|
SIDE EFFECTS
(See WARNINGS and PRECAUTIONS).
For Bupropion HCl Sustained Release Tablets for
Depression
The information included under the Incidence in Controlled
Trials section is primarily based on data from controlled
clinical trials with bupropion HCl sustained release tablets.
Information on additional adverse events associated with
the sustained-release formulation of bupropion in smoking
cessation trials, as well as immediate-release formulation
of bupropion, is included in a separate section (see Other
Events Observed During the Clinical Development and Postmarketing
Experience of Bupropion).
Incidence in Controlled Trials With Bupropion
Sustained Release Tablets for Treatment of Depression:
Adverse Events Associated With Discontinuation
of Treatment Among Patients Treated With Bupropion Sustained
Release Tablets: In placebo-controlled clinical
trials, 9% and 11% of patients treated with 300 and 400
mg/day, respectively, of bupropion HCl sustained release
tablets and 4% of patients treated with placebo discontinued
treatment due to adverse events. The specific adverse
events in these trials that led to discontinuation in
at least 1% of patients treated with either 300 or 400
mg/day of bupropion HCl sustained release tablets and
at a rate at least twice the placebo rate are listed in
TABLE 5.
| TABLE 5 Treatment
Discontinuations Due to Adverse Events in Placebo-Controlled
Trials |
| Adverse Event Term |
Bupropion HCl Sustained Release 300
mg/day (n=376) |
Bupropion HCl Sustained Release 400
mg/day (n=114) |
Placebo (n=385) |
| Rash |
2.4% |
0.9% |
0.0% |
| Nausea |
0.8% |
1.8% |
0.3% |
| Agitation |
0.3% |
1.8% |
0.3% |
| Migraine |
0.0% |
1.8% |
0.3% |
Adverse Events Occurring at an Incidence of 1% or
More Among Patients Treated With Bupropion Sustained Release
Tablets: TABLE 6 enumerates treatment-emergent
adverse events that occurred among patients treated with
300 and 400 mg/day of bupropion HCl sustained release tablets
and with placebo in placebo-controlled trials. Events that
occurred in either the 300- or 400-mg/day group at an incidence
of 1% or more and were more frequent than in the placebo
are included. Reported adverse events were classified using
a COSTART-based Dictionary.
Accurate estimates of the incidence of adverse events associated
with the use of any drug are difficult to obtain. Estimates
are influenced by drug dose, detection technique, setting,
physician judgements, etc. The figures cited cannot be used
to predict precisely the incidence of untoward events in
the course of usual medical practice where patient characteristics
and other factors differ from those that prevailed in the
clinical trials. These incidence figures also cannot be
compared with those obtained from other clinical studies
involving related drug products as each group of drug trials
is conducted under a different set of conditions.
Finally, it is important to emphasize that the tabulation
does not reflect the relative severity and/or clinical importance
of the events. A better perspective on the serious adverse
events associated with the use of bupropion HCl sustained
release tablets is provided in WARNINGS and PRECAUTIONS.
| TABLE 6 Treatment-Emergent
Adverse Events in Placebo-Controlled Trials* |
| Body System /Adverse
Event |
Bupropion HCl SR
300 mg/day (n=376) |
Bupropion HCl SR
400 mg/day (n=114) |
Placebo
(n=385) |
| Body
(General) |
| Headache |
26% |
25% |
23% |
| Infection |
8% |
9% |
6% |
| Abdominal
pain |
3% |
9% |
2% |
| Asthenia |
2% |
4% |
2% |
| Chest
pain |
3% |
4% |
1% |
| Pain |
2% |
3% |
2% |
| Fever |
1% |
2% |
¾ |
| Cardiovascular |
| Palpitation |
2% |
6% |
2% |
| Flushing |
1% |
4% |
¾ |
| Migraine |
1% |
4% |
1% |
| Hot
flashes |
1% |
3% |
1% |
| Digestive |
| Dry
mouth |
17% |
24% |
7% |
| Nausea |
13% |
18% |
8% |
| Constipation |
10% |
5% |
7% |
| Diarrhea |
5% |
7% |
6% |
| Anorexia |
5% |
3% |
2% |
| Vomiting |
4% |
2% |
2% |
| Dysphagia |
0% |
2% |
0% |
| Musculosketal |
| Mylagia |
2% |
6% |
3% |
| Arthralgia |
1% |
4% |
1% |
| Arthritis |
0% |
2% |
0% |
| Twitch |
1% |
2% |
¾ |
| Nervous
system |
| Insomnia |
11% |
16% |
6% |
| Dizziness |
7% |
11% |
5% |
| Agitation |
3% |
9% |
