Bupropion Hydrochloride

Included as part of the PRECAUTIONS section.

Mechanism Of Action

The mechanism of action of bupropion is unknown, as is the case with other antidepressants. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the reuptake of serotonin.

Pharmacokinetics

Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied.

Following single dosing under fasted conditions of FORFIVO XL tablets, the maximum peak plasma concentration (Cmax), and the area under the plasma concentration versus time curve of bupropion from zero to infinity (AUCinf), were 207.46 (± 59.40) ng/mL, and 2147.53 (± 664.12) ng·hr/mL, respectively. The elimination half-life (± SD) of bupropion after a single dose was 14.44 (± 5.00) hours.

In a single-dose study under fasting conditions, one FORFIVO XL tablet given once daily and three WELLBUTRIN XL150 mg tablets once daily were evaluated. Equivalence was demonstrated for peak concentration and area under the curve for bupropion and the 3 metabolites (hydroxybupropion, erythrohydrobupropion, and threohydrobupropion).

Following single oral administration of FORFIVO XL tablets to healthy volunteers, the median time to peak plasma concentrations for bupropion was approximately 5 hours under fasted conditions, and 12 hours under fed conditions. The presence of food did not affect the maximum peak plasma concentration for bupropion, however, mean systemic exposure to bupropion was increased by 25% when FORFIVO XL tablets were taken with food. The food effect is not considered clinically significant and FORFIVO XL can be taken with or without food.

In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that of bupropion.

Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 isoenzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion.

This may be of clinical importance because the plasma concentrations of the metabolites are as high or higher than those of bupropion.

In humans, peak plasma concentrations of hydroxybupropion occur approximately 10 hours after administration of a single dose of FORFIVO XL under fasted conditions and 16 hours under fed conditions. Following administration of WELLBUTRIN XL, peak plasma concentrations of hydroxybupropion are approximately 7 times the peak level of the parent drug at steady state.  The elimination half-life of hydroxybupropion is approximately 20 (± 5) hours, and its AUC at steady state is about 13 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, the elimination half-lives of erythrohydrobupropion and threohydrobupropion are longer, approximately 33 (± 10) and 37 (± 13) hours, respectively, and steady-state AUCs are 1.4 and 7 times that of bupropion, respectively.

Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg/day of bupropion hydrochloride.

Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.

Population Subgroups

Factors or conditions altering metabolic capacity (eg, liver disease, congestive heart failure [CHF], age, concomitant medications, etc) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.

There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An intertrial comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug Cmax and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second study, comparing normal subjects and subjects with moderate to severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that after a single 150-mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose studies, one in subjects with alcoholic liver disease and one in subjects with mild to severe cirrhosis. The first trial demonstrated that the half-life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 groups were minimal.

The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t½) in subjects with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference: by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in subjects with severe hepatic cirrhosis vs 19 hours in healthy subjects). For the metabolite hydroxybupropion, the mean Cmax was approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower. The mean AUC increased by about 1.5-fold for hydroxybupropion and about 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 [see DOSAGE AND ADMINISTRATION and Use in Specific Populations].

During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared to healthy volunteers.

The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that in younger subjects. These data suggest that there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetic study suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations].

A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion. In addition, pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared to female volunteers.

The effects of cigarette smoking on the pharmacokinetics of bupropion hydrochloride were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

Drug Interactions

In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between FORFIVO XL and drugs that are inhibitors or inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir, inhibit the hydroxylation of bupropion.

Ticlopidine, Clopidogrel: In a study in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (Cmax and AUC) of bupropion by 40% and 60% for clopidogrel and by 38% and 85% for ticlopidine, respectively. The exposures of hydroxybupropion were decreased. Prasugrel: In healthy subjects, prasugrel increased bupropion Cmax and AUC values by 14% and 18%, respectively, and decreased Cmax and AUC values of hydroxybupropion by 32% and 24%, respectively.

Cimetidine: Following oral administration of bupropion 300 mg with and without cimetidine 800 mg in 24 healthy young male volunteers, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its 3 metabolites.

Ritonavir and Lopinavir: In a healthy volunteer study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, threohydrobupropion decreased by 38%, and erythrohydrobupropion decreased by 48%. In a second healthy volunteer study, ritonavir 600 mg twice daily decreased the AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, threohydrobupropion decreased by 50%, and erythrohydrobupropion decreased by 68%. In another healthy volunteer study, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of the hydroxybupropion metabolite were decreased by 50% and 31%, respectively.

