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Wellbutrin XL

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Wellbutrin XL

Wellbutrin XL

SIDE EFFECTS

(See also WARNINGS and PRECAUTIONS.)

Major Depressive Disorder

WELLBUTRIN XL (bupropion hydrochloride extended-release) has been demonstrated to have similar bioavailability both to the immediate-release formulation of bupropion and to the sustained-release formulation of bupropion (see CLINICAL PHARMACOLOGY). The information included under this subsection is based primarily on data from controlled clinical trials with WELLBUTRIN SR, the sustained-release formulation of bupropion.

Adverse Events Leading to Discontinuation of Treatment With WELLBUTRIN or WELLBUTRIN SR

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 and 4% of patients treated with placebo discontinued treatment due to adverse events. The specific adverse events in these trials that led to discontinuation in at least 1% of patients treated with either 300 mg/day or 400 mg/day of WELLBUTRIN SR, the sustained-release formulation of bupropion, and at a rate at least twice the placebo rate are listed in Table 6.

Table 6: Treatment Discontinuations Due to Adverse Events in Placebo-Controlled Trials for Major Depressive Disorder

Adverse Event Term WELLBUTRIN SR 300 mg/day
(n = 376)
WELLBUTRIN SR 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 event. Events resulting in discontinuation, in addition to those listed above for the sustained-release formulation of bupropion, include vomiting, seizures, and sleep disturbances.

Adverse Events Occurring at an Incidence of 1% or More Among Patients Treated With WELLBUTRIN or WELLBUTRIN SR

Table 7 enumerates treatment-emergent adverse events that occurred among patients treated with 300 and 400 mg/day of the sustained-release formulation of bupropion and with placebo in controlled trials. Events 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 events were classified using a COSTART-based Dictionary.

Accurate estimates of the incidence of adverse events 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 events 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 events. A better perspective on the serious adverse events associated with the use of bupropion is provided in the WARNINGS and PRECAUTIONS sections.

Table 7: Treatment-Emergent Adverse Events in Placebo-Controlled Trials* for Major Depressive Disorder

Body System/Adverse Event WELLBUTRIN SR
300 mg/day
(n = 376)
WELLBUTRIN SR
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 events that occurred in at least 1% of patients treated with either 300 or 400 mg/day of the sustained-release formulation of bupropion, 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 events occurring in greater than 0 but less than 0.5% of patients.

Additional events to those listed in Table 7 that occurred at an incidence of at least 1% in controlled clinical trials of the immediate-release formulation of bupropion (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%).

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials

Adverse events from Table 7 occurring in at least 5% of patients treated with the sustained-release formulation of bupropion 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 WELLBUTRIN SR: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.

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

Seasonal Affective Disorder

Adverse Events Leading to Discontinuation of Treatment With WELLBUTRIN XL (bupropion hydrochloride extended-release)

In placebo-controlled clinical trials, 9% of patients treated with WELLBUTRIN XL and 5% of patients treated with placebo discontinued treatment due to adverse events. The adverse events in these trials that led to discontinuation in at least 1% of patients treated with WELLBUTRIN XL (bupropion hydrochloride extended-release) and at a rate numerically greater than the placebo rate are insomnia (2% vs < 1%) and headache (1% vs < 1%).

Adverse Events Occurring at an Incidence of 2% or More Among Patients Treated With WELLBUTRIN XL (bupropion hydrochloride extended-release)

Table 8 enumerates treatment-emergent adverse events that occurred among patients treated with WELLBUTRIN XL (bupropion hydrochloride extended-release) for up to approximately 6 months in 3 placebo-controlled trials. Events that occurred at an incidence of 2% or more and were more frequent than in the placebo group are included. Reported adverse events were classified using a MedDRA-based Dictionary.

Accurate estimates of the incidence of adverse events 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 events 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; e.g., different patient populations, different treatment durations.

Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion is provided in the WARNINGS and PRECAUTIONS sections.