2% |
| Anxiety |
5% |
6% |
3% |
| Tremor |
6% |
3% |
1% |
| Nervousness |
5% |
3% |
3% |
| Somnolence |
2% |
3% |
2% |
| Irritability |
3% |
2% |
2% |
| Memory
decreased |
¾ |
3% |
1% |
| Paresthesia |
1% |
2% |
1% |
| CNS
stimulation |
2% |
1% |
1% |
| Respiratory |
| Pharyngitis |
3% |
11% |
2% |
| Sinsusitis |
3% |
1% |
2% |
| Increased
cough |
1% |
2% |
1% |
| Skin |
| Sweating |
6% |
5% |
2% |
| Rash |
5% |
4% |
1% |
| Pruritus |
2% |
4% |
2% |
| Urticaria |
2% |
1% |
0% |
| Special
senses |
| Tinnitus |
6% |
6% |
2% |
| Taste
perversion |
2% |
4% |
¾ |
| Amblyopia |
3% |
2% |
2% |
| Urogenital |
| Urinary
frequency |
2% |
5% |
2% |
| Urinary
urgency |
¾ |
2% |
0% |
| Vaginal
hemorrhage† |
0% |
2% |
¾ |
| Urinary
tract infection |
1% |
0% |
¾ |
| *
Adverse events that occurred in at least 1% of patients
treated with either 300 or 400 mg/day of bupropion
HCl sustained release tablets, but equally or more
frequently in the placebo group, were: abnormal dreams,
accidental injury, acne, appetite increased, back
pain, bronchitis, dysmenorrhea, dyspepsia, flatulence,
flu syndrome, hypertension, neck pain, respiratory
disorder, rhinitis, and tooth disorder. |
| †
Incidence based on the number of female patients. |
| ¾
Hyphen denotes adverse events occurring in greater
than 0 but less and 0.5% of patients. |
Incidence of Commonly Observed Adverse Events in
Controlled Clinical Trials: Adverse events from
TABLE 6 occurring in at least 5% of patients treated with
bupropion HCl sustained release tablets and at a rate at
least twice the placebo rate are listed below for the 300-
and 400-mg/day dose groups.
Bupropion HCl Sustained Release 300 mg/day:
Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
Bupropion HCl Sustained Release 400 mg/day: Abdominal
pain, agitation, anxiety, dizziness, dry mouth, insomnia,
myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus,
and urinary frequency.
For Bupropion HCl for Smoking Cessation
The information included under the
SIDE EFFECTS
section is primarily based on data from the dose-response
trial and comparative trial that evaluated bupropion HCl
sustained release tablets for smoking cessation (see CLINICAL
STUDIES). Information on additional adverse events associated
with the sustained-release formulation of bupropion in depression
trials, as well as immediate-release formulation of bupropion,
is included in a separate section (see Other Events Observed
During the Clinical Development and Postmarketing Experience
of Bupropion).
Incidence of Adverse Reactions in Controlled Trials of Bupropion
Sustained Release Tablets for Smoking Cessation: This information
included under
SIDE EFFECTS
is based primarily on data from the dose-response trial
and the comparative trial that evaluated bupropion for smoking
cessation (see CLINICAL STUDIES). Information on additional
adverse events associated with bupropion sustained release
tablets in depression trials, as well as the immediate release
formulation of bupropion, is included in a separate subsection
(see Other Events Observed During the Clinical Development
and Postmarketing Experience of Bupropion).
Adverse Events Associated with Discontinuation of
Treatment: Adverse events were sufficiently troublesome
to cause discontinuation of treatment in 8% of the 706 patients
treated with bupropion HCl sustained release tablets and
5% of the 313 patients treated with placebo. The more common
events leading to discontinuation of treatment with bupropion
HCl 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 bupropion HCl 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 bupropion HCl. The occurrence of these adverse events
may be minimized by reducing the dose of bupropion HCl.
In addition, insomnia may be minimized by avoiding bedtime
doses.
Adverse Events Occurring at an Incidence of 1% or
More Among Patients Treated with Bupropion HCl for Smoking
Cessation: TABLE 7 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 bupropion HCl compared to those treated with
placebo. TABLE 8 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 bupropion HCl , NTS, or the combination of
bupropion HCl and NTS compared to those treated with placebo.
