Wellbutrin



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 weremuscle 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 wereabnormal 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, electrocardiogam (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.