At least 14 days should elapse between discontinuation of an MAOI intended to treat psychiatric disorders and bupropion initiation. Conversely, allow at least 14 days after stopping bupropion before starting an MAOI intended to treat psychiatric disorders. Starting bupropion in a patient being treated with an MAOI such as linezolid or methylene blue is also contraindicated; however, there may be circumstances when it is necessary to initiate urgent treatment with linezolid or intravenous methylene blue in a patient taking bupropion. If acceptable alternatives are not available and benefits are judged to outweigh the risks of hypertensive reactions, bupropion should be promptly discontinued before initiating treatment with linezolid or methylene blue. Monitor the patient closely for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with bupropion may be resumed 24 hours after the last dose of linezolid or methylene blue. The risk of administering methylene blue by non-intravenous routes (e.g., oral tablets, local injection) or intravenous doses much less than 1 mg/kg with bupropion is unclear; however, clinicians should be aware that the potential for an interaction exists.

    Neonates, pregnancy

    Bupropion is classified as FDA pregnancy risk category C. Results from epidemiological studies, including data from the international Bupropion Pregnancy Registry (675 first trimester bupropion exposures) and United Healthcare database (1213 first trimester bupropion exposures), indicate no overall increased risk of congenital malformations. In addition, no increased risk of cardiovascular malformations during first trimester exposure to bupropion has been observed. The rate of cardiovascular malformations following 675 exposures to bupropion in the first trimester was 1.3% versus a background rate of about 1%. Data collected from the United Healthcare database and the National Birth Defects Prevention Study (6853 infants with cardiovascular malformations and 5763 with non-cardiovascular malformations) did not show an overall increased risk from cardiovascular malformations after bupropion exposure during the first trimester. Study findings related to a possible association between first trimester bupropion exposure and the risk for left ventricular outflow tract obstruction (LVOTO) or ventricular septal defect (VSD) have been inconsistent and no definitive conclusions can be made. Studies in rabbits demonstrated a slightly increased incidence of fetal malformations and skeletal variations at the lowest dose tested (25 mg/kg/day; approximately equal to the recommended human dose on a mg/m2 basis) and greater; decreased fetal weights were seen at 50 mg/kg and greater. Other animal data reveal no teratogenicity potential. Pregnant smokers should be encouraged to attempt educational and behavioral interventions before pharmacologic approaches are used. While not reported for bupropion, neonates exposed to selected antidepressants late in the third trimester have developed symptoms consistent with either a direct toxic effect of the antidepressants or a potential drug discontinuation syndrome. When treating a pregnant woman, the physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, tapering of the medication prior to delivery may be considered.

    Breast-feeding

    According to the manufacturer, bupropion and its metabolites are excreted into human breast milk, and caution should be exercised when bupropion is administered to a breast-feeding woman. Peak breast milk concentrations of bupropion and its metabolites are present within 2 to 4 hours after an oral dose. In one lactation study (n = 10), the average daily infant exposure to bupropion and its active metabolites (assuming 150 mL/kg daily consumption) was 2% of the maternal weight-adjusted dose. One case report describes a possible seizure in a breast-fed infant during maternal use of extended-release bupropion. In two other cases, no infant-related adverse events were noted during breast-feeding. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. For smoking cessation treatment, nicotine replacement products may be considered as an alternate therapy to bupropion. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    Hepatic disease

    Forfivo XL, a 450 mg extended-release tablet formulation of bupropion, is not recommended in patients with hepatic impairment because a lower dosage strength is not available for use in this patient population. For other bupropion formulations, the dosage or dosage frequency should be reduced in patients with moderate to severe hepatic impairment (Child-Pugh Score 7—15). For patients with mild hepatic dysfunction (Child-Pugh Score 5—6), reduced dosage or dosage frequency should be considered; however, no specific guidelines are available. Monitor patients with any degree of hepatic disease carefully. Bupropion undergoes extensive hepatic metabolism and excretion in the urine as metabolites; there is a risk for accumulation in hepatic impairment. In addition, caution is advisable when using bupropion in patients with severe hepatic impairment because this condition can increase the risk of seizures.

    Renal disease, renal failure, renal impairment

    Forfivo XL, a 450 mg extended-release tablet formulation of bupropion, is not recommended in patients with renal impairment since a lower dosage strength is not available for use in this patient population. Other bupropion products should be used with extreme caution in patients with renal disease or renal failure because the parent compound or active metabolites could accumulate. Consider reduced dosages in these patient populations based on the degree of organ impairment, and closely monitor for adverse reactions that could indicate high drug or metabolite levels.

    Acute myocardial infarction, cardiac disease, heart failure, hypertension, tobacco smoking

    Rarely, bupropion may cause a fast or irregular heart beat or increases in blood pressure in some patients. It should be used with caution in patients with a recent history of acute myocardial infarction or unstable cardiac disease, including heart failure. Pharmacokinetic studies suggest that left ventricular dysfunction results in lowered metabolism and excretion of bupropion and its metabolites. Because treatment with bupropion can result in elevated blood pressure and hypertension, patients should have their blood pressure checked prior to bupropion initiation and periodically throughout treatment. Bupropion may be used in combination with nicotine transdermal systems (NTS) as an aide to smoking cessation. In clinical trials, new onset treatment-induced hypertension or exacerbation of existing high blood pressure occurred more commonly in patients using the combination bupropion-NTS therapy. In some cases the exacerbation of hypertension required discontinuation of bupropion treatment. Patients should quit tobacco smoking prior to initiating the nicotine therapy in the bupropion-NTS combination regimen to reduce the risk of unwanted cardiac side effects. Close blood pressure monitoring is recommended. Patients who are taking bupropion should not self-treat with OTC nicotine products; the bupropion-NTS combination should only be used under the prescription and advice of a health-care prescriber. When used as monotherapy, patients should schedule to stop tobacco smoking during the second week of taking bupropion. When bupropion is used for smoking cessation, it should be noted that cessation of tobacco smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline and warfarin due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation. Bupropion has been used in children and adolescents for the treatment of attention-deficit hyperactivity disorder (ADHD). Sudden unexplained death has occurred in adults and pediatric patients receiving stimulants at standard dosages for ADHD. Although bupropion is not a stimulant medication, the American Heart Association recommends conducting a detailed patient and family history and physical examination prior to initiating any ADHD pharmacologic treatment, and obtaining a baseline electrocardiogram (ECG) is a reasonable addition to the initial evaluation. Once the medication is started, a repeat ECG may be helpful if the original ECG was obtained before the child was 12 years old, if cardiac symptoms develop, or there is a change in family history. If a child or adolescent has any significant findings on physical examination, ECG, or family history, consult a pediatric cardiologist before initiating the medication.

    Geriatric

    Of roughly 6,000 patients in bupropion studies for both smoking cessation and depression, 275 were 65 and over and 47 were 75 and over. Several hundred geriatric patients 65 years of age and older have also been studied (in depression) with the immediate release formulation. Both initial and maintenance doses should be reduced in elderly patients if hepatic or renal impairment or debilitating disease is present. Multiple dose pharmacokinetic studies have indicated the elderly may be at risk for bupropion and metabolite accumulation. It may be useful to monitor renal function in the elderly. Bupropion may also cause weight loss which may be significant for elderly or otherwise debilitated patients. According to the Beers Criteria, bupropion is considered a potentially inappropriate medication (PIM) for use in geriatric patients with chronic seizures or epilepsy and should generally be avoided in these populations because bupropion lowers the seizure threshold. However, the Beers expert panel states that bupropion may be acceptable in geriatric patients with well-controlled seizures in whom alternative agents have not been effective. Bupropion labeling states the drug is contraindicated in patients with a seizure disorder. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, the duration of therapy should be in accordance with pertinent literature for the condition being treated, including clinical practice guidelines. All residents being treated for depression with any antidepressant should be monitored closely for worsening of depression and/or suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, somnolence, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk for falls. Bupropion may increase seizure risk and activity in susceptible individuals. Prior to discontinuation, many antidepressants may need a taper to avoid a withdrawal syndrome. Concurrent use of two or more antidepressants may increase the risk of side effects; in such cases there should be documentation of expected benefits that outweigh the associated risks and monitoring for any increase in side effects. Monitoring should consist of a review for continued need at least quarterly, and documentation of the rationale for continuation. When the drug is being used to manage behavior, stabilize mood, or treat a psychiatric disorder, the facility should attempt to taper the medication as outlined in the OBRA guidelines, unless a taper is clinically contraindicated.

    Driving or operating machinery, ethanol intoxication

    Patients should be warned to use caution when driving or operating machinery or performing other tasks that require mental alertness until they know how bupropion will affect them. Some patients have reported lower alcohol tolerance during treatment with bupropion; advise patients that the consumption of alcohol should be minimized or avoided; avoid ethanol intoxication.

    Closed-angle glaucoma, increased intraocular pressure

    Caution is recommended when prescribing bupropion to patients with closed-angle glaucoma. The pupillary dilation that can occur with antidepressants may precipitate a closed-angle glaucoma attack in patients with anatomically narrow angles who do not have a patent iridectomy. An acute attack of closed-angle glaucoma is considered a medical emergency because the increased intraocular pressure is rapid and severe, and may quickly result in blindness if left untreated.

    Abrupt discontinuation

    It is generally recommended to avoid abrupt discontinuation of antidepressants. If discontinuing bupropion, the medication should be tapered as rapidly as possible, but with recognition that abrupt discontinuation can also cause adverse symptoms. Because Forfivo XL is only available in a 450 mg tablet, the manufacturer recommends using another bupropion formulation for tapering the dose prior to discontinuation.