Reported adverse events were classified using a COSTART-based
dictionary.
| TABLE 7 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 8 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. |
For Bupropion HCl for Immediate Release
Adverse events commonly encountered in patients treated
with bupropion HCl are agitation, dry mouth, insomnia, headache/migraine,
nausea/vomiting, constipation, and tremor.
Adverse events were suficiently troublesome to cause discontinuation
of treatment with bupropion HCl in approximately 10% of
the 2400 patients and 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.
Accurate estimates of the incidence of adverse events associated
with the use of any drug are difficult to obtain. Estimates
are influenced by drug dose, detection technique, setting,
physician judgments, etc. Consequently, the table below
is presented soley to indicate the relative frequency of
adverse events reported in representative controlled clinical
studies conducted to evaluate the safety and efficacy of
bupropion HCl under relatively similar conditions of daily
dosage (300 to 600 mg), setting, and duration (3 to 4 weeks).
The figures cited cannot be used to predict precisely the
incidence of untoward events in the course of usual medical
practice where patient characteristics and other factors
must differ from those which prevailed in the clinical trials.
These incidence figures also cannot be compared with those
obtained from other clinical studies involving related drug
products as each group of drug trials is conducted under
a different set of conditions.
Finally, it is important to emphasize that the tabulation
does not reflect the relative severity and/or clinical importance
of the events. A better perspective on the serious adverse
events associated with the use of bupropion HCl is provided
in WARNINGS and PRECAUTIONS.
| TABLE 9 Treatment
Emergent Adverse Experience Incidence in Placebo-Controlled
Clinical Trials* |
| |
(Percent of
Patients Reporting) |
| |
Bupropion HCl Patients
|
Placebo Patients |
| Adverse Experience |
(n=323) |
(n=185) |
| Cardiovascular |
| Cardiac
arrhythmias |
5.3 |
4.3 |
| Dizziness |
22.3 |
16.2 |
| Hypertension |
4.3 |
1.6 |
| Hypotension |
2.5 |
2.2 |
| Palpitations |
3.7 |
2.2 |
| Syncope |
1.2 |
0.5 |
| Tachycardia |
10.8 |
8.6 |
| Dermatalogic |
| Pruritus |
2.2 |
0.0 |
| Rash |
8.0 |
6.5 |
| Gastrointestinal |
| Anorexia |
18.3 |
18.4 |
| Appetite
increase |
3.7 |
2.2 |
| Constipation |
26.0 |
17.3 |
| Diarrhea |
6.8 |
8.6 |
| Dyspepsia |
3.1 |
2.2 |
| Nausea/vomiting |
22.9 |
18.9 |
| Weight
gain |
13.6 |
22.7 |
| Weight
loss |
23.2 |
23.2 |
| Genitourinary |
| Impotence |
3.4 |
3.1 |
| Menstrual
complaints |
4.7 |
1.1 |
| Urinary
frequency |
2.5 |
2.2 |
| Urinary
retention |
1.9 |
2.2 |
| Musculoskeletal |
| Arthritis |
3.1 |
2.7 |
| Neurological |
| Akathisia |
1.5 |
1.1 |
| Akinesia/bradykinesia |
8.0 |
8.6 |
| Cutaneous
temperature disturbance |
1.9 |
1.6 |
| Dry
mouth |
27.6 |
18.4 |
| Excessive
sweating |
22.3 |
14.6 |
| Headache/migraine |
25.7 |
22.2 |
| Impaired
sleep quality |
4.0 |
1.6 |
| Increase
salivary flow |
3.4 |
3.8 |
| Insomnia |
18.6 |
15.7 |
| Muscle
spasms |
1.9 |
3.2 |
| Pseudoparkinsonism |
1.5 |
1.6 |
| Sedation |
19.8 |
19.5 |
| Sensory
disturbance |
4.0 |
3.2 |
| Tremor |
21.1 |
7.6 |
| Neuropsychiatric |
| Agitation |
31.9 |
22.2 |
| Anxiety |
3.1 |
1.1 |
| Confusion |
8.4 |
4.9 |
| Decreased
libido |
3.1 |
1.6 |
| Delusions |
1.2 |
1.1 |
| Disturbed
concentration |
3.1 |
3.8 |
| Euphoria |
1.2 |
0.5 |
| Hostility |
5.6 |
3.8 |
| Nonspecific |
| Fatigue |
5.0 |
8.6 |
| Fever/chills |
1.2 |
0.5 |
| Respiratory |
| Upper
respiratory complaints |
5.0 |
11.4 |
| Special
senses |
| Auditory
disturbance |
5.3 |
3.2 |
| Blurred
vision |
14.6 |
10.3 |
| Gustatory
disturbance |
3.1 |
1.1 |
| *
Events reported by at least 1% of patients receiving
bupropion HCl are included. |
Other Events Observed During the Clinical Development and
Postmarketing Experience of Bupropion Sustained Release
Tablets for Depression and Smoking Cessation
In addition to the adverse events already noted, 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 presented 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=1013) or patients who experienced
an adverse event requiring discontinuation in an open-label
surveillance study with bupropion HCl sustained release
tablets (n=3100). All treatment-emergent adverse events
are included except those listed in TABLE 3, TABLE 4, TABLE
5, TABLE 6, TABLE 7 and TABLE 8, those events listed in
other safety-related sections, those events subsumed under
COSTART terms that are either overly general or excessively
specific 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 only one patient. Events
of major clinical importance are described in the WARNINGS
and PRECAUTIONS.
