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adverse reactions
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 Amneal Pharmaceuticals at 1-877-835-5472 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 hydrochloride 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 hydrochloride sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of bupropion hydrochloride 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 Hydrochloride Immediate-Release, Bupropion Hydrochloride Sustained-Release, and Bupropion Hydrochloride Extended-Release in Major Depressive Disorder Trials In placebo-controlled clinical trials with bupropion hydrochloride 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 Hydrochloride Sustained-Release 300 mg/day (n=376) Bupropion Hydrochloride 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 hydrochloride 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 Hydrochloride Immediate-Release or Bupropion Hydrochloride Sustained-Release in MDD Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion hydrochloride 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 Hydrochloride Sustained-Release 300 mg/day (n=376) Bupropion Hydrochloride 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 hydrochloride immediate-release (300 mg per day 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 Hydrochloride 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 hydrochloride 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 Hydrochloride Sustained-Release Weight Change Bupropion Hydrochloride Sustained-Release 300 mg/day (n=339) Bupropion Hydrochloride 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 hydrochloride 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 Hydrochloride Extended-Release Weight Change Bupropion Hydrochloride Extended-Release 150 mg/day 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, and pulmonary embolism. 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 co-administered 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 Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism. 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.
adverse reactions
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 hydrochloride 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 hydrochloride sustained-release: anorexia, dry mouth, rash, sweating, tinnitus, and tremor. 400 mg/day of bupropion hydrochloride 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 Hydrochloride Immediate-Release, Bupropion Hydrochloride Sustained-Release, and Bupropion Hydrochloride Extended-Release in Major Depressive Disorder Trials In placebo-controlled clinical trials with bupropion hydrochloride 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 Hydrochloride Sustained-Release 300 mg/day (n=376) Bupropion Hydrochloride 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 hydrochloride 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 Hydrochloride Immediate-Release or Bupropion Hydrochloride Sustained-Release in MDD Table 3 summarizes the adverse reactions that occurred in placebo-controlled trials in patients treated with bupropion hydrochloride 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 Hydrochloride Sustained-Release 300 mg/day (n=376) Bupropion Hydrochloride 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 hydrochloride immediate-release (300 mg per day 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 Hydrochloride 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 hydrochloride 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 Hydrochloride Sustained-Release Weight Change Bupropion Hydrochloride Sustained-Release 300 mg/day (n=339) Bupropion Hydrochloride 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 hydrochloride 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 Hydrochloride Extended-Release Weight Change Bupropion Hydrochloride Extended-Release 150 mg/day to 300 mg/day (n=537) Placebo (n=511) Gained >5 lbs 11% 21% Lost >5 lbs 23% 11%
adverse reactions
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, and pulmonary embolism. 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 co-administered 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 Maculopapular rash, alopecia, angioedema, exfoliative dermatitis, and hirsutism. 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.