1 INDICATIONS AND USAGE Bupropion hydrochloride extended-release tablets, USP (SR) are indicated as an aid to smoking cessation treatment.

Bupropion hydrochloride extended-release tablets, USP (SR) are an aminoketone agent indicated as an aid to smoking cessation treatment.

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6 ADVERSE REACTIONS 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 adverse events 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 )] Most common adverse reactions (incidence ≥5% and ≥1% more than placebo rate) are: insomnia, rhinitis, dry mouth, dizziness, nervous disturbance, anxiety, nausea, constipation, and arthralgia.

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

at 1-855-724-3436 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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 in 8% of the 706 subjects treated with bupropion hydrochloride extended-release tablets (SR) and 5% of the 313 patients treated with placebo.

The more common events leading to discontinuation of treatment with bupropion hydrochloride extended-release tablets (SR) included nervous system disturbances (3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes.

Commonly Observed Adverse Reactions The most commonly observed adverse reactions consistently associated with the use of bupropion hydrochloride extended-release tablets (SR) were dry mouth and insomnia.

The incidence of dry mouth and insomnia may be related to the dose of bupropion hydrochloride extended-release tablets (SR).

The occurrence of these adverse reactions may be minimized by reducing the dose of bupropion hydrochloride extended-release tablets (SR).

In addition, insomnia may be minimized by avoiding bedtime doses.

Adverse reactions reported in the dose-response and comparator trials are presented in Table 2 and Table 3 , respectively.

Reported adverse reactions were classified using a COSTART-based dictionary.

Table 2.

Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in the Dose-response Trial Adverse Reaction Bupropion Hydrochloride Extended-Release Tablets (SR) 100 to 300 mg/day (n = 461) % P lacebo ( 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 Musculoskeletal 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 Pruritus 3 <1 Rash 3 <1 Dry skin 2 0 Urticaria 1 0 Special senses Taste perversion 2 <1 Table 3.

Adverse Reactions Reported by at Least 1% of Subjects on Active Treatment and at a Greater Frequency than Placebo in the Comparator Trial Adverse Experience (COSTART Term) Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day ( n = 243) % Nicotine Transdermal System (NTS) 21 mg/day (n = 243) % Bupropion Hydrochloride Extended-Release Tablets (SR) and NTS (n = 244) % Placebo (n = 159) % Body 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 Palpitations 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 Musculoskeletal Myalgia 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 Sinusitis 2 2 2 1 Dyspnea 1 0 2 1 Epistaxis 2 1 1 0 Skin Application site reaction a 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 a Subjects randomized to bupropion hydrochloride extended-release tablets (SR) or placebo received placebo patches.

Adverse reactions in a 1-year maintenance trial and a 12-week COPD trial with bupropion hydrochloride extended-release tablets (SR) were quantitatively and qualitatively similar to those observed in the dose-response and comparator trials.

In the trial of patients without or with a history of psychiatric disorder, the most common adverse events in subjects treated with bupropion hydrochloride extended-release tablets (SR) were broadly similar to those observed in premarketing studies.

Adverse events reported in >10% of subjects treated with bupropion hydrochloride extended-release tablets (SR) in the entire study population were nausea, insomnia, and anxiety disorders.

Additionally, the following psychiatric adverse events were reported in >2% of patients in either treatment group (bupropion hydrochloride extended-release tablets (SR) vs.

placebo) by cohort.

For the non-psychiatric cohort, these adverse events were anxiety, nervousness, abnormal dreams, and insomnia.

For the psychiatric cohort, these adverse events were agitation, anxiety, panic, abnormal dreams, insomnia, and crying.

Other Adverse Reactions Observed during the Clinical Development of Bupropion In addition to the adverse reactions noted above, the following adverse reactions have been reported in clinical trials with the sustained-release formulation of bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate-release formulation of bupropion.

Adverse reaction frequencies represent the proportion of subjects who experienced a treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open-label surveillance trial with bupropion sustained-release tablets (n = 3,100).

All treatment-emergent adverse reactions are included except those listed in Tables 2 and 3, those listed in other safety-related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: 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.

Bod y (General): Frequent were asthenia, fever, and headache.

Infrequent were chills, inguinal hernia, and photosensitivity.

Rare was malaise.

Cardiovascular: Infrequent were flushing, migraine, postural hypotension, stroke, tachycardia, and vasodilation.

Rare was syncope.

Digestive: Frequent were dyspepsia and vomiting.

Infrequent were abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitis, jaundice, and stomatitis.

Hemic and Lymphatic: Infrequent was ecchymosis.

M e tabolic and Nutritional: Infrequent were edema and peripheral edema.

M u sculoskeletal: Infrequent were leg cramps and twitching.

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.

Respiratory: Rare was bronchospasm.

S kin: Frequent was sweating.

Spe cial Senses: Frequent was blurred vision or diplopia.

Infrequent were accommodation abnormality and dry eye.

Urogenital: Frequent was urinary frequency.

Infrequent were impotence, polyuria, and urinary urgency.

6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of bupropion hydrochloride extended-release tablets (SR) 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 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 Cardiovascular disorder, complete atrioventricular block (AV), extrasystoles, hypotension, myocardial infarction, phlebitis, and pulmonary embolism.

Digestive Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality.

Endo crine Hyperglycemia, hypoglycemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion.

Hemic and Lymphatic Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia.

Altered prothrombin time (PT) and/or international normalized ratio (INR), infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.

M e tabolic and Nutritional Glycosuria.

M u sculoskeletal Arthritis and muscle rigidity/fever/rhabdomyolysis, and muscle weakness.

Nervous System Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome (dyskinesia, dystonia, hypokinesia, parkinsonism), hallucinations, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.

Respiratory Pneumonia.

S kin Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome.

Spe cial Senses Deafness, increased intraocular pressure, and mydriasis.

Urogenital Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.