1 INDICATIONS AND USAGE Bupropion Hydrochloride Extended-Release Tablets (XL) is an aminoketone antidepressant, indicated for: treatment of major depressive disorder (MDD) (1.1) prevention of seasonal affective disorder (SAD) (1.2) 1.1 Major Depressive Disorder (MDD) Bupropion hydrochloride extended-release tablets (XL) are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).

The efficacy of the immediate-release formulation of bupropion was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with MDD.

The efficacy of the sustained-release formulation of bupropion in the maintenance treatment of MDD was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded to bupropion in an 8-week study of acute treatment [see Clinical Studies (14.1)] .

1.2 Seasonal Affective Disorder Bupropion hydrochloride extended-release tablets (XL) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD).

The efficacy of bupropion hydrochloride extended-release tablets in the prevention of seasonal major depressive episodes was established in 3 placebo-controlled trials in adult outpatients with a history of MDD with an autumn-winter seasonal pattern as defined in the DSM [see Clinical Studies (14.2)] .

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: Suicidal thoughts and behaviors in children, adolescents, and young adults [see 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 events [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 are (incidence ≥ 5%; ≥ 2× placebo rate): dry mouth, nausea, insomnia, dizziness, pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency, rash.

(6.1) To report SUSPECTED ADVERSE REACTIONS, contact Westminster Pharmaceuticals, LLC at 1-844-221-7294 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 to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Commonly Observed Adverse Reactions in Controlled Clinical Trials of Sustained-Release Bupropion Hydrochloride Adverse reactions that occurred in at least 5% of patients treated with bupropion HCl sustained-release (300 mg and 400 mg per day) and at a rate at least twice the placebo rate are listed below.

300 mg/day of bupropion HCl sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor.

400 mg/day of bupropion HCl sustained-release: abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

Bupropion hydrochloride extended-release tablets (XL) have been demonstrated to have similar bioavailability both to the immediate-release and sustained-release formulations of bupropion.

The information included under this subsection and under subsection 6.2 is based primarily on data from controlled clinical trials with the sustained-release and extended-release formulations of bupropion hydrochloride.

Major Depressive Disorder Adverse Reactions Leading to Discontinuation of Treatment with Bupropion HCl Immediate-Release, Bupropion HCl Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive Disorder Trials In placebo-controlled clinical trials with bupropion HCl sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day groups, respectively, discontinued treatment because of adverse reactions.

The specific adverse reactions leading to discontinuation in at least 1% of the 300 mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are listed in Table 2 .

Table 2: Treatment Discontinuation Due to Adverse Reactions in Placebo-Controlled Trials in MDD Adverse Reaction Term Placebo (n = 385) Bupropion HCl Sustained-Release 300 mg/day (n = 376) Bupropion HCl Sustained-Release 400 mg/day (n = 114) Rash 0.0% 2.4% 0.9% Nausea 0.3% 0.8% 1.8% Agitation 0.3% 0.3% 1.8% Migraine 0.3% 0.0% 1.8% In clinical trials with bupropion HCl immediate-release, 10% of patients and volunteers discontinued due to an adverse reaction.

Reactions resulting in discontinuation (in addition to those listed above for the sustained-release formulation), included vomiting, seizures, and sleep disturbances.

Adverse Reactions Occurring at an Incidence of > 1% in Patients Treated with Bupropion HCl Immediate-Release or Bupropion HCl Sustained-Release in MDD Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion HCl sustained-release 300 mg/day and 400 mg/day.

These include reactions that occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and were more frequent than in the placebo group.

Table 3: Adverse Reactions in Placebo-Controlled Trials in Patients with MDD Body System/Adverse Reaction Placebo (n = 385) Bupropion HCl Sustained-Release 300 mg/day (n = 376) Bupropion HCl Sustained-Release 400 mg/day (n = 114) Body (General) Headache Infection Abdominal pain Asthenia Chest pain Pain Fever 23% 6% 2% 2% 1% 2% -- 26% 8% 3% 2% 3% 2% 1% 25% 9% 9% 4% 4% 3% 2% Cardiovascular Palpitation Flushing Migraine Hot flashes 2% -- 1% 1% 2% 1% 1% 1% 6% 4% 4% 3% Digestive Dry mouth Nausea Constipation Diarrhea Anorexia Vomiting Dysphagia 7% 8% 7% 6% 2% 2% 0% 17% 13% 10% 5% 5% 4% 0% 24% 18% 5% 7% 3% 2% 2% Musculoskeletal Myalgia Arthralgia Arthritis Twitch 3% 1% 0% -- 2% 1% 0% 1% 6% 4% 2% 2% Nervous System Insomnia Dizziness Agitation Anxiety Tremor Nervousness Somnolence Irritability Memory decreased Paresthesia Central nervous system stimulation 6% 5% 2% 3% 1% 3% 2% 2% 1% 1% 1% 11% 7% 3% 5% 6% 5% 2% 3% -- 1% 2% 16% 11% 9% 6% 3% 3% 3% 2% 3% 2% 1% Respiratory Pharyngitis Sinusitis Increased cough 2% 2% 1% 3% 3% 1% 11% 1% 2% Skin Sweating Rash Pruritus Urticaria 2% 1% 2% 0% 6% 5% 2% 2% 5% 4% 4% 1% Special Senses Tinnitus Taste perversion Blurred vision or diplopia 2% -- 2% 6% 2% 3% 6% 4% 2% Urogenital Urinary frequency Urinary urgency Vaginal hemorrhage * Urinary tract infection 2% 0% -- -- † 2% -- 0% 1% 5% 2% 2% 0% *Incidence based on the number of female patients.

†Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients.

The following additional adverse reactions occurred in controlled trials of bupropion HCl immediate-release (300 to 600 mg per day) at an incidence of at least 1% more frequently than in the placebo group were: cardiac arrhythmia (5% vs.

4%), hypertension (4% vs.

2%), hypotension (3% vs.

2%), menstrual complaints (5% vs.

1%), akathisia (2% vs.

1%), impaired sleep quality (4% vs.

2%), sensory disturbance (4% vs.

3%), confusion (8% vs.

5%), decreased libido (3% vs.

2%), hostility (6% vs.

4%), auditory disturbance (5% vs.

3%), and gustatory disturbance (3% vs.

1%).

Seasonal Affective Disorder In placebo-controlled clinical trials in SAD, 9% of patients treated with bupropion hydrochloride extended-release tablets (XL) and 5% of patients treated with placebo discontinued treatment because of adverse reactions.

The adverse reactions leading to discontinuation in at least 1% of patients treated with bupropion and at a rate numerically greater than the placebo rate were insomnia (2% vs.

< 1%) and headache (1% vs.

< 1%).

Table 4 summarizes the adverse reactions that occurred in patients treated with bupropion hydrochloride extended-release tablets (XL) for up to approximately 6 months in 3 placebo-controlled trials.

These include reactions that occurred at an incidence of 2% or more and were more frequent than in the placebo group.

Table 4: Adverse Reactions in Placebo-Controlled Trials in Patients with SAD System Organ Class /Preferred Term Placebo (n = 511) Bupropion HCl Extended-Release (n = 537) Gastrointestinal Disorder Dry mouth Nausea Constipation Flatulence Abdominal pain 15% 8% 2% 3% < 1% 26% 13% 9% 6% 2% Nervous System Disorders Headache Dizziness Tremor 26% 5% < 1% 34% 6% 3% Infections and Infestations Nasopharyngitis Upper respiratory tract infection Sinusitis 12% 8% 4% 13% 9% 5% Psychiatric Disorders Insomnia Anxiety Abnormal dreams Agitation 13% 5% 2% < 1% 20% 7% 3% 2% Musculoskeletal and Connective Tissue Disorders Myalgia Pain in extremity 2% 2% 3% 3% Respiratory, Thoracic, and Mediastinal Disorders Cough 3% 4% General Disorders and Administration Site Conditions Feeling jittery 2% 3% Skin and Subcutaneous Tissue Disorders Rash 2% 3% Metabolism and Nutrition Disorders Decreased appetite 1% 4% Reproductive System and Breast Disorders Dysmenorrhea < 1% 2% Ear and Labyrinth Disorders Tinnitus < 1% 3% Vascular Disorders Hypertension 0% 2% Changes in Body Weight Table 5 presents the incidence of body weight changes (≥5 lbs) in the short-term MDD trials using bupropion HCl sustained-release.

There was a dose-related decrease in body weight.

Table 5: Incidence of Weight Gain or Weight Loss (≥5 lbs) in MDD Trials Using Bupropion HCl Sustained-Release Weight Change Bupropion HCl Sustained-Release 300 mg/day (n = 339) Bupropion HCl Sustained-Release 400 mg/day (n = 112) Placebo (n = 347) Gained > 5 lbs 3% 2% 4% Lost > 5 lbs 14% 19% 6% Table 6 presents the incidence of body weight changes (≥5 lbs) in the 3 SAD trials using bupropion HCl extended-release.

A higher proportion of subjects in the bupropion group (23%) had a weight loss ≥ 5 lbs, compared to the placebo group (11%).

These were relatively long-term trials (up to 6 months).

Table 6: Incidence of Weight Gain or Weight Loss (≥5 lbs) in SAD Trials Using Bupropion HCl Extended-Release Weight Change Bupropion HCl Extended-Release 150 to 300 mg/day (n = 537) Placebo (n = 511) Gained > 5 lbs 11% 21% Lost > 5 lbs 23% 11% 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of bupropion hydrochloride extended-release tablets (XL).

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) Chills, facial edema, edema, peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise.

Cardiovascular Postural hypotension, hypertension, stroke, vasodilation, syncope, complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, pulmonary embolism, and Brugada pattern/syndrome.

Digestive Abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.

Endocrine Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone secretion.

Hemic and Lymphatic Ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia.

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

Metabolic and Nutritional Glycosuria.

Musculoskeletal Leg cramps, fever/rhabdomyolysis, and muscle weakness.

Nervous System Abnormal coordination, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia, derealization, abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.

Respiratory Bronchospasm and pneumonia.

Skin and Subcutaneous Tissue Disorders Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, hirsutism, acute generalized exanthematous pustulosis, and drug reaction with eosinophilias and system symptoms (DRESS).

Special Senses Accommodation abnormality, dry eye, deafness, increased intraocular pressure, angle-closure glaucoma, and mydriasis.

Urogenital Impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.