Efavirenz: In a study of healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%.

Carbamazepine, Phenobarbital, Phenytoin: Although not systematically studied, these drugs may induce the metabolism of bupropion.

Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In a study of 8 healthy male volunteers, following a 14-day administration of bupropion 100 mg 3 times daily, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.

In vitro, bupropion and hydroxybupropion are CYP2D6 inhibitors. In a clinical study of 15 male subjects (19 to 35 years of age) who were extensive metabolizers of CYP2D6, bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the Cmax, AUC, and t½ of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively.

Lamotrigine: Multiple oral doses of bupropion had no statistically significant effects on the single-dose pharmacokinetics of lamotrigine in 12 healthy volunteers.

Clinical Studies

The efficacy of bupropion in the treatment of MDD was established with the immediate-release formulation of bupropion hydrochloride in two 4-week, placebo-controlled trials in adult inpatients with MDD and in one 6-week, placebo-controlled trial in adult outpatients with MDD. In the first study, the bupropion dose range was 300 to 600 mg/day administered in 3 divided doses; 78% of patients were treated with doses of 300 to 450 mg/day. The trial demonstrated the efficacy of bupropion as measured by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (item 1), and the Clinical Global Impressions-Severity Scale (CGI-S). The second study included 2 fixed doses of bupropion (300 and 450 mg/day) and placebo. This trial demonstrated the efficacy of bupropion for only the 450-mg dose. The efficacy results were significant for the HDRS total score and the CGI-S score, but not for HDRS item 1. In the third study, outpatients were treated with bupropion at 300 mg/day. This study demonstrated the efficacy of bupropion as measured by the HDRS total score, the HDRS item 1, the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score.

A longer-term, placebo-controlled, randomized withdrawal trial demonstrated the efficacy of bupropion hydrochloride sustained-release in the maintenance treatment of MDD. The trial included adult outpatients meeting DSM-IV criteria for MDD, recurrent type, who had responded during an 8-week open-label trial of bupropion 300 mg/day. Responders were randomized to continuation of bupropion at 300 mg/day or placebo, for up to 44 weeks of observation for relapse. Response during the open-label phase was defined as a CGI-I score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator's judgment that drug treatment was needed for worsening depressive symptoms. Patients in the bupropion group experienced significantly lower relapse rates over the subsequent 44 weeks compared to those in the placebo group.

Although there are no independent trials demonstrating the efficacy of bupropion extended-release in the acute treatment of MDD, studies have demonstrated similar bioavailability between the immediate-, sustained-, and extended-release formulations of bupropion hydrochloride under steady-state conditions (ie, the exposures [Cmax and AUC] for bupropion and its metabolites are similar among the 3 formulations). Further, it has been demonstrated that FORFIVO XL is bioequivalent to WELLBUTRIN XL.

Major Depressive Disorder

Treatment of major depressive disorder.1 127 128 129 131 132 142 168 179 180

May be useful (alone or in combination with other antidepressants) in patients with refractory depression.179 180

Seasonal Affective Disorder

Prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD; also referred to as winter depression).168 169 170 171

Smoking Cessation

Adjunct in the cessation of smoking (alone or in combination with nicotine replacement therapy).143 145 146 147 152 (See Hypertension under Cautions and also see Smoking Cessation and Specific Drugs under Interactions.)

US Public Health Service (USPHS) guideline for the treatment of tobacco use and dependence recommends bupropion (as extended-release tablets) as one of several first-line drugs that may reliably increase long-term smoking abstinence rates.152 For additional information, consult the most current USPHS clinical practice guideline available at

Depression Associated with Bipolar Disorder

Treatment of patients with bipolar depression† (bipolar disorder, depressive episode).2 77 78 85 86 102 154

American Psychiatric Association (APA) considers bupropion one of several second-line agents for use when first-line agents are ineffective or not tolerated.154

Attention Deficit Hyperactivity Disorder (ADHD)

Used in a limited number of children2 44 79 80 134 156 157 158 and adults in the management of ADHD†.2 44 76 126

Panic Disorder

Ineffective in the treatment of panic disorder and concomitant phobic disorder†,2 44 99 134 but may improve symptoms of panic and depression in patients with major depression who have superimposed panic symptoms.44

