A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Wellbutrin Side Effects, and Drug Interactions - Bupropion
Wellbutrin Side Effects, and Drug Interactions - Bupropion
SIDE EFFECTS
(See WARNINGS and PRECAUTIONS).
The information included under ADVERSE REACTIONS is based primarily on data from the
dose-response trial and the comparative trial that evaluated ZYBAN for smoking cessation (see
CLINICAL TRIALS). Information on additional adverse events associated with the
sustained-release formulation of bupropion in depression trials, as well as the immediate-release
formulation of bupropion, is included in a separate section (see Other Events Observed During
the Clinical Development and Postmarketing Experience of Bupropion).
Adverse Events Associated With the Discontinuation of Treatment: Adverse events
were sufficiently troublesome to cause discontinuation of treatment in 8% of the 706 patients
treated with ZYBAN and 5% of the 313 patients treated with placebo. The more common events
leading to discontinuation of treatment with ZYBAN included nervous system disturbances
(3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes.
Incidence of Commonly Observed Adverse Events: The most commonly observed
adverse events consistently associated with the use of ZYBAN were dry mouth and insomnia.
The most commonly observed adverse events were defined as those that consistently occurred at
a rate of 5 percentage points greater than that for placebo across clinical studies.
Dose Dependency of Adverse Events: The incidence of dry mouth and insomnia may be
related to the dose of ZYBAN. The occurrence of these adverse events may be minimized by
reducing the dose of ZYBAN. In addition, insomnia may be minimized by avoiding bedtime
doses.
Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated
With ZYBAN: Table 4 enumerates selected treatment-emergent adverse events from the
dose-response trial that occurred at an incidence of 1% or more and were more common in
patients treated with ZYBAN compared to those treated with placebo. Table 5 enumerates
selected treatment-emergent adverse events from the comparative trial that occurred at an
incidence of 1% or more and were more common in patients treated with ZYBAN, NTS, or the
combination of ZYBAN and NTS compared to those treated with placebo. Reported adverse
events were classified using a COSTART-based dictionary.
| TABLE 4 Treatment-Emergent Adverse Events
in the Dose-Response Trial* |
| Body System /Adverse Event |
Bupropion HCl SR
100 to 300 mg/day (n=461) |
Placebo (n=150) |
| Body (General) |
| Neck Pain |
2% |
<1% |
| Allergic Reaction |
1% |
0% |
| Cardiovascular |
| Hot flashes |
1% |
0% |
| Hypertension |
1% |
<1% |
| Digestive |
| Dry mouth |
11% |
5% |
| Increased Appetite |
2% |
<1% |
| Anorexia |
1% |
<1% |
| Musculosketal |
| Arthralgia |
4% |
3% |
| Myalgia |
2% |
1% |
| Nervous system |
| Insomnia |
31% |
21% |
| Dizziness |
8% |
7% |
| Tremor |
2% |
1% |
| Somnolence |
2% |
1% |
| Thinking Abnormality |
1% |
0% |
| Respiratory |
| Bronchitis |
2% |
0% |
| Skin |
| Pruritis |
3% |
<1% |
| Rash |
3% |
<1% |
| Dry Skin |
2% |
0% |
| Urticaria |
1% |
0% |
| Special senses |
| Taste perversion |
2% |
<1% |
| * Selected adverse events with an
incidence of at least 1% of patients treated with bupropion
HCl and more frequent than in the placebo
group. |
| TABLE 5 Treatment-Emergent Adverse Events
in the Comparative Trial* |
| Adverse Experience (COSTART Term) |
Bupropion HCl SR
300 mg/day (n=243) |
Nicotine Transdermal System (NTS) 21 mg/day (n=243) |
Bupropion HCl and NTS (n=244) |
Placebo (n=159) |
| Body (General) |
| Abdominal pain |
3% |
4% |
1% |
1% |
| Accidental Injury |
2% |
2% |
1% |
1% |
| Chest pain |
<1% |
1% |
3% |
1% |
| Neck pain |
2% |
1% |
<1% |
0% |
| Facial edema |
<1% |
0% |
1% |
0% |
| Cardiovascular |
| Hypertension |
1% |
<1% |
2% |
0% |
| Palpitation |
2% |
0% |
1% |
0% |
| Digestive |
| Nausea |
9% |
7% |
11% |
4% |
| Dry Mouth |
10% |
4% |
9% |
4% |
| Constipation |
8% |
4% |
9% |
3% |
| Diarrhea |
4% |
4% |
3% |
1% |
| Anorexia |
3% |
1% |
5% |
1% |
| Mouth Ulcer |
2% |
1% |
1% |
1% |
| Thirst |
<1% |
<1% |
2% |
0% |
| Musculosketal |
| Mylagia |
4% |
3% |
5% |
3% |
| Arthralgia |
5% |
3% |
3% |
2% |
| Nervous system |
| Insomnia |
40% |
28% |
45% |
18% |
Dream
Abnormality |
5% |
18% |
13% |
3% |
| Anxiety |
8% |
6% |
9% |
6% |
Disturbed
concentration |
9% |
3% |
9% |
4% |
| Dizziness |
10% |
2% |
8% |
6% |
| Nervousness |
4% |
<1% |
2% |
2% |
| Tremor |
1% |
<1% |
2% |
0% |
| Dysphoria |
<1% |
1% |
2% |
1% |
| Respiratory |
| Rhinitis |
12% |
11% |
9% |
8% |
| Increased Cough |
3% |
5% |
<1% |
1% |
