1 INDICATIONS AND USAGE Bupropion hydrochloride tablets are an aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD).

( 1 ) Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).

The efficacy of bupropion hydrochloride tablets in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with MDD [see Clinical Studies ( 14) ].

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5% and ≥1% more than placebo rate) are: agitation, dry mouth, constipation, headache/migraine, nausea/vomiting, dizziness, excessive sweating, tremor, insomnia, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and auditory disturbance.

( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Avet Pharmaceuticals Inc.

at 1-866-901-DRUG (3784) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch .

The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning, Warnings and Precautions ( 5.1 )] Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Warnings and Precautions ( 5.2 )] Seizure [see Warnings and Precautions ( 5.3 )] Hypertension [see Warnings and Precautions ( 5.4 )] Activation of mania or hypomania [see Warnings and Precautions ( 5.5 )] Psychosis and other neuropsychiatric reactions [see Warnings and Precautions ( 5.6 )] Angle-closure glaucoma [see Warnings and Precautions ( 5.7 )] Hypersensitivity reactions [see Warnings and Precautions ( 5.8 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions Leading to Discontinuation of Treatment Adverse reactions were sufficiently troublesome to cause discontinuation of treatment with bupropion hydrochloride tablets in approximately 10% of the 2,400 subjects and healthy volunteers who participated in clinical trials during the product's initial development.

The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes.

It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose.

Commonly Observed Adverse Reactions Adverse reactions commonly encountered in subjects treated with bupropion hydrochloride tablets are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance.

Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials at an incidence of at least 1% of subjects receiving bupropion hydrochloride tablets and more frequently in these subjects than in the placebo group.

Table 2.

Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials Adverse Reaction Bupropion Hydrochloride Tablets (n = 323) % Placebo (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 Dermatologic Pruritus 2.2 0.0 Rash 8.0 6.5 Gastrointestinal Appetite increase 3.7 2.2 Constipation 26.0 17.3 Dyspepsia 3.1 2.2 Nausea/vomiting 22.9 18.9 Genitourinary Impotence 3.4 3.1 Menstrual complaints 4.7 1.1 Urinary frequency 2.5 2.2 Musculoskeletal Arthritis 3.1 2.7 Neurological Akathisia 1.5 1.1 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 Insomnia 18.6 15.7 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 Euphoria 1.2 0.5 Hostility 5.6 3.8 Nonspecific Fever/chills 1.2 0.5 Special senses Auditory disturbance 5.3 3.2 Blurred vision 14.6 10.3 Gustatory disturbance 3.1 1.1 Other Adverse Reactions Observed during the Clinical Development of Bupropion Hydrochloride Tablets The conditions and duration of exposure to bupropion hydrochloride tablets 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 hydrochloride tablets.

The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the database.

The following definitions of frequency are used: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects.

Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.

Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea; rare were flushing, and myocardial infarction.

Dermatologic: Infrequent was alopecia.

Endocrine: Infrequent was gynecomastia; rare was glycosuria.

Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice; rare was intestinal perforation.

Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were enuresis, and urinary incontinence.

Neurological: Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram (EEG) abnormality, and impaired attention.

Neuropsychiatric: Frequent were mania/hypomania, increased libido, hallucinations, decrease in sexual function, and depression; infrequent were memory impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, and formal thought disorder; rare was suicidal ideation.

Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum irritation, and oral edema.

Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare was pulmonary embolism.

Special Senses: Infrequent was visual disturbance; rare was diplopia.

Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare was overdose.

Altered Appetite and Weight A weight loss of greater than 5 lbs.

occurred in 28% of subjects receiving bupropion hydrochloride tablets.

This incidence is approximately double that seen in comparable subjects treated with tricyclics or placebo.

Furthermore, while 35% of subjects receiving tricyclic antidepressants gained weight, only 9.4% of subjects treated with bupropion hydrochloride tablets did.

Consequently, if weight loss is a major presenting sign of a patient's depressive illness, the anorectic and/or weight-reducing potential of bupropion hydrochloride tablets should be considered.

6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of bupropion hydrochloride tablets and are not described elsewhere in the label.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body (General) Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity.

These symptoms may resemble serum sickness [see Warnings and Precautions ( 5.8 )].

Cardiovascular Hypertension (in some cases severe), orthostatic hypotension, third degree heart block, and Brugada pattern/syndrome.

Endocrine Hyponatremia, syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia, hypoglycemia.

Gastrointestinal Esophagitis, hepatitis.

Hemic and Lymphatic Ecchymosis, leukocytosis, leukopenia, thrombocytopenia.

Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.

Musculoskeletal Muscle rigidity/fever/rhabdomyolysis, muscle weakness.

Nervous System Aggression, coma, completed suicide, delirium, dream abnormalities, paranoid ideation, paresthesia, parkinsonism, restlessness, suicide attempt, unmasking tardive dyskinesia and aseptic meningitis.

Skin and Appendages Stevens-Johnson syndrome, angioedema, exfoliative dermatitis, urticaria, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms (DRESS).

Special Senses Tinnitus, increased intraocular pressure.