Wellbutrin (Bupropion Hcl): Side Effects, Interactions, Warning, Dosage & Uses

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

Age Range Drug-Placebo Difference in Number of Cases of
Suicidality per 1,000 Subjects Treated
Increases Compared with Placebo
<18 14 additional cases
18-24 5 additional cases
Decreases Compared with Placebo
25-64 1 fewer case
≥65 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 [see BOX WARNING].

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 Adverse Events And Suicide Risk In Smoking Cessation Treatment

WELLBUTRIN is not approved for smoking cessation treatment; however, it contains the same
active ingredient as the smoking cessation medication ZYBANR®. Serious neuropsychiatric
adverse events have been reported in patients taking bupropion for smoking cessation. These
postmarketing reports have included changes in mood (including depression and mania),
psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation,
anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see ]. Some patients who stopped smoking may have been experiencing
symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including
suicidal ideation, has been reported in smokers undergoing a smoking cessations attempt without
medication. However, some of these adverse events occurred in patients taking bupropion who
continued to smoke.

Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric
disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for
the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient
should stop taking WELLBUTRIN and contact a healthcare provider immediately if agitation,
depressed mood, or changes in behavior or thinking that are not typical for the patient are
observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing
cases, resolution of symptoms after discontinuation of bupropion was reported. However, the
symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be
provided until symptoms resolve.

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 [see , ]. 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 [see ].

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 with 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.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including
WELLBUTRIN may trigger an angle-closure attack in a patient with anatomically narrow angles
who does not have a patent iridectomy.

Hypersensitivity Reactions

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 ().

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 Adverse Events 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. Inform patients that some patients
have experienced changes in mood (including depression and mania), psychosis, hallucinations,
paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as
well as suicidal ideation and suicide when attempting to quit smoking while taking bupropion.
Instruct patients to discontinue bupropion and contact a healthcare professional if they
experience such symptoms [see WARNINGS AND PRECAUTIONS, ].

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.

Angle-Closure Glaucoma

Patients should be advised that taking WELLBUTRIN can cause mild pupillary dilation, which
in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing
glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when
diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor
for angle-closure glaucoma. Patients may wish to be examined to determine whether they are
susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are
susceptible [see WARNINGS AND PRECAUTIONS].

Bupropion-Containing Products

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.

Concomitant Medications

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.

Storage Information

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.

Administration Information

Instruct patients to take WELLBUTRIN in equally divided doses 3 or 4 times a day, with doses
separated by at 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.

WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered
trademarks of the GSK group of companies. The other brands listed are trademarks of their
respective owners and are not trademarks of the GSK group of companies. The makers of these
brands are not affiliated with and do not endorse the GSK group of companies or its products.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300
and 150 mg per kg per day, respectively. These doses are approximately 7 and 2 times the
MRHD, respectively, on a mg per m2 basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg per kg per day (approximately 2 to 7
times the MRHD on a mg per 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 per kg per day revealed no evidence of impaired
fertility.

Use In Specific Populations

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.

Clinical Considerations

Consider the risks of untreated depression when discontinuing or changing treatment with
antidepressant medications during pregnancy and postpartum.

Human Data

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.

Animal Data

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 per kg per day, respectively (approximately 11
and 7 times the MRHD, respectively, on a mg per 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 per kg per
day, approximately equal to the MRHD on a mg per m2 basis) and greater. Decreased fetal
weights were observed at 50 mg per kg and greater.

When rats were administered bupropion at oral doses of up to 300 mg per kg per day
(approximately 7 times the MRHD on a mg per m2 basis) prior to mating and throughout
pregnancy and lactation, there were no apparent adverse effects on offspring development.

Nursing Mothers

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 per 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.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established [see , WARNINGS AND PRECAUTIONS].

Geriatric Use

Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustainedrelease
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 [see , Renal Impairment, ].

Renal Impairment

Consider a reduced dose and/or dosing frequency of WELLBUTRIN in patients with renal
impairment (Glomerular Filtration Rate: less than 90 mL per 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 [see , ].

Hepatic Impairment

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 [see , ].

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