Source: FDA, National Drug Code (US) Revision Year: 2020
Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.
Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older.
The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short‑term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of placebo‑controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short‑term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 subjects treated) are provided in Table 1.
Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects:
| Age Range | Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Subjects Treated |
|---|---|
| Increases Compared with Placebo | |
| <18 | 14 additional cases |
| 18-24 | 5 additional cases |
| Decreases Compared with Placebo | |
| 25-64 | 1 fewer case |
| ≥65 | 6 fewer cases |
No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.
All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases [see Boxed Warning].
The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for WELLBUTRIN SR should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
WELLBUTRIN SR is not approved for smoking cessation treatment; however, it contains the same active ingredient as the smoking cessation medication ZYBAN. Serious neuropsychiatric adverse events have been reported in patients taking bupropion for smoking cessation. These postmarketing reports have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Adverse Reactions (6.2)]. Some patients who stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these adverse events occurred in patients taking bupropion who continued to smoke.
Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses. Observe patients for the occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should stop taking WELLBUTRIN and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.
WELLBUTRIN SR can cause seizure. The risk of seizure is dose-related. The dose should not exceed 400 mg/day. Increase the dose gradually. Discontinue WELLBUTRIN SR and do not restart treatment if the patient experiences a seizure.
The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with WELLBUTRIN SR. WELLBUTRIN SR is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4), Drug Interactions (7.3)]. The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids); metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia); use of illicit drugs (e.g., cocaine); or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.
When WELLBUTRIN SR is dosed up to 300 mg/day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg/day.
The risk of seizure can be reduced if the dose of WELLBUTRIN SR does not exceed 400 mg/day, given as 200 mg twice daily, and the titration rate is gradual.
Treatment with WELLBUTRIN SR can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with WELLBUTRIN SR and monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN SR is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see Contraindications (4)].
Data from a comparative trial of the sustained-release formulation of bupropion HCl, nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this trial, 6.1% of subjects treated with the combination of sustained-release bupropion and NTS had treatment‑emergent hypertension compared with 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release bupropion, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.
In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N=36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.
Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating WELLBUTRIN SR, screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). WELLBUTRIN SR is not approved for use in treating bipolar depression.
Depressed patients treated with WELLBUTRIN SR have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct patients to contact a healthcare professional if such reactions occur.
The pupillary dilation that occurs following use of many antidepressant drugs including WELLBUTRIN SR may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.
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 WELLBUTRIN SR 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 serum sickness-like symptoms suggestive of delayed hypersensitivity.
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.
In placebo‑controlled clinical trials, 4%, 9%, and 11% of the placebo, 300-mg/day, and 400-mg/day groups, respectively, discontinued treatment due to 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 Discontinuations Due to Adverse Reactions in Placebo-Controlled Trials:
| Adverse Reaction | Placebo (n=385) | WELLBUTRIN SR 300 mg/day (n=376) | WELLBUTRIN SR 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% |
Adverse reactions from Table 3 occurring in at least 5% of subjects treated with WELLBUTRIN SR and at a rate at least twice the placebo rate are listed below for the 300- and 400‑mg/day dose groups.
WELLBUTRIN SR 300 mg/day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.
WELLBUTRIN SR 400 mg/day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.
Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported adverse reactions were classified using a COSTART‑based Dictionary.
Table 3. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials:
| Body System/Adverse Reaction | 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 hemorrhagea | 0% | 2% | — |
| Urinary tract infection | 1% | 0% | — |
a Incidence based on the number of female subjects.
— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects.
In addition to the adverse reactions noted above, the following adverse reactions have been reported in clinical trials with the sustained‑release formulation of bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate‑release formulation of bupropion.
Adverse reaction frequencies represent the proportion of subjects who experienced a treatment‑emergent adverse reaction on at least one occasion in placebo‑controlled trials for depression (n=987) or smoking cessation (n=1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open‑label surveillance trial with WELLBUTRIN SR (n=3,100). All treatment‑emergent adverse reactions are included except those listed in Table 3, those listed in other safety‑related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects.
Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: Frequent adverse reactions are defined as those occurring in at least 1/100 subjects. Infrequent adverse reactions are those occurring in 1/100 to 1/1,000 subjects, while rare events are those occurring in less than 1/1,000 subjects.