Bulimia Nervosa

Not recommended by APA for bulimia nervosa† because associated with seizures in purging bulimic patients.153

• Chemically unrelated to tricyclic, tetracyclic, or other currently available antidepressants (e.g., SSRIs);1 43 142 143 168 also chemically unrelated to nicotine or other agents currently used in treatment of nicotine dependence.143

• Mechanism of antidepressant action is unclear; noradrenergic pathways appear to be principally involved.1 2 115 142 168

• Mechanism of action as an adjunct in the cessation of smoking is unclear; noradrenergic and/or dopaminergic effects presumably are involved.143 145 146

• Produces less frequent anticholinergic effects, cardiovascular effects, antihistaminic effects, and weight gain compared with tricyclic antidepressants at usual dosages.2 23 44 104 127 128 133

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Suicidal thoughts and behaviors in children, adolescents, and young adults [see WARNINGS AND PRECAUTIONS]
• Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see WARNINGS AND PRECAUTIONS]
• Seizure [see WARNINGS AND PRECAUTIONS]
• Hypertension [see WARNINGS AND PRECAUTIONS]
• Activation of mania or hypomania [see WARNINGS AND PRECAUTIONS]
• Psychosis and other neuropsychiatric events [see WARNINGS AND PRECAUTIONS]
• Angle-closure Glaucoma [see WARNINGS AND PRECAUTIONS]
• Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Commonly Observed Adverse Reactions In Controlled Clinical Trials Of Sustained-release Bupropion Hydrochloride

Adverse reactions that occurred in at least 5% of patients treated with bupropion hydrochloride sustained-release (300 and 400 mg/day) and at a rate at least twice the placebo rate are listed below.

300 mg/day of bupropion hydrochloride sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor.

400 mg/day of bupropion hydrochloride sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

FORFIVO XL is bioequivalent to three 150-mg tablets of WELLBUTRIN XL®, which has been demonstrated to have similar bioavailability both to the immediate-release and the sustainedrelease formulations of bupropion. The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride.

Major Depressive Disorder

In placebo-controlled clinical trials with bupropion hydrochloride sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day, and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300-mg/day or 400-mg/day groups and at a rate at least twice the placebo rate are listed in Table 2.

Table 2: Treatment Discontinuation Due to Adverse Reactions in Placebo-controlled Trials in Major Depressive Disorder

In clinical trials with bupropion hydrochloride immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction. Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation) included vomiting, seizures, and sleep disturbances.

Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion hydrochloride sustained-release at 300 mg/day and 400 mg/day. These include reactions that occurred in either the 300-mg/day or 400-mg/day group at an incidence of 1% or more and were more frequent than in the placebo group.

Table 3: Adverse Reactions in Placebo-controlled Trials for Major Depressive Disorder

The following additional adverse reactions occurred in controlled trials of bupropion hydrochloride immediate-release (300 to 600 mg/day) at an incidence of at least 1% more frequently than in the placebo group: cardiac arrhythmia (5% vs 4%), hypertension (4% vs 2%), hypotension (3% vs 2%), menstrual complaints (5% vs 1%), akathisia (2% vs 1%), impaired sleep quality (4% vs 2%), sensory disturbance (4% vs 3%), confusion (8% vs 5%), decreased libido (3% vs 2%), hostility (6% vs 4%), auditory disturbance (5% vs 3%), and gustatory disturbance (3% vs 1%).

Table 4 presents the incidence of body weight changes ( ≥ 5 lbs) in the short-term MDD trials using bupropion hydrochloride sustained-release. There was a dose-related decrease in body weight.

Table 4: Incidence of Weight Gain or Weight Loss ( ≥ 5 lbs) in Placebo-controlled Trials of Bupropion Hydrochloride Sustained-release Tablets for Major Depressive Disorder

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of bupropion hydrochloride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body (General)-chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise.

Cardiovascular-postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.

Digestive-abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.

Endocrine-hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion.

Hemic and Lymphatic-ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.

Metabolic and Nutritional-glycosuria.

Musculoskeletal-leg cramps, fever/rhabdomyolysis, and muscle weakness.

Nervous System-abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.

Respiratory-bronchospasm and pneumonia.

Skin-maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism.

Special Senses-accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis.

Urogenital-impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

Read the entire FDA prescribing information for Forfivo XL (Bupropion Hydrochloride)