Wellbutrin information, interactions and side effects, WELLBUTRIN (bupropion hydrochloride), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is:
WELLBUTRIN is supplied for oral administration as 75-mg (yellow-gold) and 100-mg (red) film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: 75-mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100-mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
WELLBUTRIN (bupropion hydrochloride) is indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).
The efficacy of WELLBUTRIN in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with MDD.
DOSAGE AND ADMINISTRATION
General Instructions For Use
To minimize the risk of seizure, increase the dose gradually. Increases in dose should not exceed 100 mg per day in a 3-day period. WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN may be taken with or without food.
The recommended starting dose is 200 mg per day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg per day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg per day may be accomplished using the 75-or 100-mg tablets.
A maximum of 450 mg per day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg per day. Administer the 100-mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of WELLBUTRIN needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.
Dose Adjustment In Patients With Hepatic Impairment
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to15), the maximum dose of WELLBUTRIN is 75 mg per day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing.
Dose Adjustment In Patients With Renal Impairment
Consider reducing the dose and/or frequency of WELLBUTRIN in patients with renal impairment (Glomerular Filtration Rate < 90 mL/min).
Switching A Patient To Or From A Monoamine Oxidase Inhibitor (MAOI) Antidepressant
At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with WELLBUTRIN. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN before starting an MAOI antidepressant.
Use Of WELLBUTRIN With Reversible MAOIs Such As Linezolid Or Methylene Blue
Do not start WELLBUTRIN in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered.
In some cases, a patient already receiving therapy with WELLBUTRIN may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, WELLBUTRIN should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with WELLBUTRIN may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with WELLBUTRIN is unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use.
Dosage Forms And Strengths
- 75 mg – yellow-gold, round, biconvex tablets printed with “WELLBUTRIN 75”.
- 100 mg – red, round, biconvex tablets printed with “WELLBUTRIN 100”.
Storage And Handling
WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride, are yellow-gold, round, biconvex tablets printed with “WELLBUTRIN 75” in bottles of 100 (NDC 0173-0177-55).
WELLBUTRIN Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex tablets printed with “WELLBUTRIN 100” in bottles of 100 (NDC 0173-0178-55).
Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F).
The following adverse reactions are discussed in greater detail in other sections of the labeling:
- Suicidal thoughts and behaviors in adolescents and young adults
- Neuropsychiatric symptoms and suicide risk in smoking cessation treatment
- Activation of mania or hypomania
- Psychosis and other neuropsychiatric reactions
- Hypersensitivity reactions
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 with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
Adverse Reactions Leading to Discontinuation of Treatment
Adverse reactions were sufficiently troublesome to cause discontinuation of treatment with WELLBUTRIN in approximately 10% of the 2,400 subjects and healthy volunteers who participated in clinical trials during the product’s initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose.
Commonly Observed Adverse Reactions
Adverse reactions commonly encountered in subjects treated with WELLBUTRIN are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance.
Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials at an incidence of at least 1% of subjects receiving WELLBUTRIN and more frequently in these subjects than in the placebo group.
Table 2: Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency Than Placebo in Controlled Clinical Trials
(n = 323) %
(n = 185) %
| Cardiac arrhythmias
| Appetite increase
| Menstrual complaints
| Urinary frequency
| Musculoskeletal Arthritis
| Cutaneous temperature disturbance
| Dry mouth
| Excessive sweating
| Impaired sleep quality
| Sensory disturbance
| Decreased libido
| Nonspecific Fever/chills
| Auditory disturbance
| Blurred vision
| Gustatory disturbance
Other Adverse Reactions Observed During the Clinical Development of WELLBUTRIN
The conditions and duration of exposure to WELLBUTRIN varied greatly, and a substantial proportion of the experience was gained in open and uncontrolled clinical settings. During this experience, numerous adverse events were reported; however, without appropriate controls, it is impossible to determine with certainty which events were or were not caused by WELLBUTRIN. The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the database.
