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The following risks are discussed in greater detail in other sections of the labeling:

  • Clinical worsening and suicide risk [see WARNINGS AND PRECAUTIONS]
  • Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see WARNINGS AND PRECAUTIONS]
  • Activation of mania or hypomania [see WARNINGS AND PRECAUTIONS]
  • Seizures [see WARNINGS AND PRECAUTIONS]
  • Psychosis, and other neuropsychiatric events [see WARNINGS AND PRECAUTIONS]
  • Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
  • Severe hypertension [see WARNINGS AND PRECAUTIONS]
  • Agitation and insomnia [see WARNINGS AND PRECAUTIONS]
  • Altered appetite and weight [see WARNINGS AND PRECAUTIONS]
  • Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Commonly Observed Adverse Reactions in Controlled Clinical Trials

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 clinical practice.

Adverse reactions from Table 5 occurring in at least 5% of patients treated with the sustained-release formulation of bupropion hydrochloride and at a rate at least twice the placebo rate are listed below for the 300- and 400-mg/day dose groups.

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

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

FORFIVO XL is bioequivalent to three 150 mg tablets of WELLBUTRIN XL®, which has been demonstrated to have similar bioavailability both to the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion. The information included under this subsection and under subsections 6.2 and 6.3 is based primarily on data from controlled clinical trials with the sustained-release formulation of bupropion hydrochloride.

Adverse Reactions Leading to Discontinuation of Treatment with Bupropion Immediate Release or Bupropion Sustained Release

In placebo-controlled clinical trials, 9% and 11% of patients treated with 300 and 400 mg/day, respectively, of the sustained-release formulation of bupropion hydrochloride and 4% of patients treated with placebo discontinued treatment due to adverse reactions. The specific adverse reactions in these trials that led to discontinuation in at least 1% of patients treated with either 300 mg/day or 400 mg/day of the sustained-release formulation of bupropion hydrochloride, and at a rate at least twice the placebo rate are listed in Table 4.

Table 4: Treatment Discontinuations Due to Adverse Reactions in Placebo-Controlled Trials for Major Depressive Disorder using Bupropion Hydrochloride Sustained Release Formulation

Adverse Reaction Bupropion HCl 300mg/day
(n = 376)
Bupropion HCl 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%

In clinical trials with the immediate-release formulation of bupropion, 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 of bupropion hydrochloride, include vomiting, seizures, and sleep disturbances.

Adverse Reactions Occurring at an Incidence of 1% or More Among Patients Treated With Bupropion Immediate Release or Bupropion Sustained Release

Table 5 enumerates adverse reactions that occurred among patients treated with 300 and 400 mg/day of the sustained-release formulation of bupropion hydrochloride and with placebo in controlled trials. Reactions 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 group are included. Reported adverse reactions were classified using a COSTART-based Dictionary.

Accurate estimates of the incidence of adverse reactions associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. The figures cited cannot be used to predict precisely the incidence of untoward reactions 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 reactions. A better perspective on the serious adverse reactions associated with the use of bupropion is provided in the WARNINGS AND PRECAUTIONS.

Table 5.: Adverse Reactions in Placebo-Controlled Trials* for Major Depressive Disorder

Body System/Adverse Reaction Bupropion HCl 300 mg/day
(n = 376)
Bupropion HCl 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%
Cardiovascular
  Palpitation 2% 6% 2%
  Flushing 1% 4%
  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%
Musculoskeletal
  Myalgia 2% 6% 3%
  Arthralgia 1% 4% 1%
  Arthritis 0% 2% 0%
  Twitch 1% 2%
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 3% 1%
  Paresthesia 1% 2% 1%
  Central nervous system stimulation 2% 1% 1%
Respiratory
  Pharyngitis 3% 11% 2%
  Sinusitis 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%
  Blurred vision or diplopia 3% 2% 2%
Urogenital
  Urinary frequency 2% 5% 2%
  Urinary urgency 2% 0%
  Vaginal hemorrhage† 0% 2%
  Urinary tract infection 1% 0%
* Adverse reactions that occurred in at least 1% of patients treated with either 300 or 400 mg/day of the sustained-release formulation of bupropion hydrochloride, 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.
— Hyphen denotes adverse reactions occurring in greater than 0 but less than 0.5% of patients.

Additional reactions to those listed in Table 5 that occurred at an incidence of at least 1% in controlled clinical trials of the immediate-release formulation of bupropion hydrochloride (300 to 600 mg/day) and that were numerically more frequent than placebo were: cardiac arrhythmias (5% vs. 4%), hypertension (4% vs. 2%), hypotension (3% vs. 2%), tachycardia (11% vs. 9%), appetite increase (4% vs. 2%), dyspepsia (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%).

Other Adverse Reactions Occurring < 1% in Clinical Trials

Chills, facial edema, postural hypotension, stroke, syncope, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, mouth ulcers, stomatitis, edema of tongue, ecchymosis, edema, abnormal coordination, decreased libido, depersonalization, emotional lability, hyperkinesia, hypertonia, hypesthesia, ataxia, and derealization, bronchospasm, accommodation abnormality, dry eye, impotence, and prostate disorder.

Postmarketing Experience

The following adverse reactions have been identified during post-approval use of bupropion hydrochloride. 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.

Only those adverse reactions not previously listed for bupropion are included. The extent to which these reactions may be associated with FORFIVO XL is unknown.

Cardiovascular—complete atrioventricular block, extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.

Gastrointestinal—colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, intestinal perforation, pancreatitis, and stomach ulcer.

Endocrine—hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone.

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

Metabolic and Nutritional—glycosuria.

Musculoskeletal—muscle rigidity/fever/rhabdomyolysis and muscle weakness.

Nervous System—abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, delirium,-dysarthria, dyskinesia, dystonia, extrapyramidal syndrome, hypokinesia, increased libido, neuralgia, neuropathy, and unmasking tardive dyskinesia.

Skin—alopecia, exfoliative dermatitis, and hirsutism.

Eye—mydriasis.

Urogenital—abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, painful erection, salpingitis, urinary incontinence, and urinary retention.