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 1/1000 patients,
while rare events are those occurring in less than 1/1000
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 bupropion HCl is unknown.
For Bupropion HCl Sustained Release Tablets for
Depression
Body (General): Infrequent: Chills, facial
edema, musculoskeletal chest pain, and photosensitivity.
Rare: Malaise.
Cardiovascular: Infrequent: Postural hypotension,
stroke, tachycardia, and vasodilation. Rare: Syncope. Also
observed were complete atrioventricular block, extrasystoles,
hypotension, myocardial infarction, phlebitis, and pulmonary
embolism.
Digestive: Infrequent: Abnormal liver function,
bruxism, gastric reflux, gingivitis, glossitis, increased
salivation, jaundice, mouth ulcers, stomatitis, and thirst.
Rare: Edema of tongue. Also observed were colitis, esophagitis,
gastrintestinal hemorrhage, gum hemorrhage, hepatitis, intestinal
perforation, liver damage, pancreatitis, and stomach ulcer.
Endocrine: Also observed were hyperglycemia,
hypoglycemia, and syndrome of inappropriate antidiuretic
hormone.
Hemic and Lymphatic: Infrequent: Ecchymosis. Also observed
were anemia, leukocytosis, leukopenia, lymphadenopathy,
pancytopenia, and thrombocytopenia.
Metabolic and Nutrional: Infrequent: Edema,
increased and peripheral edema. Also observed was glycosuria.
Musculoskeletal: Infrequent: Leg cramps.
Also observed were muscle rigidity/fever/rhabdomyolysis
and muscle weakness.
Nervous system: Infrequent: Abnormal coordination,
decreased libido, depersonalization, dysphoria, emotional
labity, hostility, hyperkinesia, hypertonia, hypesthesia,
suicidal ideation, and vertigo. Rare: Amnesia, ataxia, derealization,
and hypomania. Also observed were abnormal electroencephalogram
(EEG), hypokinesia, increased libido, manic reaction, neuralgia,
neuropathy, paranoid reaction, and unmasking tardive dyskinesia.
Respiratory: Rare: Bronchospasm. Also observed
was pneumonia.
Skin: Rare: Maculopapular rash. Also observed
were alopecia, angioedema, exfoliative dermatitis, and hirsutism.
Special Senses: Infrequent: Accomodation
abnormality and dry eye. Also observed were deafness, diplopia,
and mydriasis.
Urogenital: Infrequent: Impotence, polyuria,
and prostate disorder. Also observed were abnormal ejaculation,
cycstitis, dyspareunia, dysuria, gynecomastia, menopause,
painful erection, salpingitis, urinary incontinence, urinary
retention, and vaginitis.
For Bupropion HCl Sustained Release Tablets for Smoking
Cessation
Body (General): Frequent: Asthenia, fever,
and headache. Infrequent: Back pain, chills, inguinal hernia,
musculskeletal chest pain, pain, and photosensivity. Rare:
Malaise.
Cardiovascular: Infrequent: Flushing, migraine,
postural hypotension, stroke, tachycardia, and vasodilation.