    ADVERSE REACTIONS

    Severe

    suicidal ideation / Delayed / 0.1-1.0
    seizures / Delayed / 0.1-0.4
    anaphylactoid reactions / Rapid / 0.1-0.3
    coma / Early / 0-0.1
    stroke / Early / 0-0.1
    myocardial infarction / Delayed / 0-0.1
    GI perforation / Delayed / 0-0.1
    GI bleeding / Delayed / 0-0.1
    bronchospasm / Rapid / 0-0.1
    Tourette's syndrome / Delayed / Incidence not known
    pulmonary embolism / Delayed / Incidence not known
    AV block / Early / Incidence not known
    ocular hypertension / Delayed / Incidence not known
    pancreatitis / Delayed / Incidence not known
    exfoliative dermatitis / Delayed / Incidence not known
    SIADH / Delayed / Incidence not known
    pancytopenia / Delayed / Incidence not known
    rhabdomyolysis / Delayed / Incidence not known
    erythema multiforme / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    serum sickness / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    anaphylactic shock / Rapid / Incidence not known
    akinesia / Delayed / Incidence not known
    tardive dyskinesia / Delayed / Incidence not known
    hearing loss / Delayed / Incidence not known
    neonatal abstinence syndrome / Early / Incidence not known

    Moderate

    constipation / Delayed / 4.0-26.0
    migraine / Early / 1.0-25.7
    blurred vision / Early / 2.0-14.6
    sinus tachycardia / Rapid / 0.1-10.8
    confusion / Early / 0.1-8.4
    palpitations / Early / 2.0-6.0
    hostility / Early / 0.1-5.6
    hypertension / Early / 1.0-4.3
    chest pain (unspecified) / Early / 0-4.0
    impotence (erectile dysfunction) / Delayed / 3.4-3.4
    memory impairment / Delayed / 0-3.0
    hot flashes / Early / 1.0-3.0
    hypotension / Rapid / 2.5-2.5
    dysphoria / Early / 0.1-2.0
    dysphagia / Delayed / 0-2.0
    oral ulceration / Delayed / 2.0-2.0
    vaginal bleeding / Delayed / 2.0-2.0
    urinary retention / Early / 0-1.9
    pseudoparkinsonism / Delayed / 0-1.5
    akathisia / Delayed / 0-1.5
    euphoria / Early / 1.2-1.2
    dysarthria / Delayed / 0.1-1.0
    depression / Delayed / 0.1-1.0
    psychosis / Early / 0.1-1.0
    peripheral vasodilation / Rapid / 0.1-1.0
    orthostatic hypotension / Delayed / 0.1-1.0
    jaundice / Delayed / 0.1-1.0
    elevated hepatic enzymes / Delayed / 0.1-1.0
    teeth grinding (bruxism) / Delayed / 0.1-1.0
    glossitis / Early / 0.1-1.0
    testicular swelling / Early / 0.1-1.0
    ejaculation dysfunction / Delayed / 0.1-1.0
    dyspnea / Early / 1.0-1.0
    peripheral edema / Delayed / 0.1-1.0
    hypertonia / Delayed / 0.1-1.0
    aphasia / Delayed / 0-0.1
    neuropathic pain / Delayed / 0-0.1
    EEG changes / Delayed / 0-0.1
    amnesia / Delayed / 0-0.1
    phlebitis / Rapid / 0-0.1
    colitis / Delayed / 0-0.1
    dyspareunia / Delayed / 0-0.1
    dysuria / Early / 0-0.1
    cystitis / Delayed / 0-0.1
    ataxia / Delayed / 1.0
    mania / Early / 1.0
    hallucinations / Early / 1.0
    myoclonia / Delayed / 1.0
    edema / Delayed / 1.0
    stomatitis / Delayed / 1.0
    dystonic reaction / Delayed / 1.0
    dyskinesia / Delayed / 1.0
    impulse control symptoms / Delayed / Incidence not known
    delirium / Early / Incidence not known
    esophagitis / Delayed / Incidence not known
    hepatitis / Delayed / Incidence not known
    hyperglycemia / Delayed / Incidence not known
    hypoglycemia / Early / Incidence not known
    glycosuria / Early / Incidence not known
    hyponatremia / Delayed / Incidence not known
    leukopenia / Delayed / Incidence not known
    lymphadenopathy / Delayed / Incidence not known
    thrombocytopenia / Delayed / Incidence not known
    anemia / Delayed / Incidence not known
    myasthenia / Delayed / Incidence not known
    urinary incontinence / Early / Incidence not known

    Mild

    insomnia / Early / 11.0-40.0
    headache / Early / 25.0-34.0
    agitation / Early / 2.0-31.9
    xerostomia / Early / 4.0-27.6
    weight loss / Delayed / 14.0-23.2
    vomiting / Early / 2.0-22.9
    nausea / Early / 9.0-22.9
    hyperhidrosis / Delayed / 5.0-22.3
    tremor / Early / 2.0-21.1
    anorexia / Delayed / 1.0-18.3
    weight gain / Delayed / 2.0-13.6
    pharyngitis / Delayed / 3.0-13.0
    rhinitis / Early / 12.0-12.0
    dizziness / Early / 6.0-11.0
    abdominal pain / Early / 2.0-9.0
    infection / Delayed / 8.0-9.0
    anxiety / Delayed / 3.1-8.0
    rash (unspecified) / Early / 3.0-8.0
    diarrhea / Early / 4.0-7.0
    flatulence / Early / 6.0-6.0
    myalgia / Early / 2.0-6.0
    tinnitus / Delayed / 1.0-6.0
    arthralgia / Delayed / 1.0-5.0
    sinusitis / Delayed / 1.0-5.0
    fatigue / Early / 5.0-5.0
    increased urinary frequency / Early / 1.0-5.0
    menstrual irregularity / Delayed / 4.7-4.7
    flushing / Rapid / 0-4.0
    dysgeusia / Early / 2.0-4.0
    pruritus / Rapid / 2.0-4.0
    asthenia / Delayed / 2.0-4.0
    cough / Delayed / 1.0-4.0
    appetite stimulation / Delayed / 2.0-3.7
    hypersalivation / Early / 0.1-3.4
    dyspepsia / Early / 3.1-3.1
    libido decrease / Delayed / 3.1-3.1
    drowsiness / Early / 2.0-3.0
    irritability / Delayed / 2.0-3.0
    diplopia / Early / 2.0-3.0
    restlessness / Early / 1.0-2.0
    paresthesias / Delayed / 0.1-2.0
    dysmenorrhea / Delayed / 2.0-2.0
    urticaria / Rapid / 0-2.0
    xerosis / Delayed / 2.0-2.0
    fever / Early / 1.0-2.0
    epistaxis / Delayed / 2.0-2.0
    urinary urgency / Early / 0-2.0
    syncope / Early / 0-1.2
    chills / Rapid / 1.2-1.2
    vertigo / Early / 0.1-1.0
    emotional lability / Early / 0.1-1.0
    paranoia / Early / 0.1-1.0
    xerophthalmia / Early / 0.1-1.0
    gastroesophageal reflux / Delayed / 0.1-1.0
    polydipsia / Early / 0-1.0
    gingivitis / Delayed / 0.1-1.0
    vaginal irritation / Early / 0.1-1.0
    gynecomastia / Delayed / 0.1-1.0
    acne vulgaris / Delayed / 0.1-1.0
    photosensitivity / Delayed / 0.1-1.0
    ecchymosis / Delayed / 0.1-1.0
    back pain / Delayed / 0.1-1.0
    muscle cramps / Delayed / 0.1-1.0
    dental pain / Delayed / 0.1-1.0
    polyuria / Early / 0.1-1.0
    hyperkinesis / Delayed / 0.1-1.0
    pallor / Early / 0-0.1
    maculopapular rash / Early / 0-0.1
    hirsutism / Delayed / 0-0.1
    malaise / Early / 0-0.1
    hair discoloration / Delayed / 0-0.1
    drug-induced body odor / Delayed / 0-0.1
    lethargy / Early / 19.8
    libido increase / Delayed / 1.0
    alopecia / Delayed / 1.0
    influenza / Delayed / 2.0
    nasal congestion / Early / 2.0
    nocturia / Early / 1.0
    mydriasis / Early / Incidence not known
    leukocytosis / Delayed / Incidence not known

