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Bupropion
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General Dosing Information
100 mg PO twice daily, initially. May increase the dose to 100 mg PO 3 times daily after 3 days, and then up to 450 mg/day after several weeks if inadequate response. Max: 450 mg/day and 150 mg/dose.[41086]
1.4 to 6 mg/kg/day PO, titrated upward slowly and administered in divided doses. Usual dose: 3 mg/kg/day. Max: 250 to 300 mg/day.[25844]
150 mg PO once daily, initially. May increase the dose to 150 mg PO twice daily after 3 days, and then 200 mg PO twice daily after several weeks if inadequate response. Max: 400 mg/day.[40993]
2 mg/kg/dose (Max: 100 mg/dose) PO once daily for 2 to 3 weeks, initially. May increase the dose to 3 mg/kg/dose (Max:150 mg/dose) PO once daily for 2 to 3 weeks, then 3 mg/kg/dose (Max: 150 mg/dose) PO every morning and 2 mg/kg/dose (Max: 150 mg/dose) PO every evening for 2 to 3 weeks, and then 3 mg/kg/dose (Max: 150 mg/dose) PO twice daily if inadequate response.[62394] Alternately, 100 mg PO once daily for 1 week, initially. May increase the dose to 150 mg PO once daily for 2 weeks, then 150 mg PO twice daily for 1 to 3 weeks, and then 200 mg PO twice daily if inadequate response.[32355]
150 mg PO once daily, initially. May increase the dose to 300 mg PO once daily after at least 4 days if inadequate response. Max: 450 mg/day.[41057] Taper dose to discontinue.[41057] [46944]
174 mg PO once daily in the morning, initially. After 4 days, may increase to the target dose of 348 mg PO once daily in the morning.[44095]
174 mg bupropion hydrobromide PO once daily for 150 mg/day bupropion hydrochloride, 348 mg bupropion hydrobromide PO once daily for 300 mg/day bupropion hydrochloride, and 522 mg bupropion hydrobromide PO once daily for 450 mg/day bupropion hydrochloride. Give doses in the morning.[44095]
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.[41057]
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.[44095]
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.[24871]
Off-label use in adolescents has been reported; more studies are needed in the arena of adolescent smoking cessation to determine the most effective methods for cessation; no large, well controlled trials have been performed.[62712] Dosing is the same as for 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.[62710] [62711] [62712]
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.[25849] Prior to use of combination therapy, review the complete prescribing information for both bupropion and the NTS. Monitor for treatment-induced hypertension.
150 mg PO once daily in the morning, initially. Increase the dose to 300 mg/day in 2 divided doses over 2 weeks.[58374] Doses of bupropion SR must be given at least 8 hours apart.[40993]
150 mg PO once daily in the morning for at least 1 week, initially. Increase the dose to 300 mg PO once daily during weeks 2 to 4. May further increase the dose at approximately 8 weeks based on clinical response and tolerability. Max: 450 mg PO once daily.[31600] [41057] [60873]
1.4 to 3 mg/kg/day PO in divided doses, initially. Increase the dose slowly. Average effective dose: 3 mg/kg/day. Max: 6 mg/kg/day or 150 to 300 mg/day. Limited data compared to other treatments; guidelines do not routinely recommend use in pediatric populations. Bupropion has been considered an alternative for some when other FDA-approved treatments have failed.[25850] [25851] [31603] [45900] [46924] [60873] A systematic review of available data found that bupropion had general efficacy comparable to methylphenidate but due to limited trial and effect sizes, more data are needed. Some published data suggest potential efficacy in ADHD with comorbid conditions (e.g., conduct, substance use, or depressive disorders).[64946]
150 to 300 mg/day PO, given in 2 divided doses, was reported effective in one trial. Pain relief was noted to begin at week 2 of treatment, with 73% of patients receiving bupropion reporting improvement in pain vs. 10% with placebo.[26722]
Initially, 100 mg PO twice daily. May increase to 100 mg PO 3 times per day after 3 days, if tolerated. One guideline suggests considering the use of bupropion to promote cocaine abstinence. Bupropion may be particularly helpful for patients with concomitant nicotine dependence or co-occurring depressive disorders (low certainty, conditional recommendation).[70082]
Initially, 150 mg PO once daily. May increase to 150 mg PO twice daily after 3 days, if tolerated. One guideline suggests considering the use of bupropion to promote cocaine abstinence. Bupropion may be particularly helpful for patients with concomitant nicotine dependence or co-occurring depressive disorders (low certainty, conditional recommendation).[70082]
Initially, 150 mg PO once daily. May increase to 300 mg PO once daily after at least 4 days, if tolerated. One guideline suggests considering the use of bupropion to promote cocaine abstinence. Bupropion may be particularly helpful for patients with concomitant nicotine dependence or co-occurring depressive disorders.[70082]
Initially, 150 mg PO once daily. May increase to 150 mg PO twice daily after 3 days, if tolerated. Doses of 300 mg/day were shown to have a modest effect in reducing amphetamine-type stimulant use in patients with low- to moderate-frequency stimulant use (i.e., less than 18 days per month). One guideline suggests bupropion may be particularly useful for patients with concomitant tobacco use disorder or co-occurring depressive disorders (low certainty, conditional recommendation).[70082]
Initially, 150 mg PO once daily. May increase to 300 mg PO once daily after at least 4 days, if tolerated. Doses of 300 mg/day were shown to have a modest effect in reducing amphetamine-type stimulants in patients with low- to moderate-frequency use (i.e., less than 18 days per month). One guideline suggests bupropion may be particularly useful for patients with concomitant tobacco use disorder or co-occurring depressive disorders (low certainty, conditional recommendation).[70082]
Initially, 150 mg PO once daily. After at least 4 days of dosing, may increase to 300 mg/day. Max: 450 mg/day, after appropriate titration. When given in combination with injectable naltrexone (380 mg IM every 3 to 4 weeks), bupropion appears to promote a reduction in use of amphetamine-type stimulants. In small studies of individuals with moderate or severe methamphetamine use disorder, this combination was shown to reduce methamphetamine use compared to placebo. One guideline suggests this combination may be particularly helpful for individuals with comorbid alcohol use disorder, as naltrexone has been shown to be helpful in reducing alcohol consumption. Bupropion may be helpful for individuals with comorbid tobacco use or depressive disorders (moderate certainty, conditional recommendation).[70082]
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.
