Bupropion Hydrochloride Prescribing Information
Antidepressants increased the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term trials. These trials did not show an increase in the risk of suicidal thoughts and behavior with antidepressant use in subjects over age 24; there was a reduction in risk with antidepressant use in subjects aged 65 and older
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.
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 to 24 | 5 additional cases |
| Decreases Compared with Placebo | |
| 25 to 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.
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.
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.
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 to 24 | 5 additional cases |
| Decreases Compared with Placebo | |
| 25 to 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.
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.
Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).
The efficacy of bupropion hydrochloride tablets in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with MDD
The efficacy of bupropion hydrochloride in the treatment of major depressive disorder was established in two 4-week, placebo-controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 4) and in one 6-week, placebo-controlled trial in adult outpatients with MDD (Trial 3 in Table 4). In the first trial, the dose range of bupropion hydrochloride was 300 mg to 600 mg/day administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg/day. The trial demonstrated the efficacy of bupropion hydrochloride as measured by the Hamilton Depression Rating Scale (HDRS) total score, the HDRS depressed mood item (Item 1), and the Clinical Global Impressions-severity score (CGI-S). The second trial included 2 doses of bupropion hydrochloride (300 and 450 mg/day) and placebo. This trial demonstrated the effectiveness of bupropion hydrochloride for only the 450-mg/day dose. The efficacy results were statistically significant for the HDRS total score and the CGI-S score, but not for HDRS Item 1. In the third trial, outpatients were treated with 300 mg/day of bupropion hydrochloride. This trial demonstrated the efficacy of bupropion hydrochloride as measured by the HDRS total score, the HDRS Item 1, the Montgomery-Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score. Effectiveness of bupropion hydrochloride in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials.
| n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval included for doses that were demonstrated to be effective; NA: not available. aDifference (drug minus placebo) in least-squares estimates with respect to the primary efficacy parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2 and 3, it refers to the mean change from baseline to the endpoint visit. bDoses that are demonstrated to be statistically significantly superior to placebo. | |||||||||||||||||||||||||||||||||||||||||||
Trial Number | Treatment Group | Primary Efficacy Measure: HDRS | |||||||||||||||||||||||||||||||||||||||||
Mean Baseline Score (SD) | LS Mean Score at Endpoint Visit (SE) | Placebo-subtracted Differencea(95% CI) | |||||||||||||||||||||||||||||||||||||||||
| Trial 1 | Bupropion Hydrochloride 300 to 600 mg/dayb (n = 48) | 28.5 (5.1) | 14.9 (1.3) | -4.7 (-8.8, -0.6) | |||||||||||||||||||||||||||||||||||||||
| Placebo (n = 27) | 29.3 (7.0) | 19.6 (1.6) | -- | ||||||||||||||||||||||||||||||||||||||||
Mean Baseline Score (SD) | LS Mean Change from Baseline (SE) | Placebo-subtracted Differencea(95% CI) | |||||||||||||||||||||||||||||||||||||||||
| Trial 2 | Bupropion Hydrochloride 300 mg/day (n = 36) | 32.4 (5.9) | -15.5 (1.7) | -4.1 | |||||||||||||||||||||||||||||||||||||||
| Bupropion Hydrochloride 450 mg/dayb (n = 34) | 34.8 (4.6) | -17.4 (1.7) | -5.9 (-10.5, -1.4) | ||||||||||||||||||||||||||||||||||||||||
| Placebo (n = 39) | 32.9 (5.4) | -11.5 (1.6) | -- | ||||||||||||||||||||||||||||||||||||||||
| Trial 3 | Bupropion Hydrochloride 300 mg/dayb (n = 110) | 26.5 (4.3) | -12.0 (NA) | -3.9 (-5.7, -1.0) | |||||||||||||||||||||||||||||||||||||||
| Placebo (n = 106) | 27.0 (3.5) | -8.7 (NA) | -- | ||||||||||||||||||||||||||||||||||||||||
- Starting dose: 200 mg/day given as 100 mg twice daily ()
2.1 General Instructions for UseTo minimize the risk of seizure, increase the dose gradually
[see Warnings and Precautions (5.3)]. Increases in dose should not exceed 100 mg/day in a 3-day period. Bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets may be taken with or without food.The recommended starting dose is 200 mg/day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg/day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg/day may be accomplished using the 75- or 100-mg tablets.
A maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg/day. Administer the 100-mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride tablets needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.
- General: Increase dose gradually to reduce seizure risk. (,
2.1 General Instructions for UseTo minimize the risk of seizure, increase the dose gradually
[see Warnings and Precautions (5.3)]. Increases in dose should not exceed 100 mg/day in a 3-day period. Bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets may be taken with or without food.The recommended starting dose is 200 mg/day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg/day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg/day may be accomplished using the 75- or 100-mg tablets.
A maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg/day. Administer the 100-mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride tablets needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.
)5.3 SeizureBupropion hydrochloride can cause seizure. The risk of seizure is dose-related. The dose should not exceed 450 mg/day. Increase the dose gradually. Discontinue bupropion hydrochloride 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 bupropion hydrochloride. Bupropion hydrochloride 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.
Incidence of Seizure with Bupropion Use:
Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. The estimated seizure incidence for bupropion hydrochloride increases almost 10-fold between 450 and 600 mg/day.The risk of seizure can be reduced if the dose of bupropion hydrochloride does not exceed 450 mg/day, given as 150 mg 3 times daily, and the titration rate is gradual.
- After 3 days, may increase the dose to 300 mg/day, given as 100 mg 3 times daily at an interval of at least 6 hours between doses. ()
2.1 General Instructions for UseTo minimize the risk of seizure, increase the dose gradually
[see Warnings and Precautions (5.3)]. Increases in dose should not exceed 100 mg/day in a 3-day period. Bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets may be taken with or without food.The recommended starting dose is 200 mg/day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg/day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg/day may be accomplished using the 75- or 100-mg tablets.
A maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg/day. Administer the 100-mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride tablets needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.
- Usual target dose: 300 mg/day as 100 mg 3 times daily. ()
2.1 General Instructions for UseTo minimize the risk of seizure, increase the dose gradually
[see Warnings and Precautions (5.3)]. Increases in dose should not exceed 100 mg/day in a 3-day period. Bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets may be taken with or without food.The recommended starting dose is 200 mg/day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg/day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg/day may be accomplished using the 75- or 100-mg tablets.
A maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg/day. Administer the 100-mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride tablets needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.
- Maximum dose: 450 mg/day given as 150 mg 3 times daily. ()
2.1 General Instructions for UseTo minimize the risk of seizure, increase the dose gradually
[see Warnings and Precautions (5.3)]. Increases in dose should not exceed 100 mg/day in a 3-day period. Bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets may be taken with or without food.The recommended starting dose is 200 mg/day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg/day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg/day may be accomplished using the 75- or 100-mg tablets.
A maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg/day. Administer the 100-mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride tablets needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.
- Periodically reassess the dose and need for maintenance treatment. ()
2.1 General Instructions for UseTo minimize the risk of seizure, increase the dose gradually
[see Warnings and Precautions (5.3)]. Increases in dose should not exceed 100 mg/day in a 3-day period. Bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride tablets may be taken with or without food.The recommended starting dose is 200 mg/day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg/day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg/day may be accomplished using the 75- or 100-mg tablets.
A maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients who show no clinical improvement after several weeks of treatment at 300 mg/day. Administer the 100-mg tablet 4 times daily to not exceed the limit of 150 mg in a single dose.
It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride tablets needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.
- Moderate to severe hepatic impairment: 75 mg once daily. (,
2.2 Dose Adjustment in Patients with Hepatic ImpairmentIn patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride tablets is 75 mg/day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing
[see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].)8.7 Hepatic ImpairmentIn patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride is 75 mg daily. 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)]. - Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. (,
2.2 Dose Adjustment in Patients with Hepatic ImpairmentIn patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride tablets is 75 mg/day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing
[see Use in Specific Populations (8.7), Clinical Pharmacology (12.3)].)8.7 Hepatic ImpairmentIn patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride is 75 mg daily. 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)]. - Renal impairment: Consider reducing the dose and/or frequency. (,
2.3 Dose Adjustment in Patients with Renal ImpairmentConsider reducing the dose and/or frequency of bupropion hydrochloride tablets in patients with renal impairment (Glomerular Filtration Rate [GFR] less than 90 mL/min)
[see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].)8.6 Renal ImpairmentConsider a reduced dose and/or dosing frequency of bupropion hydrochloride in patients with renal impairment (GFR: 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)].