    DRUG INTERACTIONS

    Acetaminophen; Aspirin, ASA; Caffeine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
    Acetaminophen; Butalbital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Acetaminophen; Butalbital; Caffeine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Acetaminophen; Butalbital; Caffeine; Codeine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Concomitant use of a potent CYP2D6 inhibitor like bupropion with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    Acetaminophen; Caffeine; Magnesium Salicylate; Phenyltoloxamine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
    Acetaminophen; Caffeine; Phenyltoloxamine; Salicylamide: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
    Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Acetaminophen; Codeine: (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Acetaminophen; Dextromethorphan; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Acetaminophen; Oxycodone: (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as oxycodone may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Acetaminophen; Pentazocine: (Moderate) Plasma concentrations of opiate agents metabolized by CYP2D6, such as pentazocine, may be increased if bupropion, an inhibitor of the CYP2D6 isoenzyme, is added. Dosage reductions of pentazocine may be needed. Conversely, if bupropion therapy is discontinued, dosages of pentazocine may need to be adjusted upward in some patients.
    Acetaminophen; Propoxyphene: (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as propoxyphene may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Acetaminophen; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Acetaminophen; Tramadol: (Major) Increased serum concentrations of tramadol and reduced serum concentrations of the O-desmethyltramadol metabolite (M1) would be expected from concurrent use of tramadol and a CYP2D6 inhibitor such as bupropion. As the analgesic activity of tramadol is due to both the parent drug and M1, inhibition of CYP2D6 by bupropion may affect the analgesic effect of tramadol; reduced analgesic effects are possible. Also, administration of tramadol may enhance the seizure risk in patients taking other medications that decrease the seizure threshold such as bupropion.
    Acetazolamide: (Moderate) It should be noted that when anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), that bupropion should not be used by patients with a preexisting seizure disorde; this represents a disease-drug interaction, and not a drug-drug interaction per se. Bupropion may be combined with anticonvulsant treatments with caution when an anticonvulsant is used for non-epilepsy conditions. Addiive CNS effects are possible, and the patient may feel dizzy, drowsy or more tired when taking these drugs together.
    Acrivastine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Alosetron: (Moderate) Alosetron, if used with drugs that have anticholinergic effects such as bupropion, may seriously worsen constipation, leading to events such as GI obstruction/impaction or paralytic ileus. Although specific recommendations are not available from the manufacturer, it would be prudent to avoid these drugs in patients taking alosetron.
    Amantadine: (Major) Use caution when concurrently administering bupropion and amantadine; if concurrent use is necessary, low initial dosing and slow dosage titration of bupropion should be considered. Both bupropion and amantadine have dopamine agonist effects, and coadministration may result in additive CNS dopaminergic effects. Reported adverse reactions have included neurologic side effects such as restlessness, agitation, gait disturbance, vertigo, and dizziness; some patients have required hospitalization. In reported cases, discontinuation of the drugs resulted in symptom resolution.
    Amitriptyline: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Amitriptyline; Chlordiazepoxide: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Amobarbital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Amoxapine: (Major) Concurrent administration of amoxapine with bupropion should be undertaken only with extreme caution due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus may reduce the clearance of amoxapine leading to a potential for increased Cmax, AUC and half-life. Amoxapine appears to be metabolized via CYP2D6. Low initial dosing and gradual dose increases of both drugs should be employed. If bupropion is added to a regimen of a patient already receiving amoxapine, the need to reduce the amoxapine dosage should be considered.
    Amphetamine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Amphetamine; Dextroamphetamine Salts: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Amphetamine; Dextroamphetamine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Anticonvulsants: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Aripiprazole: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Armodafinil: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Asenapine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Aspirin, ASA; Butalbital; Caffeine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Aspirin, ASA; Butalbital; Caffeine; Codeine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy. (Moderate) Concomitant use of a potent CYP2D6 inhibitor like bupropion with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Aspirin, ASA; Oxycodone: (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as oxycodone may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Atazanavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
    Atropine: (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including bupropion. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Atropine; Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving intravenous methylene blue. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with intravenous methylene blue, bupropion should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of methylene blue. It is not known if administration of methylene blue by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including bupropion. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Atropine; Difenoxin: (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including bupropion. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Atropine; Diphenoxylate: (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including bupropion. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Atropine; Edrophonium: (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including bupropion. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. (Moderate) The anticholinergic effects of atropine may be enhanced when combined with other drugs with moderate to significant anticholinergic effects including bupropion. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    atypical antipsychotic: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Azelastine; Fluticasone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Barbiturates: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Beclomethasone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Belladonna Alkaloids; Ergotamine; Phenobarbital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Benzoic Acid; Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate: (Severe) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving intravenous methylene blue. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with intravenous methylene blue, bupropion should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of methylene blue. It is not known if administration of methylene blue by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Benzphetamine: (Major) The risk of seizures from the use of bupropion may be increased with concomitant use of CNS stimulants and anorectics that may induce seizures, including benzphetamine. Concurrent use is not recommended. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
    Benztropine: (Moderate) Additive anticholinergic effects may be seen when benztropine is used concomitantly with other drugs that possess anticholinergic properties, such as bupropion. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Betamethasone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Bethanechol: (Moderate) Bupropion exhibits moderate anticholinergic properties. Avoid co-use when possible since the effects of bethanechol, a cholinergic agonist, may be diminished. If co-use is necessary, monitor for the intended clinical response.
    Brexpiprazole: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Brimonidine; Timolol: (Minor) Monitor for an increased incidence of timolol-related adverse effects if bupropion and timolol are used concomitantly. Coadministration of bupropion and timolol may result in increased plasma concentrations of timolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Timolol is a CYP2D6 substrate.
    Brompheniramine; Hydrocodone; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Brompheniramine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Budesonide: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Budesonide; Formoterol: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Butabarbital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Caffeine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
    Caffeine; Ergotamine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including caffeine, is associated with an increased seizure risk and may increase this risk during the concurrent use of bupropion. Carefully consider a patient's caffeine intake from all sources, including medicines. Monitor for irritability, tremor, increased blood pressure, insomnia and seizures. Many non-prescription medicines and weight loss aids may contain caffeine and patients should read labels carefully. Examples of foods and beverages containing caffeine include coffee, teas, colas, energy drinks, chocolate, and some herbal or dietary supplements. Patients should be advised to limit excessive caffeine intake during bupropion therapy.
    Carbamazepine: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Carbetapentane; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Carbidopa; Levodopa: (Major) Use bupropion cautiously in patients taking levodopa or combination drugs containing levodopa (e.g., carbidopa; levodopa and carbidopa; levodopa; entacapone). Both drugs are dopamine agonists; cumulative effects may result in central nervous system (CNS) toxicity. Adverse reactions reported with coadministration have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. If levodopa is used concurrently, low initial dosing and slow dosage titration of bupropion may be warranted.
    Carbidopa; Levodopa; Entacapone: (Major) Use bupropion cautiously in patients taking levodopa or combination drugs containing levodopa (e.g., carbidopa; levodopa and carbidopa; levodopa; entacapone). Both drugs are dopamine agonists; cumulative effects may result in central nervous system (CNS) toxicity. Adverse reactions reported with coadministration have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. If levodopa is used concurrently, low initial dosing and slow dosage titration of bupropion may be warranted.
    Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Carbinoxamine; Hydrocodone; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Carbinoxamine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Cariprazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Carvedilol: (Minor) Monitor for an increased incidence of carvedilol-related adverse effects if bupropion and carvedilol are used concomitantly. Coadministration of bupropion and carvedilol may result in increased plasma concentrations of carvedilol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Carvedilol is a CYP2D6 substrate.
    Cetirizine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Cevimeline: (Moderate) Cevimeline is partially metabolized by CYP2D6. Inhibitors of this isoenzyme, like bupropion, would be expected to lead to an increase in cevimeline plasma concentrations.
    Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Chlordiazepoxide; Clidinium: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should consider this when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
    Chlorpheniramine; Codeine: (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of a potent CYP2D6 inhibitor like bupropion with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary. (Moderate) Concomitant use of a potent CYP2D6 inhibitor like bupropion with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Chlorpheniramine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Chlorpromazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Ciclesonide: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Cimetidine: (Moderate) Cimetidine has resulted in increased plasma concentrations of the active metabolites, threohydrobupropion and erythrobupropion, but the clinical significance is not known.
    Citalopram: (Moderate) A pharmacokinetic interaction has been observed between bupropion and citalopram. In one study, bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the kinetics of bupropion or its metabolites. The mechanism of this interaction has not been clearly established since citalopram is primarily metabolized by the isoenzymes CYP3A4 and CYP2C19 and bupropion and its metabolite hydroxybupropion are metabolized by CYP2B6 and are inhibitors of CYP2D6.
    Clomipramine: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Clopidogrel: (Moderate) Concomitant treatment with clopidogrel and bupropion can increase bupropion exposure but decrease hydroxybupropion exposure; based on clinical response, bupropion dosage adjustment may be necessary. Adverse reactions to bupropion, such as tremor, nausea, dry mouth, insomnia, headache, or seizures, may be more likely to occur. At high concentrations in vitro, clopidogrel is a potent inhibitor of CYP2B6, and bupropion is a CYP2B6 substrate. In a study in healthy male volunteers, clopidogrel 75 mg once daily increased the Cmax and AUC of bupropion by 40% and 60%, respectively.
    Clozapine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Alafenamide: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
    Cobicistat; Elvitegravir; Emtricitabine; Tenofovir Disoproxil Fumarate: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
    Codeine: (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Codeine; Guaifenesin: (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Codeine; Phenylephrine; Promethazine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as promethazine. In addition, co-administration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as promethazine, should be approached with caution. Dosage reductions of promethazine may be needed, particularly if chronic co-administration is anticipated. If bupropion therapy is discontinued, the promethazine dosage may need to be increased in some patients. During acute therapy with promethazine, it is advisable to initiate treatment with a low dose and slowly titrate if this combination must be used; the patient should be closely monitored. (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Codeine; Promethazine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as promethazine. In addition, co-administration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as promethazine, should be approached with caution. Dosage reductions of promethazine may be needed, particularly if chronic co-administration is anticipated. If bupropion therapy is discontinued, the promethazine dosage may need to be increased in some patients. During acute therapy with promethazine, it is advisable to initiate treatment with a low dose and slowly titrate if this combination must be used; the patient should be closely monitored. (Moderate) Patients receiving inhibitors of the CYP2D6 isoenzyme, like bupropion, will have a reduction in the metabolic conversion of codeine to morphine and therefore may not experience an adequate analgesic response to codeine.
    Corticosteroids: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Corticotropin, ACTH: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Cortisone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Crizotinib: (Moderate) Monitor for an increase in bupropion-related adverse reactions if coadministration with crizotinib is necessary. Crizotinib is an inhibitor of CYP2B6 in vitro, and bupropion is extensively metabolized by CYP2B6 in vitro.
    Cyclobenzaprine: (Major) Concurrent use of cyclobenzaprine with bupropion increases the possibility of developing serotonin syndrome. If these drugs must be used together, closely monitor the patient for signs and symptoms of serotonin syndrome. If such a reaction develops, immediately discontinue both drugs. Additionally, cyclobenzaprine possesses antimuscarinic properties, which can cause dry mouth, urinary difficulties and slowing of gastrointestinal motility. If used with other drugs with antimuscarinic properties, such as bupropion, anticholinergic side effects can be additive. Particular attention should be paid to GI problems because of the possible development of paralytic ileus.
    Dabrafenib: (Major) The concomitant use of dabrafenib and bupropion may lead to decreased bupropion concentrations and loss of efficacy. Use of an alternative agent is recommended. If concomitant use of these agents is unavoidable, monitor patients for loss of bupropion efficacy. In vitro, dabrafenib is an inducer of CYP2B6 via activation of the pregnane X receptor and constitutive androstane receptor nuclear receptors. Bupropion is a sensitive CYP2B6 substrate.
    Darifenacin: (Moderate) Bupropion, an inhibitor of CYP2D6 may inhibit the metabolism of darifenacin. In addition, bupropion is associated with moderate anticholinergic effects which could be additive when coadministered with darifenacin. Patients should be monitored for increased anticholinergic effects or other adverse effects when these two drugs are coadministered. Dosage adjustments may be necessary.
    Darunavir; Cobicistat: (Moderate) Caution is warranted when cobicistat is administered with bupropion as there is a potential for elevated cobicistat concentrations. Bupropion is a CYP2D6 inhibitor in vitro, while cobicistat is a substrate of CYP2D6.
    Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%.
    Deflazacort: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Desipramine: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Desloratadine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Deutetrabenazine: (Major) Do not exceed 18 mg/dose or 36 mg/day of deutetrabenazine if must use concurrently with a strong CYP2D6 inhibitor. Bupropion is a strong CYP2D6 inhibitor, and the metabolites of deutetrabenazine, alpha- and beta-HTBZ, are CYP2D6 substrates. The systemic exposure of alpha- and beta-HTBZ may be increased resulting in an increase in deutetrabenazine-related adverse reactions, like QT prolongation and drowsiness.
    Dexamethasone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Dexmethylphenidate: (Major) Drugs that may lower the seizure threshold, such as dexmethylphenidate, should be used cautiously in patients taking bupropion, an antidepressant with a dose-related risk of seizures. Patients should be closely monitored if this combination is necessary.
    Dextroamphetamine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Dextromethorphan; Guaifenesin; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Dextromethorphan; Promethazine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as promethazine. In addition, co-administration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as promethazine, should be approached with caution. Dosage reductions of promethazine may be needed, particularly if chronic co-administration is anticipated. If bupropion therapy is discontinued, the promethazine dosage may need to be increased in some patients. During acute therapy with promethazine, it is advisable to initiate treatment with a low dose and slowly titrate if this combination must be used; the patient should be closely monitored.
    Dicyclomine: (Moderate) Additive anticholinergic effects may be seen when dicyclomine is used concomitantly with other drugs that possess anticholinergic properties, such as bupropion. Clinicians should note that anticholinergic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Diethylpropion: (Major) Drugs which may lower the seizure threshold, such as diethylpropion, should be used with great caution or avoided in patients taking bupropion. The manufacturer recommends low initial dosing and slow dosage titration of bupropion if this combination must be used concurrently; the patient should be closely monitored.
    Digoxin: (Moderate) Plasma digoxin concentrations and the patient's clinical response to digoxin therapy should be monitored during concurrent use with bupropion, due to the potential for decreased systemic exposure to digoxin. When a single oral dose of 0.5 mg of digoxin was administered 24 hours after a single 150 mg oral dose of extended-release bupropion in healthy volunteers, the digoxin exposure was decreased.
    Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary. (Moderate) Concomitant use of a potent CYP2D6 inhibitor like bupropion with dihydrocodeine-containing products may decrease the metabolism of dihydrocodeine to dihydromorphine. Although theoretical, patients may experience varying degrees of analgesia if they take dihydrocodeine with a CYP2D6 inhibitor.
    Dorzolamide; Timolol: (Minor) Monitor for an increased incidence of timolol-related adverse effects if bupropion and timolol are used concomitantly. Coadministration of bupropion and timolol may result in increased plasma concentrations of timolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Timolol is a CYP2D6 substrate.
    Doxepin: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Doxercalciferol: (Moderate) CYP450 enzyme inhibitors, like bupropion, may inhibit the 25-hydroxylation of doxercalciferol, thereby decreasing the formation of the active metabolite and thus, decreasing efficacy. Patients should be monitored for a decrease in efficacy if cytochrome P450 inhibitors are coadministered with doxercalciferol.
    Doxorubicin: (Major) In vitro, bupropion is a mild CYP2D6 inhibitor and doxorubicin is a major CYP2D6 substrate. Clinically significant interactions have been reported when doxorubicin was coadministered with inhibitors of CYP2D6, resulting in increased concentration and clinical effect of doxorubicin. Avoid coadministration of bupropion and doxorubicin if possible. If not possible, closely monitor for increased side effects of doxorubicin including myelosuppression and cardiotoxicity.
    Dutasteride; Tamsulosin: (Moderate) Use caution when administering tamsulosin with a strong CYP2D6 inhibitor such as bupropion. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure. If concomitant use in necessary, monitor patient closely for increased side effects.
    Efavirenz: (Major) Concurrent use of efavirenz 600 mg/day and bupropion in healthy volunteers resulted in a reduction of the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged and the Cmax of hydroxybupropion was increased by 50%. Healthcare providers are advised to increase the dose of bupropion based on clinical response during concurrent use with efavirenz; however, the maximum recommended dose of bupropion should not be exceeded.
    Efavirenz; Emtricitabine; Tenofovir: (Major) Concurrent use of efavirenz 600 mg/day and bupropion in healthy volunteers resulted in a reduction of the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged and the Cmax of hydroxybupropion was increased by 50%. Healthcare providers are advised to increase the dose of bupropion based on clinical response during concurrent use with efavirenz; however, the maximum recommended dose of bupropion should not be exceeded.
    Eluxadoline: (Moderate) The effect CYP enzymes have on the metabolism of eluxadoline has not been definitively established; therefore, the manufacturer recommends caution when administering eluxadoline concurrently with stong CYP2D6 inhibitors, such as bupropion. When administering these drugs together, closely monitor patients for eluxadoline-related side effects, such as impaired mental and physical abilities need to safely drive or operate machinery.
    Encainide: (Major) Encainide is significantly metabolized by CYP2D6 isoenzymes. Caution is recommended when administering encainide with CYP2D6 inhibitors, such as bupropion, since encainide exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions.
    Ethanol: (Major) Bupropion is associated with a dose-related risk of seizures. Both ethanol abuse and abrupt discontinuation of ethanol have been associated with seizures and fatalities, and may increase the risk of seizures and/or neuropsychiatric events with bupropion treatment. The use of ethanol or the abrupt discontinuation of ethanol should be avoided in patients taking bupropion. During post-marketing use of bupropion, some patients who were drinking alcohol reported reduced alcohol tolerance.
    Ethotoin: (Moderate) It should be noted that when anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), that bupropion should not be used by patients with a preexisting seizure disorder; this represents a disease-drug interaction, and not a drug-drug interaction per se. Bupropion may be combined with anticonvulsant treatments with caution when an anticonvulsant is used for non-epilepsy conditions (e.g., neuropathic pain, mood disorders). Bupropion may interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as phenytoin (as well as other hydantoins like fosphenytoin or ethotoin).
    Felbamate: (Major) Bupropion should not be used by patients taking anticonvulsants for seizures because it may decrease the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function.
    Fexofenadine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Flavoxate: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
    Flecainide: (Major) Flecainide is significantly metabolized by CYP2D6 isoenzymes. Caution is recommended when administering flecainide with CYP2D6 inhibitors, such as bupropion; flecainide exhibits a narrow therapeutic range and large increases in serum concentrations may be associated with severe adverse reactions.
    Fludrocortisone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Flunisolide: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Fluoxetine: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including fluoxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added.
    Fluoxetine; Olanzapine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including fluoxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added.
    Fluphenazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Fluticasone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Fluticasone; Salmeterol: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Fluticasone; Umeclidinium; Vilanterol: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Fluticasone; Vilanterol: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Fluvoxamine: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including fluvoxamine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that fluvoxamine inhibits the hydroxylation of bupropion.
    Formoterol; Mometasone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Fosphenytoin: (Moderate) It should be noted that when anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), that bupropion should not be used by patients with a preexisting seizure disorder; this represents a disease-drug interaction, and not a drug-drug interaction per se. Bupropion may be combined with anticonvulsant treatments with caution when an anticonvulsant is used for non-epilepsy conditions (e.g., neuropathic pain, mood disorders). Bupropion may interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as phenytoin (as well as other hydantoins like fosphenytoin or ethotoin).
    Gabapentin: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Gefitinib: (Major) Monitor for an increased incidence of gefitinib-related adverse effects if gefitinib and bupropion are used concomitantly; this also applies to combination products containing bupropion, such as bupropion; naltrexone. Gefitinib is metabolized significantly by CYP3A4 and to a lesser extent by CYP2D6; in vitro, bupriopion is a weak CYP2D6 inhibitor. Coadministration may decrease the metabolism of gefitinib and increase gefitinib concentrations. While the manufacturer has provided no guidance regarding the use of gefitinib with CYP2D6 inhibitors, in patients with poor CYP2D6 metabolism, the mean exposure to gefitinib was 2-fold higher when compared to extensive metabolizers; the contribution of drugs that inhibit CYP2D6 on gefitinib exposure has not been evaluated.
    Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Glycopyrrolate; Formoterol: (Moderate) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Guaifenesin; Hydrocodone; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Guaifenesin; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Guanfacine: (Moderate) There is one case report that describes a grand mal seizure that occurred in a child of 10 years of age receiving guanfacine and bupropion concurrently. It is not possible, based on this limited report, to determine if guanfacine was a contributor to the event. Causality has not been established.
    Haloperidol: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as haloperidol, should be approached with caution. Dosage reductions of haloperidol may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Homatropine; Hydrocodone: (Moderate) Additive anticholinergic effects may be seen when homatropine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Hydantoins: (Moderate) It should be noted that when anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), that bupropion should not be used by patients with a preexisting seizure disorder; this represents a disease-drug interaction, and not a drug-drug interaction per se. Bupropion may be combined with anticonvulsant treatments with caution when an anticonvulsant is used for non-epilepsy conditions (e.g., neuropathic pain, mood disorders). Bupropion may interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as phenytoin (as well as other hydantoins like fosphenytoin or ethotoin).
    Hydrochlorothiazide, HCTZ; Metoprolol: (Minor) Monitor for an increased incidence of metoprolol-related adverse effects if bupropion and metoprolol are used concomitantly. Coadministration of bupropion and metoprolol may result in increased plasma concentrations of metoprolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Metoprolol is primarily metabolized by CYP2D6 isoenzymes.
    Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Monitor for an increased incidence of propranolol-related adverse effects if bupropion and propranolol are used concomitantly. Coadministration of bupropion and propranolol may result in increased plasma concentrations of propranolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Propranolol is a CYP2D6 substrate.
    Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Hydrocodone; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Hydrocortisone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Hydromorphone: (Moderate) Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Hydroxyprogesterone: (Moderate) In vitro studies indicate that hydroxyprogesterone increases the metabolic rate of CYP2B6 isoenzymes. The metabolism of drugs metabolized by CYP2B6, such as bupropion may be increased during treatment with hydroxyprogesterone.
    Hyoscyamine: (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Hyoscyamine; Methenamine; Methylene Blue; Phenyl Salicylate; Sodium Biphosphate: (Severe) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving intravenous methylene blue. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with intravenous methylene blue, bupropion should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of methylene blue. It is not known if administration of methylene blue by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Ibuprofen; Oxycodone: (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as oxycodone may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Ibuprofen; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Iloperidone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Imipramine: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Indacaterol; Glycopyrrolate: (Moderate) Additive anticholinergic effects may be seen when glycopyrrolate is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Isavuconazonium: (Moderate) Caution and close monitoring are advised when administering isavuconazonium concurrently with buproprion, as decreased buproprion serum concentrations may result. If decreased bupropion efficacy is noted, it may be necessary to increase the dose (not to exceed the maximum recommended dose). Isavuconazole, the active moiety of isavuconazonium, is an inducer of hepatic isoenzyme CYP2B6; bupropion is metabolized by this enzyme.
    Isocarboxazid: (Severe) Monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with bupropion or within 14 days of discontinuing treatment with bupropion. Conversely, bupropion should not be initiated within 14 days of stopping an MAOI. There is an increased risk of hypertensive reactions when bupropion is used concurrently with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism, such as MAOIs.
    Isoniazid, INH: (Moderate) In theory, concurrent use of bupropion and isoniazid, INH may result in a hypertensive reaction. Bupropion increases monoamine neurotransmitter levels (dopamine and norepinephrine) through reuptake inhibition and isoniazid is a weak inhibitor of monoamine oxidase (MAO), an enzyme system which contributes to the degradation of monoamine neurotransmitters. The risk of hypertension is increased if bupropion is administered with monoamine oxidase inhibitors (MAOIs) or other drugs that increase dopaminergic or noradrenergic activity. Although the manufacturer of bupropion makes no recommendations regarding isoniazid, bupropion is contraindicated for use with MAOIs intended to treat psychiatric disorders (e.g., phenelzine) as well as other drugs with MAOI activity (e.g., linezolid, methylene blue).
    Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function such as rifampin. Pharmacokinetic studies describe patients who developed subtherapeutic bupropion serum concentrations when enzyme-inducing agents were added. In healthy volunteers, coadministration of bupropion with rifampin reduced the mean AUC of bupropion by 3-fold and the mean half-life from 15.9 hours to 8.2 hours. (Moderate) In theory, concurrent use of bupropion and isoniazid, INH may result in a hypertensive reaction. Bupropion increases monoamine neurotransmitter levels (dopamine and norepinephrine) through reuptake inhibition and isoniazid is a weak inhibitor of monoamine oxidase (MAO), an enzyme system which contributes to the degradation of monoamine neurotransmitters. The risk of hypertension is increased if bupropion is administered with monoamine oxidase inhibitors (MAOIs) or other drugs that increase dopaminergic or noradrenergic activity. Although the manufacturer of bupropion makes no recommendations regarding isoniazid, bupropion is contraindicated for use with MAOIs intended to treat psychiatric disorders (e.g., phenelzine) as well as other drugs with MAOI activity (e.g., linezolid, methylene blue).
    Isoniazid, INH; Rifampin: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function such as rifampin. Pharmacokinetic studies describe patients who developed subtherapeutic bupropion serum concentrations when enzyme-inducing agents were added. In healthy volunteers, coadministration of bupropion with rifampin reduced the mean AUC of bupropion by 3-fold and the mean half-life from 15.9 hours to 8.2 hours. (Moderate) In theory, concurrent use of bupropion and isoniazid, INH may result in a hypertensive reaction. Bupropion increases monoamine neurotransmitter levels (dopamine and norepinephrine) through reuptake inhibition and isoniazid is a weak inhibitor of monoamine oxidase (MAO), an enzyme system which contributes to the degradation of monoamine neurotransmitters. The risk of hypertension is increased if bupropion is administered with monoamine oxidase inhibitors (MAOIs) or other drugs that increase dopaminergic or noradrenergic activity. Although the manufacturer of bupropion makes no recommendations regarding isoniazid, bupropion is contraindicated for use with MAOIs intended to treat psychiatric disorders (e.g., phenelzine) as well as other drugs with MAOI activity (e.g., linezolid, methylene blue).
    Kava Kava, Piper methysticum: (Moderate) The German Commission E and other groups warn that any substances that act on the CNS, including psychopharmacologic agents, may interact with the phytomedicinal kava kava, Piper methysticum. These interactions are probably pharmacodynamic in nature, or result from additive mechanisms of action.
    Lacosamide: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Lamotrigine: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Levetiracetam: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Levodopa: (Major) Use bupropion cautiously in patients taking levodopa or combination drugs containing levodopa (e.g., carbidopa; levodopa and carbidopa; levodopa; entacapone). Both drugs are dopamine agonists; cumulative effects may result in central nervous system (CNS) toxicity. Adverse reactions reported with coadministration have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. If levodopa is used concurrently, low initial dosing and slow dosage titration of bupropion may be warranted.
    Linezolid: (Severe) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving linezolid, an antibiotic that is also a non-selective monoamine oxidase (MAO) inhibitor. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with linezolid, bupropion should be discontinued immediately and linezolid therapy initiated only if acceptable alternatives are not available and the potential benefits of linezolid outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of linezolid, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of linezolid.
    Lisdexamfetamine: (Major) The risk of seizures from the use of bupropion may be increased with concomitant use of CNS stimulants that may induce seizures, including the lisdexamfetamine. Concurrent use is not recommended. Extreme caution and close clinical monitoring is recommended if these agents must be used together.
    Loperamide: (Moderate) The plasma concentration of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with bupropion, a weak in vitro CYP2D6 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Loperamide; Simethicone: (Moderate) The plasma concentration of loperamide, a CYP2D6 substrate, may be increased when administered concurrently with bupropion, a weak in vitro CYP2D6 inhibitor. If these drugs are used together, monitor for loperamide-associated adverse reactions, such as CNS effects and cardiac toxicities (i.e., syncope, ventricular tachycardia, QT prolongation, torsade de pointes, cardiac arrest).
    Lopinavir; Ritonavir: (Moderate) Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%.
    Loratadine; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Lorcaserin: (Moderate) Based on the mechanism of action of lorcaserin and the theoretical potential for serotonin syndrome, use with extreme caution in combination with other drugs that may affect the serotonergic neurotransmitter systems, including, bupropion. Patients receiving this combination should be monitored for the emergence of serotonin syndrome or Neuroleptic Malignant Syndrome (NMS) like signs and symptoms.
    Loxapine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of bupropion by decreasing its systemic exposure. If used together, monitor patients closely for loss of bupropion efficacy; a bupropion dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Bupropion is a substrate of CYP2B6; in vitro data suggest that lumacaftor may induce this enzyme.
    Lumacaftor; Ivacaftor: (Moderate) Lumacaftor; ivacaftor may reduce the efficacy of bupropion by decreasing its systemic exposure. If used together, monitor patients closely for loss of bupropion efficacy; a bupropion dosage adjustment may be required to obtain the desired therapeutic effect. Do not exceed the maximum recommended dose. Bupropion is a substrate of CYP2B6; in vitro data suggest that lumacaftor may induce this enzyme.
    Lurasidone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Maprotiline: (Major) Concurrent administration of maprotiline with bupropion should be undertaken only with extreme caution due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus may reduce the clearance of maprotiline leading to a potential for increased Cmax, AUC and half-life. Maprotiline appears to be metabolized via CYP2D6. Low initial dosing and gradual dose increases of both drugs should be employed. If bupropion is added to a regimen of a patient already receiving maprotiline, the need to reduce the maprotiline dosage should be considered.
    Mepenzolate: (Moderate) Additive anticholinergic effects may be seen when mepezolate is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Meperidine: (Moderate) Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Meperidine; Promethazine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as promethazine. In addition, co-administration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as promethazine, should be approached with caution. Dosage reductions of promethazine may be needed, particularly if chronic co-administration is anticipated. If bupropion therapy is discontinued, the promethazine dosage may need to be increased in some patients. During acute therapy with promethazine, it is advisable to initiate treatment with a low dose and slowly titrate if this combination must be used; the patient should be closely monitored. (Moderate) Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Mephobarbital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Mesoridazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Methadone: (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as methadone may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Methamphetamine: (Major) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as methamphetamine. If used together, use low initial doses of bupropion and increase the dose gradually.