Body (General): Infrequent were chills, facial edema, and photosensitivity. Rare was malaise.
Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and vasodilation. Rare were syncope and myocardial infarction.
Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.
Hemic and Lymphatic: Infrequent was ecchymosis.
Metabolic and Nutritional: Infrequent were edema and peripheral edema.
Musculoskeletal: Infrequent were leg cramps.
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.
Respiratory: Rare was bronchospasm.
Special Senses: Infrequent were accommodation abnormality and dry eye.
Urogenital: Infrequent were impotence, polyuria, and prostate disorder.
Changes in Body Weight
In placebo‑controlled trials, subjects experienced weight gain or weight loss as shown in Table 4.
Table 4. Incidence of Weight Gain and Weight Loss (≥5 lbs.) in Placebo-Controlled Trials:
| Weight Change | WELLBUTRIN SR 300 mg/day (n=339) | WELLBUTRIN SR 400 mg/day (n=112) | Placebo (n=347) |
|---|---|---|---|
| Gained >5 lbs. | 3% | 2% | 4% |
| Lost >5 lbs. | 14% | 19% | 6% |
In clinical trials conducted with the immediate‑release formulation of bupropion, 35% of subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated with the immediate‑release formulation of bupropion. If weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight‑reducing potential of WELLBUTRIN SR should be considered.
The following adverse reactions have been identified during post-approval use of WELLBUTRIN SR and are not described elsewhere in the label. 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): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see Warnings and Precautions (5.8)].
Cardiovascular: Complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe), phlebitis, and pulmonary embolism.
Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, pancreatitis, and stomach ulcer.
Endocrine: Hyperglycemia, hypoglycemia, hyponatremia, and syndrome of inappropriate antidiuretic hormone secretion.
Hemic and Lymphatic: 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: Glycosuria.
Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness.
Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, euphoria, extrapyramidal syndrome (dyskinesia, dystonia, hypokinesia, parkinsonism), hallucinations, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory: Pneumonia.
Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome.
Special Senses: Deafness, increased intraocular pressure, and mydriasis.
Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between WELLBUTRIN SR and drugs that are inhibitors or inducers of CYP2B6.
Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of WELLBUTRIN SR may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology (12.3)].
Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of WELLBUTRIN SR may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended dose.
Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see Clinical Pharmacology (12.3)]. 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.
Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of WELLBUTRIN SR with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with WELLBUTRIN SR, 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 SR and such drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].
Coadministration of WELLBUTRIN SR with digoxin may decrease plasma digoxin levels. Monitor plasma digoxin levels in patients treated concomitantly with WELLBUTRIN SR and digoxin [see Clinical Pharmacology (12.3)].
Use extreme caution when coadministering WELLBUTRIN SR with other drugs that lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually [see Contraindications (4), Warnings and Precautions (5.3)].
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 SR concomitantly with these drugs.
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 WELLBUTRIN SR. The consumption of alcohol during treatment with WELLBUTRIN SR 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 SR. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN SR before starting an MAOI antidepressant [see Dosage and Administration (2.4, 2.5), Contraindications (4)].
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.
There is an independent pregnancy exposure registry that monitors pregnancy outcomes in women exposed to any antidepressants during pregnancy. Healthcare providers are encouraged to register patients by calling the National Pregnancy Registry for Antidepressants at 1-844-405-6185 or visiting online at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry/antidepressants.
Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester have not identified an increased risk of congenital malformations overall (see Data). There are risks to the mother associated with untreated depression in pregnancy (see Clinical Considerations). When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 11 times the maximum recommended human dose (MRHD) of 400 mg/day. When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations, and skeletal variations were observed at doses approximately equal to the MRHD and greater. Decreased fetal weights were seen at doses twice the MRHD and greater (see Animal Data).
The estimated background risk for major birth defects and miscarriage is unknown for the indicated population. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and of miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.
A prospective, longitudinal study followed 201 pregnant women with a history of major depressive disorder who were euthymic and taking antidepressants during pregnancy at the beginning of pregnancy. The women who discontinued antidepressants during pregnancy were more likely to experience a relapse of major depression than women who continued antidepressants. Consider the risks to the mother of untreated depression and potential effects on the fetus when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.