The following definitions of frequency are used: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.
Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea; rare were flushing, and myocardial infarction.
Dermatologic: Infrequent was alopecia.
Endocrine: Infrequent was gynecomastia; rare was glycosuria.
Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice; rare was intestinal perforation.
Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were enuresis, and urinary incontinence.
Neurological: Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram (EEG) abnormality, and impaired attention.
Neuropsychiatric: Frequent were mania/hypomania, increased libido, hallucinations, decrease in sexual function, and depression; infrequent were memory impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought disorder, and frigidity; rare was suicidal ideation.
Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum irritation, and oral edema.
Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare was pulmonary embolism.
Special Senses: Infrequent was visual disturbance; rare was diplopia.
Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare was overdose.
Altered Appetite and Weight
A weight loss of greater than 5 lbs occurred in 28% of subjects receiving WELLBUTRIN. This incidence is approximately double that seen in comparable subjects treated with tricyclics or placebo. Furthermore, while 35% of subjects receiving tricyclic antidepressants gained weight, only 9.4% of subjects treated with WELLBUTRIN did. Consequently, if weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight reducing potential of WELLBUTRIN should be considered.
The following adverse reactions have been identified during post-approval use of WELLBUTRIN and are not described elsewhere in the label. 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): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness.
Cardiovascular: Hypertension (in some cases severe), orthostatic hypotension, third degree heart block.
Endocrine: Syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia, hypoglycemia.
Gastrointestinal: Esophagitis, hepatitis.
Hemic and Lymphatic: Ecchymosis, leukocytosis, leukopenia, thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.
Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis, muscle weakness.
Nervous System: Aggression, coma, completed suicide, delirium, dream abnormalities, paranoid ideation, paresthesia, restlessness, suicide attempt, unmasking of tardive dyskinesia.
Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis, urticaria.
Special Senses: Tinnitus, increased intraocular pressure.
Potential For Other Drugs To Affect WELLBUTRIN
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between WELLBUTRIN and drugs that are inhibitors or inducers of CYP2B6.
Inhibitors of CYP2B6
Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of WELLBUTRIN may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel).
Inducers of CYP2B6
Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of WELLBUTRIN may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded.
Potential For WELLBUTRIN To Affect Other Drugs
Drugs Metabolized by CYP2D6
Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of WELLBUTRIN with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with WELLBUTRIN, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.
Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN and such drugs may require increased doses of the drug.
Drugs That Lower Seizure Threshold
Use extreme caution when coadministering WELLBUTRIN with other drugs that lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually.
Dopaminergic Drugs (Levodopa And Amantadine)
Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering WELLBUTRIN concomitantly with these drugs.
Use With Alcohol
In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with WELLBUTRIN. The consumption of alcohol during treatment with WELLBUTRIN should be minimized or avoided.
Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with WELLBUTRIN. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN before starting an MAOI antidepressant.
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This 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.
Drug Abuse And Dependence
Bupropion is not a controlled substance.
Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion produced mild amphetamine-like activity as compared with 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.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose trials does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.
Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
Suicidal Thoughts And Behaviors In Children, Adolescents, And Young Adults
Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 subjects treated) are provided in Table 1.
Table 1: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects
||Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Subjects Treated
|Increases Compared With Placebo
||14 additional cases
||5 additional cases
|Decreases Compared With Placebo
||1 fewer case
||6 fewer cases
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for WELLBUTRIN should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms And Suicide Risk In Smoking Cessation Treatment
WELLBUTRIN is not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur.
In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke.
WELLBUTRIN can cause seizure. The risk of seizure is dose-related. The dose should not exceed 450 mg per day. Increase the dose gradually. Discontinue WELLBUTRIN and do not restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with WELLBUTRIN. WELLBUTRIN is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.
Incidence Of Seizure With Bupropion Use
Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg per day. The estimated seizure incidence for WELLBUTRIN increases almost 10-fold between 450 and 600 mg per day.