    Methenamine; Sodium Acid Phosphate; Methylene Blue; Hyoscyamine: (Severe) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving intravenous methylene blue. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with intravenous methylene blue, bupropion should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of methylene blue. It is not known if administration of methylene blue by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome. (Moderate) Additive anticholinergic effects may be seen when hyoscyamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Methohexital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Methscopolamine: (Moderate) Additive anticholinergic effects may be seen when methscopolamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Methylene Blue: (Severe) Due to an increased risk of hypertensive reactions, treatment initiation with bupropion is contraindicated in patients currently receiving intravenous methylene blue. If urgent psychiatric treatment is required, interventions other than bupropion (e.g., alternative medication, hospitalization) should be considered. Conversely, in patients receiving bupropion and requiring urgent treatment with intravenous methylene blue, bupropion should be discontinued immediately and methylene blue therapy initiated only if acceptable alternatives are not available and the potential benefits of methylene blue outweigh the risks. The patient should be monitored for hypertensive reactions for two weeks or until 24 hours after the last dose of methylene blue, whichever comes first. Bupropion may be re-initiated 24 hours after the last dose of methylene blue. It is not known if administration of methylene blue by other routes (e.g., orally, local injection) or in doses less than 1 mg/kg IV can produce a similar outcome.
    Methylphenidate: (Major) Drugs which may lower the seizure threshold, such as methylphenidate, should be used with great caution or avoided in patients taking bupropion. The manufacturer recommends low initial dosing and slow dosage titration of bupropion if this combination must be used concurrently; the patient should be closely monitored.
    Methylprednisolone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Metoclopramide: (Major) Metoclopramide is a substrate of CYP2D6 and bupropion is a strong CYP2D6 inhibitor; due to the risk of increased metoclopramide plasma concentrations and extrapyramidal adverse reactions, dose adjustments of oral metoclopramide are recommended when administered in combination with strong CYP2D6 inhibitors. In patients with gastroesophageal reflux receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), the recommended dose of metoclopramide is 5 mg PO four times daily or 10 mg PO three times daily. In patients with diabetic gastroparesis receiving a strong CYP2D6 inhibitor or who are known CYP2D6 poor metabolizers (PMs), the recommended dose of metoclopramide is 5 mg PO four times daily times daily.
    Metoprolol: (Minor) Monitor for an increased incidence of metoprolol-related adverse effects if bupropion and metoprolol are used concomitantly. Coadministration of bupropion and metoprolol may result in increased plasma concentrations of metoprolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Metoprolol is primarily metabolized by CYP2D6 isoenzymes.
    Mexiletine: (Major) Coadministration of bupropion and mexiletine can increase the exposure of mexiletine. If used together, it may be necessary to decrease the dose of mexiletine and slowly titrate to effect. Mexiletine is primarily metabolized via CYP2D6 and bupropion and its metabolites are inhibitors of CYP2D6.
    Midazolam: (Moderate) Bupropion is contraindicated in patients undergoing abrupt withdrawal of benzodiazepines since the risk of seizures associated with bupropion may be increased. Excessive use of benzodiazepines is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion.
    Mifepristone, RU-486: (Moderate) Use mifepristone with caution in combination with drugs metabolized by CYP2B6, such as bupropion. Although not studied, mifepristone is an inhibitor of CYP2B6 and, theoretically, may cause significantly increased serum concentrations of drugs metabolized by CYP2B6.
    Modafinil: (Major) Bupropion is associated with a dose-related risk of seizures. It is unclear whether modafinil lowers the seizure threshold. Seizures have occurred during post-marketing use of modafinil, although the frequency is unknown.
    Molindone: (Major) Drugs which may lower the seizure threshold, such as molindone, should be used with great caution or avoided in patients taking bupropion. The manufacturer recommends low initial dosing and slow dosage titration of bupropion if this combination must be used concurrently; the patient should be closely monitored.
    Mometasone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Monoamine oxidase inhibitors: (Severe) Monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with bupropion or within 14 days of discontinuing treatment with bupropion. Conversely, bupropion should not be initiated within 14 days of stopping an MAOI. There is an increased risk of hypertensive reactions when bupropion is used concurrently with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism, such as MAOIs.
    Morphine: (Moderate) Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Morphine; Naltrexone: (Moderate) Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Naproxen; Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Nebivolol: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with bupropion. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as bupropion, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nebivolol; Valsartan: (Moderate) Monitor for increased toxicity as well as increased therapeutic effect of nebivolol if coadministered with bupropion. Nebivolol is metabolized by CYP2D6. Although data are lacking, CYP2D6 inhibitors, such as bupropion, could potentially increase nebivolol plasma concentrations via CYP2D6 inhibition; the clinical significance of this potential interaction is unknown, but an increase in adverse effects is possible.
    Nelfinavir: (Minor) In vitro studies suggest that nelfinavir inhibits the hydroxylation of bupropion. The clinical significance of this finding is unknown.
    Nicotine: (Moderate) Combination of nicotine and bupropion may induce clinically significant blood pressure elevations in some patients. Close monitoring of blood pressure is recommended if this combination is prescribed.
    Nitroglycerin: (Minor) Nitroglycerin can cause hypotension. This action may be additive with other agents that can cause hypotension such as antidepressants. Patients should be monitored more closely for hypotension if nitroglycerin is used concurrently with antidepressants.
    Non-Ionic Contrast Media: (Major) Use of medications that lower the seizure threshold should be carefully evaluated when considering intrathecal radiopaque contrast agents. Bupropion should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.
    Nortriptyline: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Olanzapine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Ombitasvir; Paritaprevir; Ritonavir: (Moderate) Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%.
    Oxcarbazepine: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Oxybutynin: (Moderate) Additive anticholinergic effects may be seen when oxybutynin is used concomitantly with other drugs with moderate to significant anticholinergic effects including bupropion. Clinicians should note that anticholinergic effects might be seen not only on bladder smooth muscle, but also on GI function, the eye, and temperature regulation. Additive drowsiness may also occur.
    Oxycodone: (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as oxycodone may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Oxymorphone: (Moderate) Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Paliperidone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Paroxetine: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including paroxetine. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that paroxetine inhibit the hydroxylation of bupropion.
    Pemoline: (Major) Drugs which may lower the seizure threshold, such as pemoline, should be used with great caution or avoided in patients taking bupropion. The manufacturer recommends low initial dosing and slow dosage titration of bupropion if this combination must be used concurrently; the patient should be closely monitored.
    Pentazocine: (Moderate) Plasma concentrations of opiate agents metabolized by CYP2D6, such as pentazocine, may be increased if bupropion, an inhibitor of the CYP2D6 isoenzyme, is added. Dosage reductions of pentazocine may be needed. Conversely, if bupropion therapy is discontinued, dosages of pentazocine may need to be adjusted upward in some patients.
    Pentazocine; Naloxone: (Moderate) Plasma concentrations of opiate agents metabolized by CYP2D6, such as pentazocine, may be increased if bupropion, an inhibitor of the CYP2D6 isoenzyme, is added. Dosage reductions of pentazocine may be needed. Conversely, if bupropion therapy is discontinued, dosages of pentazocine may need to be adjusted upward in some patients.
    Pentobarbital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Perphenazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Perphenazine; Amitriptyline: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients. (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Phendimetrazine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of phendimetrazine is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Phenelzine: (Severe) Monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with bupropion or within 14 days of discontinuing treatment with bupropion. Conversely, bupropion should not be initiated within 14 days of stopping an MAOI. There is an increased risk of hypertensive reactions when bupropion is used concurrently with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism, such as MAOIs.
    Phenobarbital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Phenothiazines: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Phentermine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, such as phentermine, may be associated with an increased seizure risk; therefore, seizures may be more likely to occur in patients receiving this weight loss aide with bupropion. Patients should be closely monitored if this combination is necessary. Do not combine therapy with phentermine or phentermine-combinations and bupropion; naltrexone due to this risk and the duplication of therapy for weight loss.
    Phentermine; Topiramate: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, such as phentermine, may be associated with an increased seizure risk; therefore, seizures may be more likely to occur in patients receiving this weight loss aide with bupropion. Patients should be closely monitored if this combination is necessary. Do not combine therapy with phentermine or phentermine-combinations and bupropion; naltrexone due to this risk and the duplication of therapy for weight loss. (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Phenylephrine; Promethazine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as promethazine. In addition, co-administration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as promethazine, should be approached with caution. Dosage reductions of promethazine may be needed, particularly if chronic co-administration is anticipated. If bupropion therapy is discontinued, the promethazine dosage may need to be increased in some patients. During acute therapy with promethazine, it is advisable to initiate treatment with a low dose and slowly titrate if this combination must be used; the patient should be closely monitored.
    Phenytoin: (Moderate) It should be noted that when anticonvulsants are used for the purpose of treating epilepsy (versus use in mood disorders or neuropathic pain or other non-epilepsy conditions), that bupropion should not be used by patients with a preexisting seizure disorder; this represents a disease-drug interaction, and not a drug-drug interaction per se. Bupropion may be combined with anticonvulsant treatments with caution when an anticonvulsant is used for non-epilepsy conditions (e.g., neuropathic pain, mood disorders). Bupropion may interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as phenytoin (as well as other hydantoins like fosphenytoin or ethotoin).
    Pimozide: (Major) Drugs which may lower the seizure threshold, such as pimozide, should be used with great caution or avoided in patients taking bupropion. The manufacturer recommends low initial dosing and slow dosage titration of bupropion if this combination must be used concurrently; the patient should be closely monitored.
    Prednisolone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Prednisone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Primidone: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Procarbazine: (Severe) There is an increased risk of hypertensive reactions when bupropion is co-administered with monoamine oxidase inhibitors (MAOIs), and the combination is contraindicated. Therefore, concurrent use of bupropion and medications with MAO activity, such as procarbazine, should be avoided.
    Prochlorperazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Promethazine: (Moderate) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as promethazine. In addition, co-administration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as promethazine, should be approached with caution. Dosage reductions of promethazine may be needed, particularly if chronic co-administration is anticipated. If bupropion therapy is discontinued, the promethazine dosage may need to be increased in some patients. During acute therapy with promethazine, it is advisable to initiate treatment with a low dose and slowly titrate if this combination must be used; the patient should be closely monitored.
    Propafenone: (Major) Bupropion is an inhibitor of CYP2D6. Concentrations of medications metabolized by CYP2D6, such as propafenone, may be increased if bupropion is added. Dosage reductions of propafenone may be needed.
    Propantheline: (Moderate) Additive anticholinergic effects may be seen when propantheline is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Propoxyphene: (Moderate) Bupropion is an inhibitor of the CYP2D6 isoenzyme. Plasma concentrations of opiate agents metabolized by CYP2D6 such as propoxyphene may be increased if bupropion is added. Dosage reductions in these agents may be needed. Conversely, if bupropion therapy is discontinued, dosages of these agents may need to be adjusted upward in some patients. Excessive use of opioid agonists (e.g., opiate addiction) is associated with an increased seizure risk; seizures may be more likely to occur during concurrent use of bupropion in these patients since bupropion is associated with a dose-related risk of seizures.
    Propranolol: (Minor) Monitor for an increased incidence of propranolol-related adverse effects if bupropion and propranolol are used concomitantly. Coadministration of bupropion and propranolol may result in increased plasma concentrations of propranolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Propranolol is a CYP2D6 substrate.
    Protriptyline: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Pseudoephedrine: (Major) Bupropion is associated with a dose-related risk of seizures. Excessive use of psychostimulants, including non-prescription stimulants and weight loss medications, is associated with an increased seizure risk; seizures may be more likely to occur in these patients during concurrent use of bupropion. Patients should be closely monitored if these combinations are necessary.
    Quetiapine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Ranolazine: (Moderate) Bupropion inhibits CYP2D6. Coadministration of bupropion with medications that are metabolized by CYP2D6, like ranolazine, may result in increased ranolazine plasma concentrations if bupropion is added.
    Rasagiline: (Severe) Monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with bupropion or within 14 days of discontinuing treatment with bupropion. Conversely, bupropion should not be initiated within 14 days of stopping an MAOI. There is an increased risk of hypertensive reactions when bupropion is used concurrently with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism, such as MAOIs. The manufacturer of rasagiline advises against concurrent use with any antidepressant.
    Rifampin: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function such as rifampin. Pharmacokinetic studies describe patients who developed subtherapeutic bupropion serum concentrations when enzyme-inducing agents were added. In healthy volunteers, coadministration of bupropion with rifampin reduced the mean AUC of bupropion by 3-fold and the mean half-life from 15.9 hours to 8.2 hours.
    Risperidone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Ritonavir: (Moderate) Concurrent administration of bupropion with ritonavir results in decreased concentrations of bupropion and its active metabolite. According to the manufacturers of bupropion, increased doses of bupropion may be necessary during concurrent therapy; however, the maximum recommended dose of bupropion should not be exceeded. Closely monitor bupropion efficacy if these drugs are given together. Ritonavir induces CYP2B6, which is responsible for bupropion's metabolism. In one study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. In addition, exposure to the active metabolite of bupropion (hydroxybupropion) was decreased by 23%. When given with ritonavir 600 mg twice daily, the AUC and Cmax of bupropion decreased by 66% and 63% respectively and exposure to hydroxybupropion decreased by 78%.
    Scopolamine: (Moderate) Additive anticholinergic effects may be seen when scopolamine is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Secobarbital: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Selegiline: (Severe) Monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with bupropion or within 14 days of discontinuing treatment with bupropion. Conversely, bupropion should not be initiated within 14 days of stopping an MAOI. There is an increased risk of hypertensive reactions when bupropion is used concurrently with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism, such as MAOIs.
    Sertraline: (Moderate) Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by CYP2D6 should be approached with caution. Many selective serotonin reuptake inhibitors (SSRIs) are CYP2D6 substrates including sertraline. Although clinical evidence of interactions is lacking, plasma concentrations of SSRIs metabolized by CYP2D6 may be increased if bupropion is added. In addition, in vitro studies suggest that sertraline inhibits the hydroxylation of bupropion.
    Sodium Oxybate: (Major) Use extreme caution when coadministering bupropion with other drugs that lower the seizure threshold, such as sodium oxybate. The risk of seizures with bupropion is dose related and is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment If used together, use low initial doses of bupropion and increase the dose gradually.
    Tamoxifen: (Major) Tamoxifen is converted to endoxifen and other active metabolites by cytochrome P450 (CYP) enzymes (e.g., 2D6, 3A4). Bupropion is considered a moderate to potent inhibitor of CYP2D6; reduced tamoxifen efficacy is possible with concomitant use. If treatment with an antidepressant and tamoxifen is necessary, it may be preferable to use an agent that exhibits mild inhibition of CYP2D6.
    Tamsulosin: (Moderate) Use caution when administering tamsulosin with a strong CYP2D6 inhibitor such as bupropion. Tamsulosin is extensively metabolized by CYP2D6 hepatic enzymes. In clinical evaluation, concomitant treatment with a strong CYP2D6 inhibitor resulted in increases in tamsulosin exposure. If concomitant use in necessary, monitor patient closely for increased side effects.
    Theophylline, Aminophylline: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as aminophylline. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, when bupropion is used for smoking cessation, it should be noted that cessation of smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline or aminophylline, due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation. (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as theophylline. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, when bupropion is used for smoking cessation, it should be noted that cessation of smoking may result in elevated serum concentrations of some drugs that are hepatically metabolized, such as theophylline or aminophylline, due to lowered induction of hepatic oxidative microsomal enzymes (tobacco smoke induces hepatic enzymes). Downward dosage adjustments of such drugs and more frequent monitoring may be required during smoking cessation.
    Thiethylperazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Thiopental: (Moderate) Bupropion may interact with drugs that induce hepatic microsomal isoenzyme function via CYP2B6 such as the barbiturates. While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded. Advise patients that until they are reasonably certain that the combination does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
    Thioridazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Thiothixene: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Tiagabine: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Ticlopidine: (Moderate) Ticlopidine is a potent inhibitor of CYP2B6. By inhibiting this isoenzyme, ticlopidine theoretically could increase the plasma concentrations of drugs that are metabolized by CYP2B6, such as bupropion. Adverse reactions of bupropion, such as tremor, nausea, dry mouth, insomnia, headache, or seizures, may be more likely to occur.
    Timolol: (Minor) Monitor for an increased incidence of timolol-related adverse effects if bupropion and timolol are used concomitantly. Coadministration of bupropion and timolol may result in increased plasma concentrations of timolol. Bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Timolol is a CYP2D6 substrate.
    Tobacco: (Moderate) Tobacco contains nicotine as one of its active components, but it is unclear if continuing to smoke concurrently with bupropion use increases the risk of blood pressure elevation. Bupropion has not been reported to interact pharmacokinetically with tobacco when used as monotherapy for smoking cessation; however, when bupropion is used as monotherapy, patients should schedule a date to stop tobacco smoking during the second week of taking bupropion. If the patient is prescribed a combination of bupropion with nicotine replacement therapy (like Nicotine patches) to stop smoking; then the patient should stop Tobacco smoking before starting to use the nicotine replacement therapy. Monitor blood pressure during smoking cessation treatment.
    Tolterodine: (Moderate) Bupropion exhibits moderate anticholinergic effects. Clinicians should keep this in mind when using antimuscarinics and other medications with anticholinergic activity in combination with bupropion.
    Topiramate: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Tramadol: (Major) Increased serum concentrations of tramadol and reduced serum concentrations of the O-desmethyltramadol metabolite (M1) would be expected from concurrent use of tramadol and a CYP2D6 inhibitor such as bupropion. As the analgesic activity of tramadol is due to both the parent drug and M1, inhibition of CYP2D6 by bupropion may affect the analgesic effect of tramadol; reduced analgesic effects are possible. Also, administration of tramadol may enhance the seizure risk in patients taking other medications that decrease the seizure threshold such as bupropion.
    Tranylcypromine: (Severe) Monoamine oxidase inhibitors (MAOIs) intended to treat psychiatric disorders are contraindicated for use with bupropion or within 14 days of discontinuing treatment with bupropion. Conversely, bupropion should not be initiated within 14 days of stopping an MAOI. There is an increased risk of hypertensive reactions when bupropion is used concurrently with other drugs that inhibit the reuptake of dopamine or norepinephrine or inhibit their metabolism, such as MAOIs.
    Triamcinolone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as systemic corticosteroids. The manufacturer recommends low initial dosing and slow dosage titration if these combinations must be used; the patient should be closely monitored.
    Triazolam: (Moderate) Bupropion is contraindicated in patients undergoing abrupt withdrawal of benzodiazepines since the risk of seizures associated with bupropion may be increased. Excessive use of a benzodiazepine is associated with an increased seizure risk upon discontinuation of the drug; seizures may be more likely to occur in these patients during concurrent use of bupropion.
    Tricyclic antidepressants: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Trifluoperazine: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored. In addition, bupropion and hydroxybupropion, the major active metabolite, are inhibitors of CYP2D6 in vitro. Coadministration of bupropion with medications that are metabolized by the CYP2D6 isoenzyme, such as phenothiazines and many other antipsychotics (e.g., haloperidol, risperidone), should be approached with caution. Dosage reductions of these medications may be needed. Conversely, if bupropion therapy is discontinued, the antipsychotic dosage may need to be increased in some patients.
    Trihexyphenidyl: (Moderate) Additive anticholinergic effects may be seen when trihexyphenidyl is used concomitantly with bupropion. Additive drowsiness may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.
    Trimipramine: (Major) Bupropion may interact with tricyclic antidepressants (TCAs). The manufacturer of bupropion warns of using any TCAs with bupropion due to the potential for increased risk of seizures from the lowering of seizure threshold. In addition, bupropion inhibits the hepatic isozyme CYP2D6 and thus reduces the clearance of TCAs. Bupropion-induced elevations in both imipramine and desipramine plasma concentrations may occur. TCA half-lives have increased in pharmacokinetic studies. The anticholinergic effects of bupropion may also be additive with those of the TCAs. Prolonged seizure activity has been reported following the combined use clomipramine and bupropion. The manufacturer recommends low initial dosing and slow dosage titration if these drugs must be used concurrently; the patient should be closely monitored.
    Trospium: (Moderate) Depending on the specific agent, additive anticholinergic effects may be seen when drugs with antimuscarinic properties like trospium and bupropion are used concomitantly. Clinicians should note that additive antimuscarinic effects may be seen not only on GI smooth muscle, but also on bladder function and temperature regulation. While CNS-related side effects such as drowsiness and blurred vision are not typically noted with trospium, they may occur in some patients.
    Valproic Acid, Divalproex Sodium: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Vigabatrin: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.
    Vortioxetine: (Major) The primary isoenzyme involved in the metabolim of vortioxetine is CYP2D6; therefore, the manufacturer recommends a reduction in the vortioxetine dose by one-half during co-administration with strong inhibitors of CYP2D6 such as bupropion. The vortioxetine dose should be increased to the original level when the CYP2D6 inhibitor is discontinued.
    Warfarin: (Moderate) When bupropion is used for smoking cessation, be aware that changes in the INR may occur in patients previously stabilized on warfarin as tobacco smoking is reduced or halted, as smoking affects CYP1A2, one of the enzymes involved in warfarin metabolism. Physiological changes resulting from smoking cessation, with or without treatment with bupropion, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g.,warfarin) for which dosage adjustment may be necessary. A case report of potential interaction with warfarin and bupropion used for depression has been reported; when bupropion was abruptly halted in the patient prior to surgery, the patient's INR increased to 8.0. The authors could not discern a probable mechanism for the potential interaction, but the patient was also reducing his daily tobacco smoking status, Patients who are receiving warfarin with bupropion should be carefully monitored if the patient is also altering their smoking status.
    Ziprasidone: (Major) Bupropion is associated with a dose-related risk of seizures. Extreme caution is recommended during concurrent use of other drugs that may lower the seizure threshold such as antipsychotics. The manufacturer of bupropion recommends low initial dosing and slow dosage titration if this combination must be used; the patient should be closely monitored.
    Zolpidem: (Moderate) Rare cases of hallucinations have occurred when zolpidem was administered concurrently with bupropion. Dosage reductions in zolpidem may be needed if bupropion is used concurrently.
    Zonisamide: (Moderate) Bupropion should not be used by patients with a preexisting seizure disorder because it may lower the seizure threshold. Bupropion may also interact pharmacokinetically with anticonvulsant drugs that induce hepatic microsomal isoenzyme function such as carbamazepine, barbiturates, or phenytoin, as well as fosphenytoin and ethotoin.

    PREGNANCY AND LACTATION

    Pregnancy

    According to the manufacturer, bupropion and its metabolites are excreted into human breast milk, and caution should be exercised when bupropion is administered to a breast-feeding woman. Peak breast milk concentrations of bupropion and its metabolites are present within 2 to 4 hours after an oral dose. In one lactation study (n = 10), the average daily infant exposure to bupropion and its active metabolites (assuming 150 mL/kg daily consumption) was 2% of the maternal weight-adjusted dose. One case report describes a possible seizure in a breast-fed infant during maternal use of extended-release bupropion. In two other cases, no infant-related adverse events were noted during breast-feeding. Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because a pooled analysis found that maternal use of sertraline, along with nortriptyline and paroxetine, usually produced undetectable or low drug concentrations in infant serum, these agents may be the preferred antidepressants when initiating antidepressant therapy in a breast-feeding mother. For smoking cessation treatment, nicotine replacement products may be considered as an alternate therapy to bupropion. The decision of whether to use nicotine replacement therapy in a woman who is breast-feeding should be evaluated in comparison to the risks associated with exposure of the infant to nicotine and other tobacco contaminants in the breast milk as well as those of passive exposure to tobacco smoke. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

    MECHANISM OF ACTION

    The action of bupropion is not fully understood. Bupropion selectively inhibits the neuronal reuptake of dopamine and is significantly more potent than either imipramine or amitriptyline in this regard. Actions on dopaminergic systems, however, require doses higher than those needed for a clinical antidepressant effect. The blockade of norepinephrine reuptake at the neuronal membrane is weaker for bupropion than for tricyclic antidepressants. CNS-stimulant effects are dose-related. Bupropion does not inhibit monoamine oxidase or the reuptake of serotonin. Bupropion does exhibit moderate anticholinergic effects, and produces a sensation of mild local anesthesia on the oral mucosa. Antidepressant activity is usually noted within 1—3 weeks of initiation of bupropion treatment; full effects may not be seen until 4 weeks of therapy.
     
    The mechanism by which bupropion enhances the ability to abstain from tobacco smoking is unknown, but is probably related to inhibition of noradrenergic or dopaminergic neuronal uptake. The resultant increase in norepinephrine may attenuate nicotine withdrawal symptoms. Increased dopamine at neuronal sites may reduce nicotine cravings and the urge to smoke. Because the onset of activity is usually after 1 week of treatment, patients should start bupropion 1—2 weeks prior to their chosen smoking 'quit-day'. In smoking cessation, the ability to abstain from smoking continuously through the seventh week of bupropion therapy is associated with maintenance of long-term abstinence. Patients who have not stopped smoking by the seventh week of treatment are generally considered non-responsive to bupropion treatment.

    PHARMACOKINETICS

    Bupropion is administered orally as the hydrochloride salt (Wellbutrin, Wellbutrin SR, Wellbutrin XL, Zyban, Forfivo XL) or hydrobromide salt (Aplenzin). Bupropion is a racemic mixture; however, the pharmacologic actions and pharmacokinetics of the individual enantiomers have not been evaluated. The drug readily crosses the blood-brain barrier. Plasma protein binding is about 84%.
     
    Metabolism takes place in the liver, producing several metabolites; the 3 major active metabolites are hydroxybupropion, threohydrobupropion, and erythrohydrobupropion. CYP2B6 is involved in forming hydroxybupropion, the major metabolite, previously known as morpholinol. All active metabolites are present in higher concentrations in the plasma than the parent compound. In mice, hydroxybupropion appears to have one-half the potency of bupropion; the other metabolites are one-tenth to one-half as potent. Bupropion appears to induce its own metabolism, but this does not appear to be clinically significant. The terminal elimination half-life of immediate-release bupropion is approximately 14 hours with a range of 8—24 hours. The terminal elimination half-life of the sustained-release hydrochloride product and the extended-release hydrobromide product is roughly 21 hours. Half-lives for hydroxybupropion, erythrohydroxybupropion, and threohydroxybupropion are 20 hours, 33 hours, and 37 hours, respectively. Less than 1% is excreted unchanged in the urine. Over 60% is excreted as metabolites in the urine within 24 hours; over 80% is eliminated in 96 hours. Less than 10% of metabolites are excreted in the feces.
     
    Steady-state concentrations of bupropion and its metabolites are achieved in 5—8 days; however, antidepressant effects have an onset of roughly 1—3 weeks.
     
    Affected cytochrome P450 isoenzymes: CYP2D6, CYP2B6
    Because of the extensive metabolism of bupropion by CYP2B6, clinically significant drug interactions are possible with drugs that are metabolized by or are inhibitors or inducers of this isoenzyme. In vitro data indicate that bupropion and hydroxybupropion are inhibitors of CYP2D6.

    Oral Route

    Based on animal data, the oral bioavailability is roughly 5—20%; oral bioavailability in humans has not been determined.
    Wellbutrin, Wellbutrin SR, and Wellbutrin XL: Bupropion XL has been found to be bioequivalent to the immediate-release tablet, sustained-release tablet, and extended-release hydrobromide tablet. In studies of healthy volunteers, administration with food increased Cmax and AUC by 11—35% and 16—19%, respectively. These changes are not considered clinically significant; therefore, bupropion can be taken with or without food. Peak plasma concentrations are achieved within 1.5 hours after administration of immediate-release bupropion, and within 3 hours after administration of sustained-release hydrochloride formulations. Peak plasma concentrations of the active metabolite hydroxybupropion occur about 3 hours after administration of immediate-release bupropion. Peak plasma concentrations of hydroxybupropion are about 10 times those of bupropion at steady state. Plasma bupropion concentrations are dose-proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma levels are maintained in chronic use.
    Aplenzin: Peak plasma concentrations are achieved within approximately 5 hours after administration of the hydrobromide tablet. Peak plasma concentrations of the active metabolite hydroxybupropion occur about 6 hours after administration. Peak plasma concentrations of hydroxybupropion are about 10 times those of bupropion at steady state.
    Forfivo XL: Following a single dose of Forfivo XL, a 450 mg extended-release bupropion tablet formulation, the median time to peak plasma concentrations is about 5 hours under fasting conditions and 12 hours under fed conditions. The mean systemic exposure to bupropion is increased by 25% when taken with food. Peak plasma concentrations of hydroxybupropion occur about 10 hours after a dose of Forfivo XL under fasting conditions and 16 hours under fed conditions. The food effect is not considered clinically significant; therefore, Forfivo XL may be taken without regard to meals. In a single dose study under fasting conditions, one 450 mg dose of Forfivo XL was equivalent to a dose consisting of three 150 mg tablets of Wellbutrin XL.