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Mechanism of Action
US Drug Names
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.
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.
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.
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.
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.
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).
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.
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.
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.
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.
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.
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.
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.
Bupropion is an oral antidepressant drug of the aminoketone class. It is not a tricyclic antidepressant and is unrelated to other known antidepressants. Bupropion has been well tolerated in patients experiencing orthostatic hypotension with tricyclic antidepressant drugs, however, it shows a greater potential for causing seizures than other antidepressants. Bupropion is also indicated for use as an aide to smoking cessation, and is used off-label for addiction to smokeless tobacco. The drug has been shown to help people with COPD quit smoking when combined with behavior modification. Bupropion is also used off-label for multiple neurological/psychological uses, including ADHD  and neuropathic pain . Bupropion hydrochloride was originally approved by the FDA in December 1985 but was removed from marketing for several years due to concern over drug-induced seizures. It was reintroduced in July 1989 as an antidepressant (i.e., Wellbutrin), and later in a sustained-release formulation (i.e., Wellbutrin SR). Another sustained-release oral dosage form, Zyban, was approved for the management of smoking cessation in May 1997. Zyban received an additional indication for use in combination with nicotine transdermal systems (NTS) for treating the symptoms of smoking cessation in 1999. A controlled-release formulation (Wellbutrin XL) was approved in August 2003 as a once-daily formulation for major depression in adults. In June 2006, Wellbutrin XL was FDA-approved for prevention of major depressive episodes in patients with a history of seasonal affective disorder (SAD). Wellbutrin XL is the first prescription product approved for patients with a history of SAD. In April 2008, a once-daily formulation of bupropion hydrobromide (Aplenzin) was approved by the FDA for depression, and in August 2012 Aplenzin was approved for the prevention of seasonal major depressive episodes in patients with SAD. Aplenzin differs from all previously marketed formulations which are the hydrochloride salt of bupropion.
For storage information, see the specific product information within the How Supplied section.
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.  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 > 450 mg/day (immediate-release). 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.    
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—31% vs 6—21%), dizziness (6—11% vs 5—7%), tremor (2—21.1% vs < 1—7.6%), drowsiness (2—3% vs 1—2%), sedation or lethargy (19.8% vs 19.5%), cutaneous temperature disturbance (1.9% vs 1.6%), headache (25—34% vs 22.2—26%), migraine (1—25.7% vs 1—22.2%), impaired sleep quality (4% vs 1.6%), paresthesias (1—2% vs 1%), CNS stimulation or restlessness (1—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%, < 1%, 2%, 0%). The incidence of ataxia/incoordination ranged from < 0.1% to >= 1% of patients during pre-marketing or post-marketing use of bupropion. CNS effects reported in 0.1—1% of patients included vertigo, dysarthria, abnormal coordination, CNS stimulation, hypesthesia, and paresthesias. Rarely reported effects (< 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.    
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.    
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.    
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.    
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.    
Bupropion may cause weight loss. A weight loss of more than 5 pounds occurred in 23.2% of patients taking immediate-release bupropion, approximately double that seen for patients on tricyclic antidepressants or placebo. Approximately 14% of patients on sustained-release formulations lose weight. Roughly 23% of patients receiving bupropion XL enrolled in seasonal affective disorder (SAD) trials had a weight loss of > 5 lbs. compared to 11% on placebo; alternatively 11% of bupropion XL patients had a weight gain > 5 lbs. compared to 21% on placebo. Weight gain may be associated with untreated depression. In general, weight gain is typically rare with bupropion treatment; across all formulations, weight gain occurred in 2—13.6% of bupropion recipients during clinical trials. It is not known if bupropion, like other ADHD therapies, causes growth inhibition in pediatric patients. The incidence of anorexia reported during trials was similar for patients taking bupropion and patients on placebo (roughly 1—18%) and may represent a symptom of the depressive illness rather than an adverse event. Although not as common, appetite stimulation (2—3.7%) was also reported following administration of bupropion during clinical trials.    
Cardiac toxicity is relatively uncommon for bupropion when compared with tricyclic antidepressants. Hypertension occurred in 1—4.3% of patients taking bupropion during clinical trials, compared to 0—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 immediate-release or extended-release bupropion formulations than placebo during clinical trials included: unspecified cardiac arrhythmias (5.3% vs 4.3%), dizziness (22.3% vs 16.2%), hypotension (2.5% vs 2.2%), palpitations (2—6% vs 0—2.2%), syncope (1.2% vs 0.5%), sinus tachycardia (10.8% vs 8.6%), chest pain (unspecified) (< 1% to 4% vs 1%), and flushing (1—4% vs < 0.5%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, nicotine transdermal system (NTS) monotherapy, Zyban/NTS combination, or placebo, the following cardiac effects and incidences were reported: hypertension (1%, < 1%, 2%, 0%), palpitations (2%, 0%, 1%, 0%), and chest pain (< 1%, 1%, 3%, 1%). Edema was reported in >= 1% of patients during pre-marketing evaluation of bupropion. Flushing was reported in <= 1% of patients. Cardiac effects reported in 0.1—1% of patients included unspecified chest pain, ECG abnormalities (premature beats and nonspecific ST-T changes), dyspnea, orthostatic hypotension, stroke, sinus tachycardia, and peripheral vasodilation. Pallor, phlebitis, syncope, and myocardial infarction occurred rarely (< 0.1%). Also observed were complete AV block, extrasystoles, and pulmonary embolism; however, the frequencies are unknown. Cardiac effects noted after overdose of bupropion as a single agent have included sinus tachycardia, ECG changes including QRS prolongation, and arrhythmias (unspecified). Hypotension has been reported after overdose of bupropion in conjunction with other medications.    