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.
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.
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.
Safety and efficacy have not been established.
Safety and efficacy have not been established.
In patients with moderate to severe hepatic impairment (Child-Pugh Score 7 to 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 to 6); however, no guidelines are available.[41057][41086][44095][44094] 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.[46944]
CrCl less than 90 mL/minute: Consider reduced dosage and/or dosage frequency but specific recommendations are not available. Bupropion and its metabolites are renally eliminated and may accumulate in patients with renal impairment.[41057][41086][44095][44094] Use of Forfivo XL, a 450 mg extended-release tablet formulation, is not recommended because there is no lower dose strength.[46944]
† Off-label indication
Bupropion is an oral aminoketone antidepressant medication that is unrelated to other known antidepressants. Bupropion was initially approved for treatment of depression in 1985 but was removed from market for several years due to concerns for drug-induced seizures. Bupropion was reintroduced as a treatment for major depressive disorder in an immediate-release form (Wellbutrin) and was later approved in a twice-daily sustained-release formulation (Wellbutrin SR) and a once-daily formulation (Wellbutrin XL) for treatment of depression in adults and for treatment of depressive episodes in adults with a history of seasonal affective disorder (SAD). A once-daily formulation of bupropion hydrobromide (Aplenzin) is also approved for the treatment of major depression and depressive episodes in patients with SAD. A sustained-release formulation is approved for use as an aid in smoking cessation (Zyban) and may be used as monotherapy or in combination with nicotine transdermal systems (NTS). Bupropion has been used off-label for other conditions, including ADHD and neuropathic pain. Bupropion carries a dose-related risk for seizures. Given the multiple products available with different indications, it is important to use care in product selection and to not duplicate bupropion prescriptions, which could lead to overdosage. Additionally, all product labels for antidepressants contain a boxed warning related to an increased risk of suicidality in children, adolescents, and young adults during the initial stages of therapy when treating depression or other conditions (e.g., smoking cessation); therefore, the necessity of pharmacologic therapy versus the potential risks should be carefully considered in these populations.[23945][58403][41086][40993][41057][44095][32323][31600][26722]
For storage information, see the specific product information within the How Supplied section.
Immediate-release bupropion hydrochloride tablets (e.g., Wellbutrin):
Sustained-release bupropion hydrochloride tablets (e.g., Wellbutrin SR):
Extended-release bupropion hydrochloride tablets (e.g., Wellbutrin XL, Forfivo XL):
Sustained-release bupropion hydrochloride tablets (Smoking cessation) (e.g., Zyban):
Bupropion hydrobromide extended-release tablets (i.e., Aplenzin):
Bupropion exhibits a greater potential for causing seizures than other antidepressants; the incidence of seizures with bupropion exceeds that of other commercially available antidepressants by up to 4-fold.[23945] [41086] The incidence of seizures occurring with bupropion is dose-dependent. Seizures occur in roughly 0.1% of patients receiving up to 300 mg/day (sustained-release) and 0.4% of patients receiving up to 450 mg/day (immediate-release) of bupropion. According to the manufacturer, the incidence of seizures in patients taking Wellbutrin XL as a single dose of 450 mg is 0.4%. Although seizure incidence has not been evaluated in clinical trials of the extended-release formulation of bupropion, its bioequivalence with the immediate-release and sustained-release formulations suggests that the risk may be similar to that encountered with use of these products. The incidence of seizures rises disproportionately at dosages greater than 450 mg/day (immediate-release).[23945] In patients receiving a 600 mg/day immediate-release regimen of bupropion, the risk of seizures was estimated to be 10-fold that of patients administered the 450 mg maximum daily recommended dose. The incidence of seizures during use of bupropion hydrobromide (Aplenzin) has not been formally evaluated by the manufacturer. To limit the risk of seizures, recommended single or maximum daily dosages of any dosage form of bupropion should not be exceeded. Some patients may be more at risk of experiencing seizures with bupropion therapy. The use or withdrawal of some medication regimens, including ethanol, may lower seizure threshold; these should be utilized cautiously with bupropion. When possible, concomitant use of these medications with bupropion should be avoided.[40993] [41057] [41086] [44094] [44095]
