Bupropion Hydrochloride XL (Page 4 of 10)
5.8 Hypersensitivity Reactions
Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea, requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue bupropion hydrochloride extended-release tablets (XL) and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.
There are reports of arthralgia, myalgia, fever with rash and other symptoms of serum sickness suggestive of delayed hypersensitivity.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
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Suicidal thoughts and behaviors in children, adolescents, and young adults [see Warnings and Precautions (5.1)]
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Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see Warnings and Precautions (5.2)]
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Seizure [see Warnings and Precautions (5.3)]
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Hypertension [see Warnings and Precautions (5.4)]
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Activation of mania or hypomania [see Warnings and Precautions (5.5)]
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Psychosis and other neuropsychiatric events [see Warnings and Precautions (5.6)]
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Angle-Closure Glaucoma [see Warnings and Precautions (5.7)]
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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 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.
| 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.
| 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 | 23% | 26% | 25% |
| Infection | 6% | 8% | 9% |
| Abdominal pain | 2% | 3% | 9% |
| Asthenia | 2% | 2% | 4% |
| Chest pain | 1% | 3% | 4% |
| Pain | 2% | 2% | 3% |
| Fever | — | 1% | 2% |
| Cardiovascular Palpitation | 2% | 2% | 6% |
| Flushing | — | 1% | 4% |
| Migraine | 1% | 1% | 4% |
| Hot flashes | 1% | 1% | 3% |
| Digestive Dry mouth | 7% | 17% | 24% |
| Nausea | 8% | 13% | 18% |
| Constipation | 7% | 10% | 5% |
| Diarrhea | 6% | 5% | 7% |
| Anorexia | 2% | 5% | 3% |
| Vomiting | 2% | 4% | 2% |
| Dysphagia | 0% | 0% | 2% |
| Musculoskeletal Myalgia | 3% | 2% | 6% |
| Arthralgia | 1% | 1% | 4% |
| Arthritis | 0% | 0% | 2% |
| Twitch | — | 1% | 2% |
| Nervous System Insomnia | 6% | 11% | 16% |
| Dizziness | 5% | 7% | 11% |
| Agitation | 2% | 3% | 9% |
| Anxiety | 3% | 5% | 6% |
| Tremor | 1% | 6% | 3% |
| Nervousness | 3% | 5% | 3% |
| Somnolence | 2% | 2% | 3% |
| Irritability | 2% | 3% | 2% |
| Memory decreased | 1% | — | 3% |
| Paresthesia | 1% | 1% | 2% |
| Central nervous system stimulation | 1% | 2% | 1% |
| Respiratory Pharyngitis | 2% | 3% | 11% |
| Sinusitis | 2% | 3% | 1% |
| Increased cough | 1% | 1% | 2% |
| Skin Sweating | 2% | 6% | 5% |
| Rash | 1% | 5% | 4% |
| Pruritus | 2% | 2% | 4% |
| Urticaria | 0% | 2% | 1% |
| Special Senses Tinnitus | 2% | 6% | 6% |
| Taste perversion | — | 2% | 4% |
| Blurred vision or diplopia | 2% | 3% | 2% |
| Urogenital Urinary frequency | 2% | 2% | 5% |
| Urinary urgency | 0% | — | 2% |
| Vaginal hemorrhage* | — | 0% | 2% |
| Urinary tract infection | —† | 1% | 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.
| System Organ Class/ Preferred Term | Placebo (n=511) | Bupropion HCl Extended-Release (n=537) |
| Gastrointestinal Disorder Dry mouth | 15% | 26% |
| Nausea | 8% | 13% |
| Constipation | 2% | 9% |
| Flatulence | 3% | 6% |
| Abdominal pain | <1% | 2% |
| Nervous System Disorders Headache | 26% | 34% |
| Dizziness | 5% | 6% |
| Tremor | <1% | 3% |
| Infections and Infestations Nasopharyngitis | 12% | 13% |
| Upper respiratory tract infection | 8% | 9% |
| Sinusitis | 4% | 5% |
| Psychiatric Disorders Insomnia | 13% | 20% |
| Anxiety | 5% | 7% |
| Abnormal dreams | 2% | 3% |
| Agitation | <1% | 2% |
| Musculoskeletal and Connective Tissue Disorders Myalgia | 2% | 3% |
| Pain in extremity | 2% | 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.
| 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).
| 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% |
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