Blurred vision affected 2—14.6% of bupropion-treated patients during clinical trials, compared to 2—10.3% taking placebo. Diplopia was reported in 2—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% of patients. Other ocular effects that occurred in clinical trials or during post-marketing use included abnormal accommodation (0.1—1%), xerophthalmia (0.1—1%), ocular hypertension, and mydriasis.    
During clinical trials of immediate-release or extended-release bupropion formulations, the following gastrointestinal effects and incidences compared to placebo included: dyspepsia (3.1% vs 2.2)), nausea (9—22.9% vs 8—18.9%), vomiting (2—22.9% vs 2—18.9%), diarrhea (4—7% vs 6—8.6%), constipation (5—26% vs 2—17.3%), xerostomia (10—27.6% vs 5—18.4%), hypersalivation (3.4% vs 3.8%), dysphagia (0—2% vs 0%), flatulence (6% vs 3%), abdominal pain (2—9% vs < 1—2%), and dysgeusia (2—4% vs < 0.5%). In a comparative trial of sustained-release bupropion (Zyban) monotherapy, 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 (< 1%, < 1%, 2%, 0%). During other pre-marketing evaluations, stomatitis was reported in >= 1% of patients. Adverse digestive reactions occurring in roughly 0.1—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 < 0.1% of patients have included colitis, GI bleeding, GI perforation, and stomach ulcer. Digestive adverse reactions reported during post-marketing use of bupropion include esophagitis, gum bleeding, hepatitis, and pancreatitis. Due to the voluntary nature of post-market reports, neither incidence nor definitive association to bupropion can established.    
Twice as many patients taking bupropion reported libido decrease (3.1%) compared to patients taking placebo (1.6%). Conversely, libido increase has been reported in >= 1% of patients receiving bupropion. Menstrual irregularity was reported as unspecified menstrual complaints by 4.7% of patients and as dysmenorrhea (2% vs < 1% for placebo) and/or vaginal bleeding in 0—2% of patients vs < 0.5% of placebo-treated patients. Impotence (erectile dysfunction) occurred in 3.4% and painful erections occurred in 0.1—1% of bupropion recipients during clinical trials. Cases of gynecomastia, prostate disorder, and testicular swelling have been reported in 0.1—1% of bupropion-treated patients. Other sexual or reproductive system reactions have also occurred and include ejaculation dysfunction (0.1—1%, reported as retarded ejaculation or painful ejaculation), painful erection, dyspareunia (< 0.1%), salpingitis, and vaginal irritation (0.1—1%). Causal effect may be uncertain as trials were not always conducted with adequate controls.    
Depending on the dosage form of bupropion used, hot flashes have been reported in 1—3% of patients; menopause was reported in < 0.1% of bupropion recipients during clinical trials.    
During clinical trials of immediate-release or extended-release bupropion formulations, hyperhidrosis occurred more frequently in the bupropion groups than the placebo groups (5—22.3% vs 2—14.6%). Rash (unspecified) (3—8%), pruritus (2—4%), urticaria (1—2%), alopecia (>= 1%), and xerosis (2%) were other dermatologic adverse reactions commonly reported by recipients of bupropion. Acne vulgaris (0.1—1%), maculopapular rash (< 0.1%), hirsutism (< 0.1%), photosensitivity (0.1—1%), and exfoliative dermatitis have also occurred infrequently or rarely with bupropion 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%).    
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.    
Hematologic and lymphatic effects reported with bupropion include infrequent cases of ecchymosis (0.1—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.    
Musculoskeletal events reported during clinical trials by patients receiving bupropion therapy included arthralgia (1—5% vs 1—3%), asthenia (2—4% vs 2%), myalgia (2—6% vs 1—3%), and muscle spasms (1.9% vs 3.2%). Other musculoskeletal adverse reactions reported during bupropion use include muscle twitching (1—2% vs < 0.5%), arthritis (0—3.1% vs 0—2.7%), neck pain (2% vs 0—1%), sciatica (< 0.1%), pain in extremity (3% vs 2%), and pain (unspecified) (2—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 musculoskeletal effects and incidences were reported: myalgia (4%, 3%, 5%, 3), arthralgia (5%, 3%, 3%, 2%), and neck pain (2%, 1%, < 1%, 0%). Musculoskeletal effects reported in 0.1—1% of patients receiving bupropion during pre-marketing or post-marketing use included leg muscle cramps, back pain, inguinal hernia, and muscle twitching. Musculoskeletal chest pain was reported in <= 1% of patients and sciatica occurred rarely (< 0.1%). Arthralgia, myalgia, muscle weakness (myasthenia), and muscle rigidity with increased temperature and rhabdomyolysis have been reported during post-marketing use.    
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 according to the Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Manifestations of DRESS typically include pyrexia, rash, facial swelling, and/or lymph node involvement in conjunction with other organ system abnormalities including hepatitis, nephritis, hematologic abnormalities, myocarditis, or myositis. Eosinophilia is often present. Early manifestations of DRESS such as pyrexia and lymph node involvement may be present without evidence of a rash. Bupropion should be promptly discontinued and appropriate medical treatment should be initiated in patients presenting with a rash or symptoms indicative of DRESS in whom an unrelated etiology cannot be identified. 
Infections (8—9% vs 6% for placebo) have been reported by bupropion recipients during clinical trials. The types of infection included upper respiratory tract infections (5—9%) (e.g., sinusitis (1—5%), pharyngitis (3—13%), bronchitis (2%), pneumonia (< 0.1%)), urinary tract infections (1%), pelvic infections (< 0.1%), and influenza (>= 2%). Symptoms reported during use of bupropion that may be associated with these infections included rhinitis (12%), epistaxis (2%), increased cough (1—4%), nasal congestion (>= 2%), sinus congestion (>= 2%), pharyngolaryngeal pain (>= 2%), malaise (< 0.1%), fever (1—2%), fever/chills (1.2%), and bronchospasm (< 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%, < 1%, 1%), pharyngitis (3%, 2%, 3%, 0%), sinusitis (2%, 2%, 2%, 1%), dyspnea (1%, 0%, 2%, 1%), and epistaxis (2%, 1%, 1%, 0%).    
Adverse reactions reported by recipients of bupropion during pre-marketing or post-marketing use, and not discussed elsewhere in the monograph, include peripheral edema (0.1—1%), fatigue (5% vs 8.6% for placebo), dental pain (0.1—1%), drug-induced body odor (< 0.1%), facial edema (0.1—1%), and hair discoloration (< 0.1%). Facial edema was also reported in a comparative trial of sustained-release bupropion (Zyban) monotherapy (< 1%), nicotine transdermal system (NTS) monotherapy (0%), Zyban/NTS combination (1%), or placebo (0%).    
Urinary tract reactions reported more frequently with immediate-release or extended-release bupropion formulations than placebo during clinical trials included increased urinary frequency (2—5% vs 2—2.2%), urinary urgency (< 0.5—2% vs 0%), urinary retention (1.9% vs 2.2%), and urinary tract infection (0—1% vs < 0.5%). Nocturia and urinary frequency occurred in >= 1% of patients during pre-marketing evaluation. Polyuria, urinary urgency, and prostate disorder were reported in 0.1—1% of patients. Cystitis and dysuria occurred rarely (< 0.1%). Also observed post-marketing were cystitis, dysuria, urinary incontinence, and urinary retention; however, the frequencies were not reported.    
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.    
During clinical trials of immediate-release or extended-release bupropion formulation, tinnitus was reported more frequently in patients receiving bupropion than placebo (3—6% vs < 1% to 2%). Unspecified sensory disturbance (4% vs 3.2%), auditory or hearing disturbance (5.3% vs 3.2%), and gustatory disturbance (3.1% vs 1.1%) were also reported more frequently in 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 (< 1%), and placebo (0%). During pre-marketing or post-marketing use of bupropion, deafness (hearing loss) has been reported.    
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.    
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. 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.
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. 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.
IMPORTANT: 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. 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.
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.
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.    
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. Careful screening and monitoring is recommended by the American Heart Association if bupropion is used in pediatric patients. 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.   
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. 
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.
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. 
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/clinical-and-research-programs/pregnancyregistry/antidepressants by calling 1-866-961-2388 or 1-844-405-6185.       
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 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. 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.
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.    
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.
Of roughly 6,000 patients in bupropion sustained-release studies for both smoking cessation and depression, 275 were 65 and over and 47 were 75 and over. Several hundred geriatric patients 65 years and older have also been studied (in depression) with the immediate-release formulation. Both initial and maintenance bupropion doses should be reduced in geriatric 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.     The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antidepressants in residents of long-term care facilities. According to OBRA, follow the recommended duration of therapy per 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 suicidal behavior or thinking, especially during initiation of therapy and during dose changes. Antidepressants may cause dizziness, nausea, diarrhea, anxiety, nervousness, insomnia, sedation, weight gain, anorexia, or increased appetite. Many of these effects can increase the risk of falls. Bupropion may increase seizure risk and activity in susceptible individuals. Before discontinuation, taper bupropion 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 an 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.
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.
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.
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.
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.
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.     
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.
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 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.
Affected cytochrome P450 isoenzymes: 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.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. 
Based on animal data, the oral bioavailability is roughly 5—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. 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.
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. 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.
Adolescents have been shown to metabolize bupropion SR to its active metabolites more rapidly than adults. 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.
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