"Jan. 1, 2013 -- Antidepressant use during pregnancy, long debated for its safety, is linked with a higher overall risk of stillbirth and newborn death. Now, a new study shows that risk may not be warranted.
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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]
- Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see WARNINGS AND PRECAUTIONS]
- Seizure [see WARNINGS AND PRECAUTIONS]
- Hypertension [see WARNINGS AND PRECAUTIONS]
- Activation of mania or hypomania [see WARNINGS AND PRECAUTIONS]
- Psychosis and other neuropsychiatric events [see WARNINGS AND PRECAUTIONS]
- Angle Closure Glaucoma [see WARNINGS AND PRECAUTIONS]
- Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS]
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 clinical 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.
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.
WELLBUTRIN XL has 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 the 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
|Bupropion HCl Sustained-Release 300 mg/day
|Bupropion HCl Sustained-Release 400 mg/day
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 are included.
Table 3: Adverse Reactions in Placebo-Controlled
Trials in Patients with MDD
|Body System/ Adverse Reaction||Placebo
|Bupropion HCl Sustained-Release 300 mg/day
|Bupropion HCl Sustained-Release 400 mg/day
|Central nervous system stimulation||1%||2%||1%|
|Blurred vision of diplopia||2%||3%||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 WELLBUTRIN 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 WELLBUTRIN 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
|Bupropion HCl Extended-Release
|Abdominal pain||< 1%||2%|
|Nervous System Disorders|
|Infections and Infestations|
|Upper respiratory tract infection||8%||9%|
|Musculoskeletal and Connective Tissue Disorders|
|Pain in extremity||2%||3%|
|Respiratory, Thoracic, and Mediastinal Disorders|
|General Disorders and Administration Site Conditions|
|Skin and Subcutaneous Tissue Disorders|
|Metabolism and Nutrition Disorders|
|Reproductive System and Breast Disorders|
|Ear and Labyrinth Disorders|
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
|Weight Change||Bupropion HCl Sustained-Release 300 mg/day
|Bupropion HCl Sustained-Release 400 mg/day
|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
|Gained > 5 lbs||11%||21%|
|Lost > 5 lbs||23%||11%|
The following adverse reactions have been identified during post-approval use of WELLBUTRIN 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.
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.
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
Leg cramps, fever/rhabdomyolysis, and muscle weakness.
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.
Bronchospasm and pneumonia.
Impotence, polyuria, prostate disorder, abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
Read the Wellbutrin XL (bupropion hydrochloride extended-release) Side Effects Center for a complete guide to possible side effects
Potential For Other Drugs To Affect WELLBUTRIN XL
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between WELLBUTRIN XL and drugs that are inhibitors or inducers of CYP2B6.
Inhibitors of CYP2B6
Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposures but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of WELLBUTRIN XL may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see CLINICAL PHARMACOLOGY].
Inducers of CYP2B6
Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of WELLBUTRIN XL may be necessary when coadministered with ritonavir, lopinavir, or efavirenz but should not exceed the maximum recommended dose [see CLINICAL PHARMACOLOGY].
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce metabolism of bupropion and may decrease bupropion exposure. [see CLINICAL PHARMACOLOGY]. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion but the maximum recommended dose should not be exceeded.
Potential For WELLBUTRIN XL To Affect Other Drugs
Drugs Metabolized by CYP2D6
Bupropion and its metabolites (erythohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of WELLBUTRIN XL with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g. haloperidol, risperidone, and thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g. propafenone, and flecainide). When used concomitantly with WELLBUTRIN XL, it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.
Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen), theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with WELLBUTRIN XL and such drugs may require increased doses of the drug [see CLINICAL PHARMACOLOGY].
Drugs That Lower Seizure Threshold
Use extreme caution when coadministering WELLBUTRIN XL with other drugs that lower the seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses of WELLBUTRIN XL and increase the dose gradually [see WARNINGS AND PRECAUTIONS].
Dopaminergic Drugs (Levodopa and Amantadine)
Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering WELLBUTRIN XL concomitantly with these drugs.
Use With Alcohol
In post-marketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with WELLBUTRIN XL. The consumption of alcohol during treatment with WELLBUTRIN XL should be minimized or avoided.
Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with WELLBUTRIN XL. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN XL before starting an MAOI antidepressant [see DOSAGE AND ADMINISTRATION and CONTRAINDICATIONS].
Drug-Laboratory Test Interactions
False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.
Drug Abuse And Dependence
Bupropion is not a controlled substance.
Controlled clinical studies of bupropion HCl immediate-release conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients demonstrated an increase in motor activity and agitation/excitement.
Benzedrine Subscale of the Addiction Research Center Inventories (ARCI), and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.
Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavioral response, and increase rates of responding in several schedule-controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.
Read the Wellbutrin XL Drug Interactions Center for a complete guide to possible interactions
Last reviewed on RxList: 1/27/2015
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