Table 8: Treatment-Emergent Adverse Events* in Placebo-Controlled Trials of Seasonal Affective Disorder

System Organ Class/ Preferred Term WELLBUTRIN XL
(n = 537)
Placebo
(n = 511)
Gastrointestinal Disorder
  Dry Mouth 26% 15%
  Nausea 13% 8%
  Constipation 9% 2%
  Flatulence 6% 3%
  Abdominal pain 2% < 1%
Nervous System Disorders
  Headache 34% 26%
  Dizziness 6% 5%
  Tremor 3% < 1%
Infections and Infestations
  Nasopharyngitis 13% 12%
  Upper respiratory tract infection 9% 8%
  Sinusitis 5% 4%
Psychiatric Disorders
  Insomnia 20% 13%
  Anxiety 7% 5%
  Abnormal dreams 3% 2%
  Agitation 2% < 1%
Musculoskeletal and Connective Tissue Disorders
  Myalgia 3% 2%
  Pain in extremity 3% 2%
Respiratory, Thoracic and Mediastinal Disorders
  Cough 4% 3%
General Disorders and Administration Site Conditions
  Feeling jittery 3% 2%
Skin and Subcutaneous Tissue Disorders
  Rash 3% 2%
Metabolism and Nutrition Disorders
  Decreased appetite 4% 1%
Reproductive System and Breast Disorders
  Dysmenorrhea 2% < 1%
Ear and Labyrinth Disorders
  Tinnitus 3% < 1%
Vascular Disorders
  Hypertension 2% 0%
*Adverse events that occurred in at least 2% of patients treated with WELLBUTRIN XL, but equally or more frequently in the placebo group, were: abdominal pain upper, arthralgia, back pain, diarrhea, dyspepsia, fatigue, gastroenteritis viral, hyperhidrosis, influenza, irritability, migraine, nasal congestion, neck pain, palpitations, pharyngolaryngeal pain, sinus congestion.

Incidence of Commonly Observed Adverse Events in Controlled Clinical Trials

Adverse events from Table 8 that occurred in at least 5% of patients treated with WELLBUTRIN XL (bupropion hydrochloride extended-release) and at a rate at least twice the placebo rate were constipation and flatulence.

Adverse Events During Taper or Following Discontinuation of WELLBUTRIN XL (bupropion hydrochloride extended-release)

Adverse events with onset during the 2 weeks following down-titration of WELLBUTRIN XL from 300 mg/day to 150 mg/day were reported by 14% of patients compared to 18% of patients who continued on placebo.

Adverse events with onset during the 2 weeks following discontinuation of WELLBUTRIN XL were reported by 9% of patients compared with 12% of patients following discontinuation of placebo.

Other Events Observed During the Clinical Development and Postmarketing Experience of Bupropion

In addition to the adverse events noted above, the following events have been reported in clinical trials and postmarketing experience with the sustained-release formulation of bupropion in depressed patients and in nondepressed smokers, as well as in clinical trials and postmarketing clinical experience with the immediate-release formulation of bupropion.

Adverse events for which frequencies are provided below occurred in clinical trials with the sustained-release formulation of bupropion. The frequencies represent the proportion of patients who experienced a treatment-emergent adverse event on at least one occasion in placebo-controlled studies for depression (n = 987) or smoking cessation (n = 1,013), or patients who experienced an adverse event requiring discontinuation of treatment in an open-label surveillance study with the sustained-release formulation of bupropion (n = 3,100). All treatment-emergent adverse events are included except those listed in Tables 2 through 8, those events listed in other safety-related sections, those adverse events subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those events not reasonably associated with the use of the drug, and those events that were not serious and occurred in fewer than 2 patients. Events of major clinical importance are described in the WARNINGS and PRECAUTIONS sections of the labeling.

Events are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.

Adverse events for which frequencies are not provided occurred in clinical trials or postmarketing experience with bupropion. Only those adverse events not previously listed for sustained-release bupropion are included. The extent to which these events may be associated with WELLBUTRIN XL (bupropion hydrochloride extended-release) is unknown.