| Pharyngitis |
3% |
2% |
3% |
0% |
| Sinsusitis |
2% |
2% |
2% |
1% |
| Dyspnea |
1% |
0% |
2% |
1% |
| Epistaxis |
2% |
1% |
1% |
0% |
| Skin |
| Application Site Reaction† |
11% |
17% |
15% |
7% |
| Rash |
4% |
3% |
3% |
2% |
| Pruritus |
3% |
1% |
5% |
1% |
| Urticaria |
2% |
0% |
2% |
0% |
| Special senses |
| Taste perversion |
3% |
1% |
3% |
2% |
| Tinnitus |
1% |
0% |
<1% |
0% |
| * Selected adverse events with an
incidence of at least 1% of patients treated with either bupropion
HCl, NTS, or the combination of bupropion
HCl and NTS and more frequent than in the placebo group. |
| † Patients randomized to bupropion
HCl or placebo received
placebo patches. |
ZYBAN was well-tolerated in the long-term maintenance trial, that evaluated chronic
administration of ZYBAN for up to 1 year and in the COPD trial that evaluated patients with
mild-to-moderate COPD for a 12-week period. Adverse events in both studies were
quantitatively and qualitatively similar to those observed in the dose-response and comparative
trials.
Other Events Observed During the Clinical Development and Postmarketing
Experience of Bupropion: In addition to the adverse events noted above, the following
events have been reported in clinical trials and postmarketing experience with the
sustained-release formulation of bupropion in depressed patients and in nondepressed smokers,
as well as in clinical trials and postmarketing clinical experience with the immediate-release
formulation of bupropion.
Adverse events for which frequencies are provided below occurred in clinical trials with
bupropion sustained-release. The frequencies represent the proportion of patients who
experienced a treatment-emergent adverse event on at least one occasion in placebo-controlled
studies for depression (n = 987) or smoking cessation (n = 1,013), or patients who experienced
an adverse event requiring discontinuation of treatment in an open-label surveillance study with
bupropion sustained-release tablets (n = 3,100). All treatment-emergent adverse events are
included except those listed in Tables 4 and 5, those events listed in other safety-related sections of the insert,
those adverse events subsumed under COSTART terms that are either overly
general or excessively specified so as to be uninformative, those events not reasonably associated
with the use of the drug, and those events that were not serious and occurred in fewer than
2 patients.
Events are further categorized by body system and listed in order of decreasing frequency
according to the following definitions of frequency: Frequent adverse events are defined as those
occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to
1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.
Adverse events for which frequencies are not provided occurred in clinical trials or
postmarketing experience with bupropion. Only those adverse events not previously listed for
sustained-release bupropion are included. The extent to which these events may be associated
with ZYBAN is unknown.
Body (General): Frequent were asthenia, fever, and headache. Infrequent were back pain,
chills, inguinal hernia, musculoskeletal chest pain, pain, and photosensitivity. Rare was malaise.
Also observed were arthralgia, myalgia, and fever with rash and other symptoms suggestive of
delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS).
Cardiovascular: Infrequent were flushing, migraine, postural hypotension, stroke,
tachycardia, and vasodilation. Rare was syncope. Also observed were cardiovascular disorder,
complete AV block, extrasystoles, hypotension, hypertension (in some cases severe, see
PRECAUTIONS), myocardial infarction, phlebitis, and pulmonary embolism.
Digestive: Frequent were dyspepsia, flatulence, and vomiting. Infrequent were abnormal
liver function, bruxism, dysphagia, gastric reflux, gingivitis, glossitis, jaundice, and stomatitis.
Rare was edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage,
gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage,
pancreatitis, stomach ulcer, and stool abnormality.
Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of
inappropriate antidiuretic hormone.
Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia,
leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT
and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were
observed when bupropion was co-administered with warfarin.
Metabolic and Nutritional: Infrequent were edema, increased weight, and peripheral
edema. Also observed was glycosuria.
Musculoskeletal: Infrequent were leg cramps and twitching. Also observed were arthritis
and muscle rigidity/fever/rhabdomyolysis, and muscle weakness.