During clinical trials of immediate-release or extended-release bupropion formulations, the following centrally-mediated effects occurred more frequently with bupropion that placebo: insomnia (11% to 31% vs. 6% to 21%), dizziness (6% to 11% vs. 5% to 7%), tremor (2% to 21.1% vs. less than 1% to 7.6%), drowsiness (2% to 3% vs. 1% to 2%), sedation or lethargy (19.8% vs. 19.5%), cutaneous temperature disturbance (1.9% vs. 1.6%), headache (25% to 34% vs. 22.2% to 26%), migraine (1% to 25.7% vs. 1% to 22.2%), impaired sleep quality (4% vs. 1.6%), paresthesias (1% to 2% vs. 1%), CNS stimulation or restlessness (1% to 2% vs. 1%), and feeling jittery (3% vs. 2%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following CNS effects and incidences were reported: insomnia (40%, 28%, 45%, 18%) and nervousness (1%, less than 1%, 2%, 0%). The incidence of ataxia/incoordination ranged from less than 0.1% to 1% or more of patients during pre-marketing or post-marketing use of bupropion. CNS effects reported in 0.1% to 1% of patients included vertigo, dysarthria, abnormal coordination, CNS stimulation, hypesthesia, and paresthesias. Rarely reported effects (less than 0.1%) included EEG changes, abnormal neurological exam, impaired attention, and aphasia. Also observed were coma, neuralgia (neuropathic pain), neuropathy, and restlessness. Some symptoms may be dose-related and may respond to dosage reduction. To limit insomnia, do not give doses close to bedtime. In some cases these symptoms may require treatment with sedative/hypnotic therapy. In roughly 2% of patients treated, CNS symptoms will necessitate drug discontinuation.[40993] [41057] [41086] [44094] [44095]
All effective antidepressants can precipitate mania in predisposed individuals suffering from bipolar disorder. Mania and hypomania have been reported in 1% or more of bupropion recipients during clinical trials. Hypomania was reported rarely (less than 0.1%) during other pre-marketing evaluations. If mania occurs, bupropion should be held and appropriate therapy to treat the manic symptoms should be initiated.[40993] [41057] [41086] [44094] [44095]
Psychiatric effects reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trials included agitation (2% to 31.9%), anxiety (3.1% to 8%), memory impairment (less than 0.5 and up to 3% ), confusion (8.4%), delusions (1.2%), impaired concentration (3.1% to 9%), hostility (5.6%), irritability (2% to 3%), thinking abnormality (1%), and abnormal dreams (3% to 5%). These reactions may happen in patients treated for major depressive disorder (MDD) or in those who use bupropion for smoking cessation. In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following psychiatric effects and incidences were reported: dysphoria (less than 1%, 1%, 2%, 1%), anxiety (8%, 6%, 9%, 6%), impaired concentration (9%, 3%, 9%, 4%), and abnormal dreams (5%, 18%, 13%, 3%). During other pre-marketing or postmarketing use, hallucinations and agitation occurred in 1% or more of patients. Memory impairment, depersonalization, psychosis, confusion, dysphoria, emotional lability, hostility, paranoia, formal thought disorder (unspecified), and frigidity were reported in 0.1 to 1% of patients. Amnesia and derealization occurred rarely (less than 0.1%). Also observed were aggression, delirium, delusions. Aggression, paranoia, and abnormal dreams have been reported during postmarketing use.[40993] [41057] [41086] [44094] [44095]
Depressive symptoms have been reported in smoking cessation studies as well as psychiatric studies with bupropion. During clinical trials for major depressive disorder, akathisia (psychomotor restlessness) was reported in 1.5% of bupropion-treated patients. Suicide attempt and completed suicide have occurred in 0.1% to 1% of patients during clinical trial evaluation or postmarketing use of bupropion. Mania can occur in predisposed patients during treatment with an antidepressant. Monitor all antidepressant-treated patients for any indication for worsening of depression or the condition being treated and the emergence of suicidal behaviors or suicidal ideation, especially during the initial few months of drug therapy and after dosage changes. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in the absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. These studies did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in patients over 24 years of age; there was a reduction in risk with antidepressant use in patients aged 65 and older. A ten-year retrospective postmarketing safety review conducted by the FDA indicated that bupropion smoking cessation products were associated with 46 cases of suicidal ideation and 29 cases of suicidal behavior in patients with a prior psychiatric history (n = 18), without this history (n = 24), or an unknown psychiatric history (n = 33). In the cases of suicidal ideation for which demographics were available, 40% were male, 60% were female, and the median age was 46 years (range 26 to 70 years). In the cases reporting suicidal behavior, 59% were male, 41% were female, and the median age was 35 years (range 15 to 70 years). A significant change in thinking and/or behaviors was reported by 23% of the patients after treatment initiation. Seventy percent of the studied patients also had a diagnosis of depression. Of the cases considered serious (n = 59), outcomes were categorized as follows and were not mutually exclusive: death (17%), hospitalization (36%), life-threatening (27%), disability (8%), intervention required (3%), and other (31%). Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation.[44094] [40993] [41057] [41086] [44095]
Frequent neurological adverse events associated with bupropion include myoclonia. During clinical trials, the incidence of myoclonia in bupropion recipients was 1% or more. Patients with Gilles de la Tourette's syndrome or a family history of this syndrome may have motor or phonetic tics unmasked or exacerbated by the use of bupropion for ADHD symptoms. Exacerbation of tics may respond to dosage reduction; in some cases bupropion may need to be discontinued.[40993] [41057] [41086] [44094] [44095]