Bupropion Hydrochloride Tablets, USP are available containing 75 mg or 100 mg of bupropion hydrochloride, USP.
- The 75 mg tablets are a peach, film-coated, round, biconvex, beveled edge tablet debossed with 75 on one side of the tablet and B on the other side.
- The 100 mg tablets are a light blue, film-coated, round, biconvex, beveled edge tablet debossed with 100 on one side of the tablet and B on the other side.
Pregnancy Exposure Registry
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/research/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
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.
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 a pre- and postnatal development study, bupropion administered orally to pregnant rats at doses of up to 150 mg/kg/day (approximately 3 times the MRHD on a mg/m2 basis) from embryonic implantation through lactation had no effect on pup growth or development.
- Bupropion hydrochloride tablets are contraindicated in patients with a seizure disorder.
- Bupropion hydrochloride tablets are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with bupropion hydrochloride tablets [see.]
5.3 SeizureBupropion hydrochloride can cause seizure. The risk of seizure is dose-related. The dose should not exceed 450 mg/day. Increase the dose gradually. Discontinue bupropion hydrochloride 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 bupropion hydrochloride. Bupropion hydrochloride 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.
Incidence of Seizure with Bupropion Use:
Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. The estimated seizure incidence for bupropion hydrochloride increases almost 10-fold between 450 and 600 mg/day.The risk of seizure can be reduced if the dose of bupropion hydrochloride does not exceed 450 mg/day, given as 150 mg 3 times daily, and the titration rate is gradual.
- Bupropion hydrochloride tablets are contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see.,
5.3 SeizureBupropion hydrochloride can cause seizure. The risk of seizure is dose-related. The dose should not exceed 450 mg/day. Increase the dose gradually. Discontinue bupropion hydrochloride 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 bupropion hydrochloride. Bupropion hydrochloride 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.
Incidence of Seizure with Bupropion Use:
Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. The estimated seizure incidence for bupropion hydrochloride increases almost 10-fold between 450 and 600 mg/day.The risk of seizure can be reduced if the dose of bupropion hydrochloride does not exceed 450 mg/day, given as 150 mg 3 times daily, and the titration rate is gradual.
]7.3 Drugs that Lower Seizure ThresholdUse extreme caution when coadministering bupropion hydrochloride 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)]. - The use of MAOIs (intended to treat psychiatric disorders) concomitantly with bupropion hydrochloride tablets or within 14 days of discontinuing treatment with bupropion hydrochloride tablets are contraindicated. There is an increased risk of hypertensive reactions when bupropion hydrochloride tablets are used concomitantly with MAOIs. The use of bupropion hydrochloride tablets within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting bupropion hydrochloride tablets in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see.,
2.4 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) AntidepressantAt least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with bupropion hydrochloride tablets. Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride tablets before starting an MAOI antidepressant
[see Contraindications (4), Drug Interactions (7.6)].,2.5 Use of Bupropion Hydrochloride Tablets with Reversible MAOIs Such as Linezolid or Methylene BlueDo not start bupropion hydrochloride tablets in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered
[see Contraindications (4), Drug Interactions (7.6)].In some cases, a patient already receiving therapy with bupropion hydrochloride tablets may require urgent treatment with linezolid or intravenous methylene blue. If acceptable alternatives to linezolid or intravenous methylene blue treatment are not available and the potential benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of hypertensive reactions in a particular patient, bupropion hydrochloride tablets should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous methylene blue, whichever comes first. Therapy with bupropion hydrochloride tablets may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.
The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with bupropion hydrochloride tablets are unclear. The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use
[see Contraindications (4), Drug Interactions (7.6)].,5.4 HypertensionTreatment with bupropion hydrochloride can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with bupropion hydrochloride and monitor periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride 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.
]7.6 MAO InhibitorsBupropion 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 bupropion hydrochloride. Conversely, at least 14 days should be allowed after stopping bupropion hydrochloride before starting an MAOI antidepressant
[see Dosage and Administration (2.4, 2.5), Contraindications (4)]. - Bupropion hydrochloride tablets are contraindicated in patients with known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride tablets. Anaphylactoid/ anaphylactic reactions and Stevens-Johnson syndrome have been reported [see.]
5.8 Hypersensitivity ReactionsAnaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue bupropion hydrochloride 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.