Data from the international bupropion Pregnancy Registry (675 first trimester exposures) and a retrospective cohort study using the United Healthcare database (1,213 first trimester exposures) did not show an increased risk for malformations overall. The Registry was not designed or powered to evaluate specific defects but suggested a possible increase in cardiac malformations.
No increased risk for cardiovascular malformations overall has been observed after bupropion exposure during the first trimester. The prospectively observed rate of cardiovascular malformations in pregnancies with exposure to bupropion in the first trimester from the international Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first trimester maternal bupropion exposures), which is similar to the background rate of cardiovascular malformations (approximately 1%). Data from the United Healthcare database, which had a limited number of exposed cases with cardiovascular malformations, and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) of self-reported bupropion use from the National Birth Defects Prevention Study (NBDPS) did not show an increased risk for cardiovascular malformations overall after bupropion exposure during the first trimester.
Study findings on bupropion exposure during the first trimester and risk for left ventricular outflow tract obstruction (LVOTO) are inconsistent and do not allow conclusions regarding a possible association. The United Healthcare database lacked sufficient power to evaluate this association; the NBDPS found increased risk for LVOTO (n=10; adjusted OR = 2.6; 95% CI: 1.2, 5.7), and the Slone Epidemiology case control study did not find increased risk for LVOTO.
Study findings on bupropion exposure during the first trimester and risk for ventricular septal defect (VSD) are inconsistent and do not allow conclusions regarding a possible association. The Slone Epidemiology Study found an increased risk for VSD following first trimester maternal bupropion exposure (n=17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not find increased risk for any other cardiovascular malformations studied (including LVOTO as above). The NBDPS and United Healthcare database study did not find an association between first trimester maternal bupropion exposure and VSD.
For the findings of LVOTO and VSD, the studies were limited by the small number of exposed cases, inconsistent findings among studies, and the potential for chance findings from multiple comparisons in case control studies.
In studies conducted in pregnant rats and rabbits, bupropion was administered orally during the period of organogenesis at doses of up to 450 and 150 mg/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis). There was no evidence of fetal malformations in rats. When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2basis) and greater. Decreased fetal weights were observed at doses of 50 mg/kg/day (approximately 2 times the MRHD on a mg/m² basis) and greater. No maternal toxicity was evident at doses of 50 mg/kg/day or less.
In a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 4 times the MRHD on a mg/m² basis) from embryonic implantation through lactation had no effect on pup growth or development.
Data from published literature report the presence of bupropion and its metabolites in human milk (see Data). There are no data on the effects of bupropion or its metabolites on milk production. Limited data from postmarketing reports have not identified a clear association of adverse reactions in the breastfed infant. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for WELLBUTRIN SR and any potential adverse effects on the breastfed child from WELLBUTRIN SR or from the underlying maternal condition.
In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Postmarketing reports have described seizures in breastfed infants. The relationship of bupropion exposure and these seizures is unclear.
Safety and effectiveness in the pediatric population have not been established [see Boxed Warning, Warnings and Precautions (5.1)].
Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.
Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see Dosage and Administration (2.3), Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].
Consider a reduced dose and/or dosing frequency of WELLBUTRIN SR in patients with renal impairment (Glomerular Filtration Rate: less than 90 mL/min). Bupropion and its metabolites are cleared renally and may accumulate in such patients to a greater extent than usual. Monitor closely for adverse reactions that could indicate high bupropion or metabolite exposures [see Dosage and Administration (2.3), Clinical Pharmacology (12.3)].
In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN SR is 100 mg/day or 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Dosage and Administration (2.2), Clinical Pharmacology (12.3)].
Bupropion is not a controlled substance.
Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement, often typical of central stimulant activity.
In a population of individuals experienced with drugs of abuse, a single oral dose of 400 mg of bupropion produced mild amphetamine‑like activity as compared with placebo on the Morphine‑Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score greater than placebo but less than 15 mg of the Schedule II stimulant dextroamphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug liking which are often associated with abuse potential.
Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single‑dose trials does suggest that the recommended daily dosage of bupropion when administered orally in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (which could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.
WELLBUTRIN SR is intended for oral use only. The inhalation of crushed tablets or injection of dissolved bupropion has been reported. Seizures and/or cases of death have been reported when bupropion has been administered intranasally or by parenteral injection.
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 behavior 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.
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