Nervous System: Frequent were agitation, depression, and irritability. Infrequent were
abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory,
depersonalization, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia,
paresthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and
hypomania. Also observed were abnormal electroencephalogram (EEG), akinesia, aphasia,
coma, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome,
hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid
reaction, and unmasking tardive dyskinesia.
Respiratory: Rare was bronchospasm. Also observed was pneumonia.
Skin: Frequent was sweating. Infrequent was acne and dry skin. Rare was maculopapular
rash. Also observed were alopecia, angioedema, exfoliative dermatitis, and hirsutism.
Special Senses: Frequent was amblyopia. Infrequent were accommodation abnormality
and dry eye. Also observed were deafness, diplopia, and mydriasis.
Urogenital: Frequent was urinary frequency. Infrequent were impotence, polyuria, and
urinary urgency. Also observed were abnormal ejaculation, cystitis, dyspareunia, dysuria,
gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence,
urinary retention, urinary tract disorder, and vaginitis.
DRUG INTERACTIONS
In vitro studies indicate that bupropion
is primarily metabolized to the morpholinol metabolite
(hydroxybupropion) by the cytochrome
P450IIB6 (CYP2B6) isoenzyme. Therefore, the potential
exists for a drug interaction
between bupropion HCl and
drugs that affect the CYP2B6
isoenzyme (e.g.,
orphenadrine and cyclophosphamide). The threohydrobupropion metabolite
of bupropion does not appear
to be produced by the cytochrome
P450 iosenzyme. Few systemic data have been
collected on the metabolism of ZYBAN following concomitant administration with other drugs
or, alternatively, the effect of concomitant administration of ZYBAN on the metabolism of other
drugs.
Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in
humans. However, following chronic administration of bupropion, 100 mg t.i.d. to 8 healthy
male volunteers for 14 days, there was no evidence of induction of its own metabolism. Because
bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical
activity. In particular, certain drugs may induce the metabolism of bupropion (e.g.,
carbamazepine, phenobarbital, phenytoin), while other drugs may inhibit the metabolism of
bupropion (e.g., cimetidine). The effects of concomitant administration of cimetidine on the
pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male
volunteers. Following oral administration of two 150-mg ZYBAN tablets with and without
800 mg of cimetidine, the pharmacokinetics of bupropion and its hydroxy metabolite were
unaffected. However, there were 16% and 32% increases, respectively, in the AUC and Cmax of
the combined moieties of threohydro- and erythrohydro- bupropion.
Drugs Metabolized by Cytochrome P450IID6 (CYP2D6): Many
drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers,
antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme.
Although bupropion is not
metabolized by this isoenzyme, bupropion
and hydroxybupropion are inhibitors of the CYP2D6 isoenzyme
in vitro. In a study of 15 males subjects (ages 19 to 35 years)
who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of
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. Comcomitant use of bupropion
with other drugs metabolized by CYP2D6 has not been formally studied.
Therefore, co-adminstration of bupropion
with drugs that are metabolized by CYP2D6 isoenzyme
including certain antidepressants (e.g., nortriptyline, imipramine,
desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g.,
haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol),
and Type 1C antiarrhythmics (e.g., propafenone, flecanide), should
be approached with caution and should be initiated at the lower end of
the dose range
of the concomitant medication.
If bupropion is added to
the treatment regimen
of a patient already receiving
a drug metabolized by CYP2D6,
the need to decrease the dose
of the original medication
should be considered, particularly for those concomitant
medications with a narrow therapeutic index.
MAO Inhibitors: Studies in animals demonstrate that the
acute toxicity of bupropion
is enhanced by the MAO inhibitor
phenelzine (see CONTRAINDICATIONS.)
Levodopa and Amantadine: Limited clinical data suggest a higher incidence of adverse
experiences in patients receiving bupropion concurrently with either levodopa or amantadine.
Administration of ZYBAN to patients receiving either levodopa or amantadine concurrently
should be undertaken with caution, using small initial doses and gradual dose increases.
Drugs That Lower Seizure Threshold:
Concurrent administration of ZYBAN and agents
(e.g., antipsychotics, antidepressants, theophylline, systemic steroids, etc.) that lower seizure
threshold should be undertaken only with extreme caution (see WARNINGS.)
Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).
Smoking Cessation:Physiological changes resulting from smoking cessation itself, with
or without treatment with ZYBAN, may alter the pharmacokinetics of some concomitant
medications, which may require dosage adjustment. Blood concentrations of concomitant
medications that are extensively metabolized, such as theophylline and warfarin, may be
expected to increase following smoking cessation due to de-induction of hepatic enzymes.
Alcohol: In post-marketing experience, there have been rare reports of adverse
neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol
during treatment with ZYBAN. The consumption of alcohol during treatment with ZYBAN
should be minimized or avoided (also see CONTRAINDICATIONS).
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