Bupropion may cause weight loss. A weight loss of more than 5 pounds (lb.) occurred in 23.2% of patients taking immediate-release bupropion, approximately double that of patients taking tricyclic antidepressants or placebo. Approximately 14% of patients on sustained-release formulations of bupropion lose weight. Roughly 23% of patients receiving bupropion XL enrolled in seasonal affective disorder (SAD) trials had a weight loss of more than 5 lb. vs. 11% with placebo; alternatively, just 11% of bupropion XL patients had a weight gain of more than 5 lb. vs. 21% taking placebo. Weight gain may be associated with untreated depression. In general, weight gain is rare with bupropion treatment; weight gain occurred in 2% to 13.6% of bupropion recipients receiving any formulation/product during clinical trials. The incidence of anorexia reported during trials was similar for patients taking bupropion vs. placebo (roughly 1% to 18%) and may represent a symptom of the depressive illness rather than an adverse event. Although not as common, appetite stimulation (2% to 3.7%) was also reported with bupropion during clinical trials.[40993] [41057] [41086] [44094] [44095]
During clinical trials of immediate-release or extended-release bupropion formulations, the following gastrointestinal (GI) effects and incidences were reported as greater than placebo and included: dyspepsia (3.1%), nausea (9% to 22.9%), vomiting (2% to 22.9%), diarrhea (4% to 7%), constipation (5% to 26%), xerostomia (10% to 27.6%), hypersalivation (3.4%), dysphagia (0% to 2%), flatulence (6%), abdominal pain (2% to 9%), and dysgeusia (2% to 4%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy for smoking cessation, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following GI effects and incidences were reported: nausea (9%, 7%, 11%, 4%), xerostomia (10%, 4%, 9%, 4%), constipation (8%, 4%, 9%, 3%), diarrhea (4%, 4%, 3%, 1%), oral ulceration (2%, 1%, 1%, 1%), abdominal pain (3%, 4%, 1%, 1%), dysgeusia (3%, 1%, 3%, 2%), and thirst (less than 1%, less than 1%, 2%, 0%). During other pre-marketing evaluations, stomatitis was reported in 1% or more of patients. Adverse GI reactions occurring in roughly 0.1% to 1% of patients included teeth grinding (bruxism), elevated hepatic enzymes, jaundice, liver damage, excessive thirst (polydipsia), gastroesophageal reflux, gingivitis, glossitis, and hypersalivation. Rare events in less than 0.1% of patients have included colitis, GI bleeding, GI perforation, and stomach ulcer. GI adverse reactions reported during post-marketing use of bupropion include esophagitis, gum bleeding, hepatitis, and pancreatitis. Due to the voluntary nature of postmarketing reports, neither incidence nor definitive association to bupropion have been established.[40993] [41057] [41086] [44094] [44095]
Cardiac toxicity is relatively uncommon for bupropion when compared with tricyclic antidepressants. Hypertension occurred in 1% to 4.3% of patients taking bupropion during clinical trials, compared to 0% to 1.6% taking placebo. New onset or worsening of existing hypertension occurred in a higher percentage of patients (i.e., 6.1%) taking bupropion concurrently with nicotine transdermal systems (NTS) for smoking cessation; in some cases hypertension was severe. Other cardiovascular effects which occurred more frequently in those receiving bupropion formulations vs. those receiving placebo during clinical trials included: unspecified cardiac arrhythmias (5.3%), dizziness (22.3%), hypotension (2.5%), palpitations (2% to 6%), syncope (1.2%), sinus tachycardia (10.8%), chest pain (unspecified) (less than 1% to 4%) and flushing (1% to 4%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, respectively, the following cardiac effects and incidences were reported: hypertension (1%, less than 1%, 2%, 0%), palpitations (2%, 0%, 1%, 0%), and chest pain (less than 1%, 1%, 3%, 1%). Edema was reported in 1% or more of patients during pre-marketing evaluation of bupropion and flushing was reported in 1% or less. Cardiac effects reported in 0.1% to 1% of patients included unspecified chest pain, ECG changes or abnormalities (premature beats and nonspecific ST-T changes), dyspnea, orthostatic hypotension, stroke, sinus tachycardia, and peripheral vasodilation. Pallor, phlebitis, syncope, and myocardial infarction rarely occurred (less than 0.1%). Also observed in postmarketing use were complete AV block, extrasystoles, and pulmonary embolism. Drug-induced Brugada syndrome/pattern has also been reported postmarketing with bupropion-containing products.[40993] [41057] [41086] [44094] [44095]
Blurred vision affected 2% to 14.6% of bupropion-treated patients during clinical trials, compared to 2% to 10.3% taking placebo. Diplopia was reported in 2% to 3% of those receiving active drug versus 2% of those receiving placebo. During other pre-marketing or post-marketing use, blurred vision or diplopia was reported in 1% or more of patients. Other ocular effects that occurred in clinical trials or during post-marketing use included abnormal accommodation (0.1% to 1%), xerophthalmia (0.1% to 1%), ocular hypertension, and mydriasis.[40993] [41057] [41086] [44094] [44095]
Twice as many patients taking bupropion reported libido decrease (3.1%) vs. placebo (1.6%). Conversely, libido increase has been reported in 1% or more of patients receiving bupropion. Menstrual irregularity was reported as unspecified menstrual complaints by 4.7% of bupropion-treated patients as dysmenorrhea (2%) and/or as vaginal bleeding (0% to 2%), and at higher incidences vs. placebo. Impotence (erectile dysfunction) occurred in 3.4% and painful erections occurred in 0.1% to 1% of bupropion recipients during clinical trials. Cases of gynecomastia, prostate disorder, and testicular swelling have been reported in 0.1% to 1% of bupropion-treated patients. Other sexual or reproductive system reactions have also occurred and include ejaculation dysfunction (0.1% to 1%, reported as retarded ejaculation or painful ejaculation), painful erection, dyspareunia (less than 0.1%), salpingitis, and vaginal irritation (0.1% to 1%). Causal effect may be uncertain as trials were not always conducted with adequate controls.[40993] [41057] [41086] [44094] [44095]
Depending on the dosage form of bupropion used, hot flashes have been reported in 1% to 3% of treated patients; menopause was reported in less than 0.1% of bupropion recipients during clinical trials.[40993] [41057] [41086] [44094] [44095]
During clinical trials of immediate-release or extended-release bupropion formulations, hyperhidrosis occurred more frequently in the bupropion groups (5% to 22.3%) vs. placebo. Rash (unspecified) (3% to 8%), pruritus (2 to 4%), urticaria (1% to 2%), alopecia (1% or more), and xerosis (2%) were other dermatologic adverse reactions commonly reported by recipients of bupropion. Acne vulgaris (0.1% to 1%), maculopapular rash (less than 0.1%), hirsutism (less than 0.1%), photosensitivity (0.1% to 1%), and exfoliative dermatitis have also occurred infrequently or rarely with bupropion use. Acute generalized exanthematous pustulosis (AGEP) has also been reported with postmarketing use. In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following dermatologic effects and incidences were reported: rash (4%, 3%, 3%, 2%), pruritus (3%, 1%, 5%, 1%), and urticaria (2%, 0%, 2%, 0%).[40993] [41057] [41086] [44094] [44095]
Rarely, anaphylactoid reactions characterized by symptoms such as rash, pruritus, urticaria (1% to 2%), angioedema, edema, chest pain, and dyspnea (1%) requiring medical treatment have been reported in clinical trials with bupropion. Most of these events occur in 0.1% to 0.3% or less of patients treated. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome (SJS), and anaphylactic shock associated with bupropion. A case of a serum sickness reaction has also been reported in the literature. Serum-sickness-like reactions consist of delayed hypersensitivity reactions, arthralgia, myalgia, pyrexia, and rash. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) has been reported during postmarketing use of bupropion.[40993] [41057] [41086] [44094] [44095] [62974] Bupropion should be promptly discontinued and appropriate medical treatment should be initiated in patients presenting with serious hypersensitivity reactions or symptoms indicative of DRESS in whom an unrelated etiology cannot be identified.[62975] [62976]
Some endocrine side effects have been reported during postmarketing use of bupropion. These rare endocrine-related side effects have included hyperglycemia, hypoglycemia, glycosuria, hyponatremia, and syndrome of inappropriate antidiuretic hormone (SIADH). Due to the voluntary nature of postmarketing reports, neither causality nor the incidence can be established.[40993] [41057] [41086] [44094] [44095]
Hematologic and lymphatic effects reported with bupropion include infrequent cases of ecchymosis (0.1% to 1%). Anemia, leukocytosis, leukopenia, lymphadenopathy, thrombocytopenia, pancytopenia, and changes in the INR and/or PT have been noted; the incidence has not been reported. Causality has not been established.[40993] [41057] [41086] [44094] [44095]
Musculoskeletal events reported during clinical trials by patients receiving bupropion therapy and at higher incidences than with placebo included arthralgia (1% to 5%), asthenia (2% to 4%), myalgia (2% to 6%), and muscle spasms (1.9%). Other musculoskeletal adverse reactions reported during bupropion use include muscle twitching (1% to 2%), arthritis (0% to 3.1%), neck pain (2%), sciatica (less than 0.1%), pain in extremity (3%), and pain (unspecified) at 2% to 3%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following musculoskeletal effects and incidences were reported: myalgia (4%, 3%, 5%, 3), arthralgia (5%, 3%, 3%, 2%), and neck pain (2%, 1%, less than 1%, 0%). Musculoskeletal effects reported in 0.1% to 1% of patients receiving bupropion during premarketing or postmarketing use included leg muscle cramps, back pain, inguinal hernia, and muscle twitching. Musculoskeletal chest pain was reported in 1% or less of patients and sciatica rarely occurred (less than 0.1%). Arthralgia, myalgia, muscle weakness (myasthenia), and muscle rigidity with increased temperature and rhabdomyolysis have been reported during postmarketing use.[40993] [41057] [41086] [44094] [44095]
Infections (overall incidence 8% to 9% vs. 6% for placebo) have been reported by bupropion recipients during clinical trials. The types of infection in treated patients included upper respiratory tract infections (5% to 9%) [e.g., sinusitis (1% to 5%), pharyngitis (3% to 13%), bronchitis (2%), pneumonia (less than 0.1%)], urinary tract infections (1%), pelvic infections (less than 0.1%), and influenza (2% or more). Symptoms reported during use of bupropion that may be associated with these infections included rhinitis (12%), epistaxis (2%), increased cough (1% to 4%), nasal congestion (2% or more), sinus congestion (2% or more), pharyngolaryngeal pain (2% or more), malaise (less than 0.1%), fever (1% to 2%), fever/chills (1.2%), and bronchospasm (less than 0.1%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following effects and incidences were reported: rhinitis (12%, 11%, 9%, 8%), increased cough (3%, 5%, less than 1%, 1%), pharyngitis (3%, 2%, 3%, 0%), sinusitis (2%, 2%, 2%, 1%), dyspnea (1%, 0%, 2%, 1%), and epistaxis (2%, 1%, 1%, 0%).[40993] [41057] [41086] [44094] [44095]
Adverse reactions reported by recipients of bupropion during premarketing or postmarketing use, and not discussed elsewhere in the monograph, include peripheral edema (0.1% to 1%), fatigue (5%), dental pain (0.1% to 1%), drug-induced body odor (less than 0.1%), facial edema (0.1% to 1%), and hair discoloration (less than 0.1%). Facial edema was also reported in a comparative trial of sustained-release bupropion (Zyban) monotherapy (less than 1%), nicotine transdermal system (NTS) monotherapy (0%), Zyban/NTS combination (1%), or placebo (0%).[40993] [41057] [41086] [44094] [44095]
Urinary tract reactions reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trials included: increased urinary frequency (2% to 5%), urinary urgency (less than 0.5% to 2%), urinary retention (1.9%), and urinary tract infection (0% to 1%). Nocturia and urinary frequency occurred in 1% or more of bupropion-treated patients during premarketing evaluation. Polyuria, urinary urgency, and prostate disorder were reported in 0.1% to 1%. Cystitis and dysuria rarely occurred (less than 0.1%). Also observed postmarketing: cystitis, dysuria, urinary incontinence, and urinary retention; however, the frequencies have not been reported.[40993] [41057] [41086] [44094] [44095]
During clinical trials of immediate-release or extended-release bupropion formulations, the following extrapyramidal symptoms occurred in the bupropion groups at similar incidences to placebo: bradykinesia (8%), and pseudoparkinsonism (1.5%). Extrapyramidal syndrome (unspecified) has been reported during use of bupropion. Extrapyramidal symptoms that have occurred in 1% or more of patients during pre-marketing evaluation include dystonic reaction and dyskinesia. Hyperkinesis and hypertonia have been reported in 0.1% to 1% of patients. Akinesia, hypokinesia, dystonia, dyskinesia, pseudoparkinsonism, and unmasking of tardive dyskinesia have also occurred during postmarketing use; however, the incidences are unknown.[40993] [41057] [41086] [44094] [44095]
During clinical trials of immediate-release or extended-release bupropion formulation, tinnitus was reported more frequently in patients receiving bupropion than placebo (3% to 6%). Unspecified sensory disturbance (4%), auditory or hearing disturbance (5.3%), and gustatory disturbance (3.1%) were also reported more frequently in bupropion active treatment groups than placebo groups. Tinnitus occurred during a comparative trial of sustained-release bupropion (Zyban) monotherapy (1%), nicotine transdermal system (NTS) monotherapy (0%), Zyban/NTS combination (less than 1%), and placebo (0%). During pre-marketing or post-marketing use of bupropion, deafness (hearing loss) has been reported.[40993] [41057] [41086] [44094] [44095]
While not reported for bupropion, a neonatal abstinence syndrome has been reported in infants exposed to certain antidepressants in utero. After birth, symptoms consistent with withdrawal (i.e., poor feeding, hypoglycemia, hypothermia, lethargy or irritability, vomiting, etc.) were noted. Such complications can arise immediately upon delivery. In some reports, serum concentrations of the agent were measurable in the infants affected, so the symptoms may have been due to a direct adverse effect of the antidepressant. The physician should carefully consider the potential risks and benefits of treatment. If clinically feasible, and taking the drug half-life into consideration, appropriate tapering of the agent prior to delivery may be considered as an alternative.[40993] [41057] [41086] [44094] [44095]
Euphoria was reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trial evaluation (1.2% vs. 0.5%). During controlled trials in patients with a history of multiple substance abuse, normal volunteers, and depressed patients, there was an increase in motor activity and agitation/excitement. In a single dose study of bupropion 400 mg in a population of individuals experienced with drugs of abuse, a mild amphetamine-like activity was produced as compared to placebo on the Morphine-Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability. Although use of recommended daily dosages of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers, higher doses (that could not be tested because of seizure risk) could theoretically be modestly attractive to those who abuse CNS stimulant drugs.[41057] In addition, the inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection.[44094]
In an ISMP safety report, bupropion was noted as 1 of the 19 overall drugs and one of the 9 antidepressants having the strongest signals for serotonin syndrome with 18 cases reported over 1 year to the FDA Adverse Event Reporting System (FAERS). Serotonin syndrome rarely happens with single drug therapy, and more commonly is reported with interactions between multiple serotonergic drugs or accidental or intentional drug overdoses.[63529] How bupropion might promote serotonergic excess is unclear, as bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase. The manufacturers have not reported serotonin syndrome as a postmarketing event.
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 serious rash including Stevens-Johnson syndrome have also been reported.[40993][41057][41086][44094][44095]
Ensure correct formulation selection for bupropion use. Given that there are multiple dosage forms of bupropion available, 2 different salt forms, and different indications for some products, it is important to be familiar with each product name, indications, dosage form, and dosing schedule to avoid dosing errors. Bupropion products should not be used with other bupropion products, including the combination of bupropion-naltrexone. Duplication of bupropion can result in serious toxicity and convulsions.[40993] [41057] [41086] [44094] [44095]
Bupropion is contraindicated in individuals with a seizure disorder or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs. Bupropion is also contraindicated in individuals with a current or previous diagnosis of anorexia nervosa or bulimia nervosa as a higher incidence of seizures was observed in such individuals treated with bupropion. The following conditions can also increase the risk of seizure: severe head trauma; cerebral arteriovenous malformation; central nervous system tumor (e.g., brain tumor) or central nervous system infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); substance abuse of illicit drugs (e.g., cocaine); or abuse or misuse of certain medications such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic medications or insulin; use of anorectic drugs; and excessive use of alcohol (i.e., alcoholism), benzodiazepines, sedative/hypnotics, or opioids. 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 subjects. 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 medications, weigh the benefits of treatment against the potential for abuse prior to administering bupropion to individuals with a history of substance abuse.[40993] [41057] [41086] [44094] [44095]
The safety and efficacy of bupropion is not established in pediatric patients less than 18 years of age. 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. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. No suicides occurred in any of the pediatric trials. Nevertheless, the need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of bupropion may be necessary in patients with emerging suicidality or worsening depression. Additionally, all pediatric patients under consideration for bupropion treatment should undergo a detailed personal and family history, physical examination, and ECG screening prior to starting bupropion to assess for underlying cardiovascular disease. Because bupropion has increased blood pressure in some patients, routine monitoring of blood pressure and heart rate at follow-up visits has been recommended for pediatric patients.[44094] [41086] [46944] [34206]
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.[60080] [60081]
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.[41086] 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.[61618]
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.[41057] [41086]
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.[46944] For other bupropion formulations, the dosage or dosage frequency should be reduced in patients with moderate to severe hepatic impairment (Child-Pugh Score 7 to 15). For patients with mild hepatic dysfunction (Child-Pugh Score 5 to 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.[44095] [41086] [40993] [41057] [44094]
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.[46944] Other bupropion products should be used with extreme caution in patients with renal impairment or renal failure because the parent compound or active metabolites could accumulate. Consider reduced dosages in these patient populations based on the degree of renal impairment, and closely monitor for adverse reactions that could indicate high drug or metabolite levels.[41086] [40993] [41057]
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 (ethanol ingestion) should be minimized or avoided.[41086] [40993] [41057]
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.[41086] [40993] [41057] [44095]
Use bupropion with caution during pregnancy; use during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 labor and obstetric delivery may be considered. Pregnant smokers should be encouraged to attempt educational and behavioral interventions before pharmacologic approaches are used; nicotine has been used in pregnancy to help patients quit smoking. Smoking cessation programs in pregnancy reduce the proportion of women who continue to smoke, and reduce the risk for low birthweight and preterm birth. Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no 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 (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) did not show an overall increased risk from cardiovascular malformations after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO, and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure but did not find increased risk for any other cardiovascular malformations studied (including LVOTO). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to or more than the maximum recommended human dose (MRHD) and decreased fetal weights were seen at doses twice the MRHD and greater. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to bupropion; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry/antidepressants by calling 1-866-961-2388 or 1-844-405-6185.[40993] [41057] [41086] [42078] [44094] [44095] [61843]
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.[41057] [41086] 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.[34206] 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.
Bupropion and its metabolites are excreted into human breast milk, and caution should be exercised when bupropion is administered to a breast-feeding individual.[40993] [41057] [41086] [44094] [44095] 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.[47279] One case report describes a possible seizure in a breast-fed infant during maternal use of extended-release bupropion.[47277] In 2 other cases, no infant-related adverse events were noted during breast-feeding.[47278] Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment for depression is deemed necessary during breast-feeding. Alternatives may be considered in some cases. 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.[45642] For smoking cessation treatment, nicotine replacement products may be considered as an alternate therapy to bupropion if non-pharmacologic interventions are inadequate. 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. Breast-feeding and eliminating an infant's exposure to tobacco smoke are considered important protective factors for serious pediatric health risks.[37408]
No overall differences in safety or effectiveness were observed between geriatric and younger subjects during clinical trials of bupropion for depression or smoking cessation, respectively. Greater sensitivity of some older individuals cannot be ruled out. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in older adults with impaired renal function. Because older adults are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function.[44095] [41086] [40993] [41057] [44094] The U.S. Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities (LTCFs). When an antidepressant 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. Dosages and durations of treatment used in the geriatric adult should be in accordance with prescribing labels, published literature recommendations, and expert guidelines.[60742]
Laboratory test interference has been reported with bupropion use. False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. The false-positive result is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.[40993] [41057] [41086] [44094] [44095]
The action of bupropion in the treatment of major depressive disorder and seasonal affective disorder is not fully understood, but is likely related to dual-reuptake inhibition of dopamine and norepinephrine. This reuptake inhibition is associated with increased synaptic levels of dopamine and norepinephrine in the brain, particularly within the nucleus accumbens and the prefrontal cortex. In contrast to most antidepressants, bupropion does not inhibit monoamine oxidase or the reuptake of serotonin and does not have appreciable activity at histamine, acetylcholine, or alpha- or beta-adrenergic receptors. The unique activity of bupropion allows for use as monotherapy for depression as well as an add-on treatment option for partial responders. Antidepressant activity is usually noted within 1 to 3 weeks of initiation of bupropion treatment; full effects may not be seen until 4 weeks of therapy.[41086][40993][41057][70051]
The specific mechanism by which bupropion enhances the ability to abstain from tobacco smoking is likely also related to the inhibition of noradrenergic and dopaminergic neuronal reuptake. The resultant increase in norepinephrine may attenuate nicotine withdrawal symptoms, while increased dopamine at neuronal sites may reduce nicotine cravings and the urge to smoke. Because the attainment of steady-state blood levels requires approximately 1 week of treatment, patients should start bupropion 1 to 2 weeks prior to their "target quit date". 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 after 7 to 12 weeks of treatment are generally considered non-responsive to bupropion treatment.[44094][70051]
Revision Date: 10/27/2024, 09:42:29 AMBupropion 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. 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 to 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 to 8 days; however, antidepressant effects have an onset of roughly 1 to 3 weeks.[41086][40993][41057][46944][44094]
Affected cytochrome P450 (CYP450) isoenzymes and drug transporters: CYP2D6, CYP2B6, OCT2
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.[41086]In vitro data indicate that bupropion and hydroxybupropion are inhibitors of CYP2D6. In vitro, bupropion and its 3 metabolites are inhibitors of the renal organic transporter OCT2 to a clinically significant extent; however, in vivo drug interaction studies have not found clinically significant drug-drug interactions with OCT-2 substrates.[41086][41057][44095]
Based on animal data, the oral bioavailability is roughly 5% to 20%; oral bioavailability in humans has not been determined.
Half-lives of bupropion and/or its major metabolites are prolonged in patients with alcoholic liver disease, cirrhosis, or left-ventricular dysfunction. In patients with hepatic disease, the mean AUC increased by roughly 1.5-fold for hydroxybupropion and roughly 2.5-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers. Dosage adjustment is required in patients with hepatic dysfunction.[41086][44095][44094] Use of Forfivo XL, a 450 mg extended-release tablet formulation, is not recommended in patients with hepatic impairment, as the dose is fixed and no lower strength is available.[46944]
An inter-study comparison of healthy subjects and those with end-stage renal failure showed that although the elimination of the parent compound was similar between groups, the Cmax and AUC of bupropion's active metabolites were increased in the renal failure group. In a separate study of patients with moderate to severe renal impairment, bupropion exposure after administration of the sustained-release product was about 2-fold higher in the renally impaired group than in normal subjects, while concentrations of the active metabolites of bupropion and placebo were similar.[41086] The clinical impact of these findings, if any, have not been described. Use of Forfivo XL, a 450 mg extended-release tablet formulation, is not recommended in patients with renal impairment as the dose is fixed and lower dosage strengths are not available.[46944]
Adolescents have been shown to metabolize bupropion SR to its active metabolites more rapidly than adults.[32356] Areas under the concentration curves for the hydroxybupropion, threohydrobupropion, and erythrohydrobupropion were 20, 12, and 2.7 times higher, respectively, than for bupropion. Relative to adults, the mean half-lives of bupropion (12.1 h) and threohydrobupropion (26.3 h) were significantly shorter, and AUC ratios of metabolites to bupropion were 19 to 80% higher. Until the clinical importance of bupropion's metabolites is clarified, bupropion SR should be given in divided doses to adolescents.[32356]
Use bupropion with caution during pregnancy; use during pregnancy only if the potential benefit justifies the potential risk to the fetus. 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 labor and obstetric delivery may be considered. Pregnant smokers should be encouraged to attempt educational and behavioral interventions before pharmacologic approaches are used; nicotine has been used in pregnancy to help patients quit smoking. Smoking cessation programs in pregnancy reduce the proportion of women who continue to smoke, and reduce the risk for low birthweight and preterm birth. Data from epidemiological studies including pregnant women exposed to bupropion in the first trimester indicate no 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 (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) did not show an overall increased risk from cardiovascular malformations after bupropion exposure during the first trimester. Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO, and the Slone Epidemiology case control study did not find increased risk for LVOTO. Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure but did not find increased risk for any other cardiovascular malformations studied (including LVOTO). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD. For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits. However, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to or more than the maximum recommended human dose (MRHD) and decreased fetal weights were seen at doses twice the MRHD and greater. There is a pregnancy exposure registry that monitors outcomes in pregnant patients exposed to bupropion; information about the registry can be obtained at womensmentalhealth.org/research/pregnancyregistry/antidepressants by calling 1-866-961-2388 or 1-844-405-6185.[40993] [41057] [41086] [42078] [44094] [44095] [61843]
Bupropion and its metabolites are excreted into human breast milk, and caution should be exercised when bupropion is administered to a breast-feeding individual.[40993] [41057] [41086] [44094] [44095] 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.[47279] One case report describes a possible seizure in a breast-fed infant during maternal use of extended-release bupropion.[47277] In 2 other cases, no infant-related adverse events were noted during breast-feeding.[47278] Due to individual variability in response to antidepressants, it may be prudent to continue the existing regimen if ongoing treatment for depression is deemed necessary during breast-feeding. Alternatives may be considered in some cases. 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.[45642] For smoking cessation treatment, nicotine replacement products may be considered as an alternate therapy to bupropion if non-pharmacologic interventions are inadequate. 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. Breast-feeding and eliminating an infant's exposure to tobacco smoke are considered important protective factors for serious pediatric health risks.[37408]
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