Body (General): Infrequent were chills, facial edema, musculoskeletal chest pain, and photosensitivity. Rare was malaise. Also observed were arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness (see PRECAUTIONS).

Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and vasodilation. Rare was syncope. Also observed were complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe, see PRECAUTIONS), myocardial infarction, phlebitis, and pulmonary embolism.

Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, glossitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue. Also observed were colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage, pancreatitis, and stomach ulcer.

Endocrine: Also observed were hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone.

Hemic and Lymphatic: Infrequent was ecchymosis. Also observed were anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.

Metabolic and Nutritional: Infrequent were edema and peripheral edema. Also observed was glycosuria.

Musculoskeletal: Infrequent were leg cramps. Also observed were muscle rigidity/fever/rhabdomyolysis and muscle weakness.

Nervous System: Infrequent were abnormal coordination, decreased libido, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania. Also observed were abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.

Respiratory: Rare was bronchospasm. Also observed was pneumonia.

Skin: Rare was maculopapular rash. Also observed were alopecia, angioedema, exfoliative dermatitis, and hirsutism.

Special Senses: Infrequent were accommodation abnormality and dry eye. Also observed were deafness, diplopia, increased intraocular pressure, and mydriasis.

Urogenital: Infrequent were impotence, polyuria, and prostate disorder. Also observed were abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis

Drug Abuse And Dependence

Controlled Substance Class

Bupropion is not a controlled substance.

Humans

Controlled clinical studies of bupropion (immediate-release formulation) conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed patients showed some increase in motor activity and agitation/excitement.

In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion produced mild amphetamine-like activity as compared to placebo on the Morphine-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 especially reinforcing to amphetamine or stimulant abusers. However, higher doses that could not be tested because of the risk of seizure might be modestly attractive to those who abuse stimulant drugs.

Animals

Studies in rodents and primates have shown 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 to assess 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 (bupropion hydrochloride extended-release) Side Effects Center for a complete guide to possible side effects

DRUG INTERACTIONS

Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs.

Because bupropion is extensively metabolized, the coadministration of other drugs may affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction between WELLBUTRIN XL (bupropion hydrochloride extended-release) and drugs that are substrates of or inhibitors /inducers of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine, and clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150-mg tablets of the sustained-release formulation of bupropion with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir (KALETRA) 400 mg twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% to 80%. This effect is thought to be due to the induction of bupropion metabolism. Patients receiving ritonavir may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded (see CLINICAL PHARMACOLOGY: Metabolism).

While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g., carbamazepine, phenobarbital, phenytoin).

Multiple oral doses of bupropion had no statistically significant effects on the single dose pharmacokinetics of lamotrigine in 12 healthy volunteers.

Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of coadministered drugs.

Drugs Metabolized By Cytochrome P450IID6 (CYP2D6)

Many drugs, including most antidepressants (SSRIs, many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro . In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the Cmax, AUC, and t½ of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

Therefore, coadministration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (e.g., nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index. Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.

MAO Inhibitors

Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).

Levodopa and Amantadine

Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine. Administration of WELLBUTRIN XL (bupropion hydrochloride extended-release) to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and gradual dose increases.

Drugs That Lower Seizure Threshold

Concurrent administration of WELLBUTRIN XL (bupropion hydrochloride extended-release) and agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution (see WARNINGS). Low initial dosing and gradual dose increases should be employed.

Nicotine Transdermal System

(see PRECAUTIONS: Cardiovascular Effects).

Alcohol

In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion. The consumption of alcohol during treatment with WELLBUTRIN XL should be minimized or avoided (also see CONTRAINDICATIONS).

Read the Wellbutrin XL Drug Interactions Center for a complete guide to possible interactions

Last reviewed on RxList: 1/24/2011
This monograph has been modified to include the generic and brand name in many instances.

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