Rare: Syncope. Also observed were cardiovascular disorder,
complete AV block, extrasystoles, hypotension, myocardial
infarction, phlebitis, and pulmonary embolism.
Digestive: Frequent: Dyspepsia, flatulence,
and vomiting. Infrequent: Abnormal liver function, bruxism,
dysphagia, gastric reflux, gingivitis, glossitis, jaundice,
stomatitis. Rare: 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: Ecchymosis.
Also observed were anemia, leukocytosis, leukopenia, lymphadenopathy,
pancytopenia, and thrombocytopenia.
Metabolic and Nutrional: Infrequent: Edema,
increased weight, and peripheral edema. Also observed was
glycosuria.
Musculoskeletal: Infrequent: Leg cramps
and twitching. Also observed were arthritis and muscle rigidty/fever/rhabdomyolysis,
and muscle weakness.
Nervous system: Frequent: Agitation, depression,
and irritability. Infrequent: Abnormal coordination, CNS
stimulation, confusion, decreased libido, decreased memory,
depersonalization, emotional labity, hostility, hyperkinesia,
hypertonia, hypesthesia, paresthesia, suicidal ideation,
and vertigo. Rare: Amnesia, ataxia, derealization, and hypomania.
Also observed were abnormal electroencephalogram (EEG) ,
akinesia, aphasia, coma delirium, delusions, dysarthria,
dyskinesia, dystonia, euphoria, extrapyramidal syndrome,
hypokinesia, increased libido, manic reaction, neuralgia,
neuropathy, paranoid reaction, and unmasking tardive dyskinesia.
Respiratory: Rare: Bronchospasm. Also observed
was pneumonia.
Skin: Frequent: Sweating. Infrequent: Acne
and dry skin. Rare: Maculopapular rash. Also observed were
alopecia, angioedema, exfoliative dermatitis, and hirsutism.
Special Senses: Frequent: Amblyopia. Infrequent:
Accomodation abnormality and dry eye. Also observed were
deafness, diplopia, and mydriasis.
Urogenital: Frequent: Urinary frequency. Infrequent:
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.
Other Events Observed During the Development of the Immediate
Release Formulation of Bupropion
The conditions and duration of exposure to bupropion HCl
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 bupropion HCl. The following enumeration is organized
by organ system and describes events in terms of their relative
frequency of reporting in the data base. Events of major
clinical importance are also described in WARNINGS and PRECAUTIONS.
The following definitions of frequency are used:
Frequent adverse events are defined as those occurring
in at least 1/100 patients. Infrequent adverse events are
those occurring in 1/100 to 1/1000 patients, while rare
events are those occurring in less than 1/1000 patients.
Cardiovascular: Frequent: Edema. Infrequent:
Chest pain, electrocardiogram (ECG) abnormalities (premature
beats and nonspecific ST-T changes), and shortness of breath/dyspnea.
Rare: Flushing, pallor, phlebitis, and mycocardial infarction.
Dermatologic: Frequent: Nonspecific rashes.
Infrequent: Alopecia and dry skin.Rare: Change in hair color,
hirsutism, and acne.
Endocrine: Infrequent: Dysphagia, thirst
disturbance, and liver damage/jaundice. Rare: Rectal complaints,
colitis, gastrointestinal bleeding, intestinal perforation,
and stomach ulcer.
Genitourinary: Frequent: Nocturia. Infrequent:
Vaginal irritation, testicular swelling, urinary tract infection,
painful erection, and retarded ejaculation. Rare: Dysuria,
enuresis, urinary incontinence, menopause, ovarian disorder,
pelvic infection, cystitis, dyspareunia, and painful ejaculation.
Hematologic/Oncologic: Rare: Lymphadenopathy,
anemia, and pancytopenia.
Musculoskeletal: Rare: Musculoskeletal
chest pain.
Neurological: (See WARNINGS.) Frequent:
Ataxia/incoordination, seizure, myoclonus, dyskinesia, and
dystonia. Infrequent: Mydriasis, vertigo, and dysarthria.
Rare: Electroencephalogram (EEG) abnormality, abnormal neurological
exam, impaired attention, sciatica, and aphasia.
Neuropsychiatric: (See PRECAUTIONS.) Frequent:
Mania/hypomania, increased libido, hallucinations, decrease
in sexual function, and depression. Infrequent: Memory impairment,
depersonalization, psychosis, dysphoria, mood instability,
paranoia, formal thought disorder, and frigidity. Rare:
Suicidal ideation.
Oral Complaints: Frequent: Stomatitis.
Infrequent: Toothache, bruxism, gum irritation, and oral
edema. Rare: Glossitis.
Respiratory: Infrequent: Bronchitis and
shortness of breath/dyspnea.Rare: Epistaxis, rate or rhythm
disorder, pneumonia, and pulmonary embolism.
Special Senses: Infrequent: Visual disturbance.
Rare: Diplopia.
Nonspecific: Frequent: Flu-like symptoms.
Infrequent: Nonspecific pain. Rare: Body odor, surgically
related pain, infection, medication reaction, and overdose.
Postintroduction Reports
Voluntary reports of adverse events temporally associated
with bupropion that have been received since marekt introduction
and which may have no causal relationship with the drug
include the following:
Cardiovascular: Orthostatic hypotension
and third degree heart block.
Endocrine: Syndrome of inappropriate antiduretic hormone
secretion, hyperglycemia, and hypoglycemia.
Gastrointestinal: Esophagitis, hepatitis,
and liver damage.
Hemic and Lymphatic: Ecchymosis, leukocytosis, leukopenia,
and thrombocytopenia.
Musculoskeletal: Arthralgia, myalgia, rigidity/fever/rhabdomyolysis,
and muscle weakness.
Nervous: Coma, delirium, dream abnormalities,paresthesia,
and unmasking of tardive dyskinesia.
Skin: Stevens-Johnson syndrome, angioedema,
exfoliative dermatitis, and urticaria.
Special Senses: Tinnitus.
DRUG ABUSE AND DEPENDENCE
Controlled Substance Class: Bupropion is
not a controlled substance.
Humans
Controlled clinical studies of bupropion conducted in normal
volunteers, in subjects with a history of multiple drug
abuse, and in depressed patients showed some increase in
motor activity and agitation/excitement. There have been
few reported cases of drug dependence and withdrawal symptions
associated with the immediated release form of bupropion.
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 to placebo on the
Morphine-Benzedrine Subscale of the Addiction Research Center
Inventories (ARCI), and a score intermediate between placebo
and amphetimine 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 reliably. Nonetheless,
evidence from single-dose studies does suggest that the
recommended daily dosage of bupropion when administered
in divided doses is not likely to be especially reinforcing
to amphetamine or stimulant abusers. However, higher doses
that could not be tested because of the risk of seizure
might be modestly attractive to those who abuse stimulant
drugs.
Animals
Studies in rodents and primates have shown that bupropion
exhibits some pharmacological 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 to assess 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.
The possibility that bupropion may induce dependence should
be kept in mind when evaluating the desirability of including
the drug in smoking cessation programs of individual patients.
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.
Animal data indicated that bupropion may be an inducer of
drug-metabolized enzymes in humans. This may be of potential
clinical importance because the blood levels of coadministered
drugs may be altered. However, following chronic administration
of bupropion, 100 mg three times daily 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 bupropion HCl sustained release tablets with
and without 800 mg of cimetidine, 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.
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 two-, five-and twofold, 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: Limited clinical data suggest
a higher incidence of adverse experiences in patients receiving
concurrent administration of bupropion HCl and levodopa.
Administration of bupropion HCl to patients receiving levodopa
concurrently should be undertaken with caution, using small
initial doses and gradual dose increases.
Drugs That Lower Seizure Threshold: Concurrent
administration of bupropion HCl and agents (e.g., antipyschotics,
other antidepressants, theophyllinem systemic steroids,
etc.) or treatment regimens (e.g., abrupt discontinuation
of benzodiazepines) that lower seizure threshold should
be undertaken only with extreme caution (see WARNINGS.)
Low initial dosing and gradual dose increases should be
employed.
Smoking Cessation: Physiological changes
resulting from smoking cessation itself, with or without
treatment with bupropion HCl, may alter the pharmacokinetics
of some concomitant medications, which may require dosage
adjustment.
Nicotine Transdermal System: Data from
a comparative study of the sustained-release formulation
of bupropion, 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 bupropion and NTS. In this study, 6.1%
of patients treated with the combination of bupropion and
NTS had treatment-emergent hypertension compared to 2.5%,
1.6%, and 3.1% of patients treated with bupropion, NTS,
and placebo, respectively. Monitoring for treatment-emergent
hypertension is recommended in patients receiving the combination
of bupropion and NTS.
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