The risk of seizure can be reduced if the dose of WELLBUTRIN does not exceed 450 mg per day, given as 150 mg 3 times daily, and the titration rate is gradual.
Treatment with WELLBUTRIN can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with WELLBUTRIN, and monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity.
Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.
Activation Of Mania/Hypomania
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating WELLBUTRIN, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). WELLBUTRIN is not approved for use in treating bipolar depression.
Psychosis And Other Neuropsychiatric Reactions
Depressed patients treated with WELLBUTRIN have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct patients to contact a healthcare professional if such reactions occur.
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue WELLBUTRIN and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.
There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like symptoms suggestive of delayed hypersensitivity.
Patient Counseling Information
Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with WELLBUTRIN and counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About WELLBUTRIN?” is available for WELLBUTRIN. Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients regarding the following issues and to alert their prescriber if these occur while taking WELLBUTRIN.
Suicidal Thoughts and Behaviors
Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or healthcare professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment
Although WELLBUTRIN is not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN® which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness. Some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions
Educate patients on the symptoms of hypersensitivity and to discontinue WELLBUTRIN if they have a severe allergic reaction.
Instruct patients to discontinue and not restart WELLBUTRIN if they experience a seizure while on treatment. Advise patients that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Advise patients to minimize or avoid use of alcohol.
Educate patients that WELLBUTRIN contains the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that WELLBUTRIN should not be used in combination with ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN SR®, the sustained-release formulation and WELLBUTRIN XL® or FORFIVO XL™, the extended-release formulations, and APLENZIN®, the extended-release formulation of bupropion hydrobromide). In addition, there are a number of generic bupropion HCl products for the immediate-, sustained-, and extended-release formulations.
Potential for Cognitive and Motor Impairment
Advise patients that any CNS-active drug like WELLBUTRIN may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that WELLBUTRIN does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. WELLBUTRIN may lead to decreased alcohol tolerance.
Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs because WELLBUTRIN and other drugs may affect each others’ metabolisms.
Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
Precautions for Nursing Mothers
Advise patients that WELLBUTRIN is present in human milk in small amounts.
Instruct patients to store WELLBUTRIN at room temperature, between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.
Instruct patients to take WELLBUTRIN in equally divided doses 3 or 4 times a day, with doses separated by least 6 hours to minimize the risk of seizure. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN can be taken with or without food.
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg/m² basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.
Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.
A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.
Use In Specific Populations
Pregnancy Category C
Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. 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 the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. WELLBUTRIN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.
Data from the international bupropion Pregnancy Registry (675 first-trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall.
No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall 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 (n = 10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), 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 (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). 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.
In studies conducted in rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m² basis) and greater. Decreased fetal weights were observed at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m² basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when WELLBUTRIN is administered to a nursing woman.
Safety and effectiveness in the pediatric population have not been established.
Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥ 65 years and 47 were aged ≥ 75 years. In addition, several hundred subjects aged ≥ 65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function.
Consider a reduced dose and/or dosing frequency of WELLBUTRIN in patients with renal impairment (Glomerular Filtration Rate: < 90 mL/min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures.
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN is 75 mg daily. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing.
Human Overdose Experience
Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.
Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR). Call 1-800-222-1222 or refer to www.poison.org.
There are no known antidotes for bupropion. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended.
- WELLBUTRIN is contraindicated in patients with a seizure disorder.
- WELLBUTRIN is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with WELLBUTRIN.
- WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs.
- The use of MAOIs (intended to treat psychiatric disorders) concomitantly with WELLBUTRIN or within 14 days of discontinuing treatment with WELLBUTRIN is contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN is used concomitantly with MAOIs. The use of WELLBUTRIN within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated.
- WELLBUTRIN is contraindicated in patients with known hypersensitivity to bupropion or other ingredients of WELLBUTRIN. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported.