buPROPion HCl 100 MG Oral Tablet
Generic Name: BUPROPION HYDROCHLORIDE
Brand Name: Bupropion Hydrochloride
- Substance Name(s):
- BUPROPION HYDROCHLORIDE
7 •CYP2B6 inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir, lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) based on clinical response, but should not exceed the maximum recommended dose.
(7.1) •Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants (e.g., venlafaxine, 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).
Consider dose reduction when using with bupropion.
(7.2) •Drugs that lower seizure threshold: Dose bupropion with caution.
(5.3, 7.3) •Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with bupropion.
(7.4) •MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with bupropion.
(7.6) •Drug-laboratory test interactions: Bupropion can cause false-positive urine test results for amphetamines.
(7.7) 7.1 Potential for Other Drugs to Affect Bupropion Bupropion is primarily metabolized to hydroxybupropion by CYP2B6.
Therefore, the potential exists for drug interactions between bupropion and drugs that are inhibitors or inducers of CYP2B6.
Inhibitors 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 bupropion may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology (12.3)].
Inducers of CYP2B6 Ritonavir, Lopinavir, and Efavirenz Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure.
Dosage increase of bupropion 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.
7.2 Potential for Bupropion to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors.
Therefore, coadministration of bupropion 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 bupropion, 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 bupropion and such drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].
7.3 Drugs That Lower Seizure Threshold Use extreme caution when coadministering bupropion 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) and Warnings and Precautions (5.3)].
7.4 Dopaminergic Drugs (Levodopa and Amantadine) Bupropion, levodopa, and amantadine have dopamine agonist effects.
CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine.
Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness.
It is presumed that the toxicity results from cumulative dopamine agonist effects.
Use caution when administering bupropion concomitantly with these drugs.
7.5 Use with 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 bupropion should be minimized or avoided.
7.6 MAO Inhibitors 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 bupropion.
Conversely, at least 14 days should be allowed after stopping bupropion before starting an MAOI antidepressant [see Dosage and Administration (2.4, 2.5) and Contraindications (4)].
7.7 Drug-Laboratory Test Interactions False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion.
This is due to lack of specificity of some screening tests.
False-positive test results may result even following discontinuation of bupropion therapy.
Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.
10 10.1 Human Overdose Experience Overdoses of up to 30 grams or more of bupropion have been reported.
Seizure was reported in approximately one-third of all cases.
Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias.
Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug.
Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.
10.2 Overdosage Management Consult a Certified Poison Control Center for up-to-date guidance and advice.
Telephone numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR).
Call 1-800-222-1222 or refer to www.poison.org.
There are no known antidotes for bupropion.
In case of an overdose, provide supportive care, including close medical supervision and monitoring.
Consider the possibility of multiple drug overdose.
Ensure an adequate airway, oxygenation, and ventilation.
Monitor cardiac rhythm and vital signs.
Induction of emesis is not recommended.
11 Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents.
Its structure closely resembles that of diethylpropion; it is related to phenylethylamines.
It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride.
The molecular weight is 276.2.
The molecular formula is C13H18ClNO•HCl.
Bupropion hydrochloride powder is white or almost white, crystalline, and highly soluble in water.
It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.
The structural formula is: Bupropion hydrochloride tablets, USP for oral administration, are available containing 75 mg or 100 mg of bupropion hydrochloride, USP.
Each tablet also contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, crospovidone, hydrochloric acid, hypromellose, microcrystalline cellulose, polydextrose, polyethylene glycol, stearic acid, titanium dioxide and triacetin.
In addition, the 75 mg tablets contain synthetic red iron oxide and synthetic yellow iron oxide and the 100 mg tablets contain FD&C Blue No.
2 Aluminum Lake and FD&C Yellow No.
6 Aluminum Lake.
Bupropion Hydrochloride Structural Formula
14 The efficacy of bupropion 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 was 300 to 600 mg/day administered in three divided doses; 78% of subjects were treated with doses of 300 to 450 mg/day.
The trial demonstrated the efficacy of bupropion 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 two doses of bupropion (300 and 450 mg/day) and placebo.
This trial demonstrated the effectiveness of bupropion 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.
This trial demonstrated the efficacy of bupropion 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 in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials.
Efficacy of Bupropion for the Treatment of Major Depressive Disorder 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.
Trial Number Treatment Group Primary Efficacy Measure: HDRS Mean Baseline Score (SD) LS Mean Score at Endpoint Visit (SE) Placebo-subtracted Difference Difference (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.
(95% CI) Trial 1 Bupropion 300 to 600 mg/dayDoses that are demonstrated to be statistically significantly superior to placebo.
(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 Difference (95% CI) Trial 2 Bupropion 300 mg/day (n = 36) 32.4 (5.9) 15.5 (1.7) -4.1 Bupropion 450 mg/day (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 300 mg/day (n = 110) 26.5 (4.3) -12 (NA) -3.9 (-5.7, -1) Placebo (n = 106) 27 (3.5) -8.7 (NA) —
16 /STORAGE AND HANDLING Bupropion Hydrochloride Tablets, USP are available containing 75 mg or 100 mg of bupropion hydrochloride, USP.
The 75 mg tablets are peach film-coated, round, unscored tablets debossed with M on one side of the tablet and 433 on the other side.
They are available as follows: NDC 0378-0433-01 bottles of 100 tablets NDC 0378-0433-05 bottles of 500 tablets The 100 mg tablets are light blue film-coated, round, unscored tablets debossed with M on one side of the tablet and 435 on the other side.
They are available as follows: NDC 0378-0435-01 bottles of 100 tablets NDC 0378-0435-05 bottles of 500 tablets Store at 20° to 25°C (68° to 77°F).
[See USP Controlled Room Temperature.] Protect from light and moisture.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.
PHARMACIST: Dispense a Medication Guide with each prescription.
RECENT MAJOR CHANGES
Dosage and Administration (2.4, 2.5) 03/2013 Contraindications (4) 03/2013
8.5 Geriatric Use 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 and 47 were aged ≥ 75 years.
In addition, several hundred patients 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), and Clinical Pharmacology (12.3)].
DOSAGE FORMS AND STRENGTHS
3 •75 mg – peach film-coated, round, unscored tablets debossed with M on one side of the tablet and 433 on the other side •100 mg – light blue film-coated, round, unscored tablets debossed with M on one side of the tablet and 435 on the other side Tablets: 75 mg and 100 mg.
MECHANISM OF ACTION
12.1 Mechanism of Action The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms.
Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin.
Bupropion does not inhibit monoamine oxidase.
INDICATIONS AND USAGE
1 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 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 [see Clinical Studies (14)].
Bupropion hydrochloride is an aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD).
8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions (5.1)].
8.1 Pregnancy Teratogenic Effects.
Pregnancy Category C Risk Summary Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall.
All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss.
No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater.
Bupropion should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Clinical Considerations Consider the risks of untreated depression when discontinuing or changing treatment with antidepressant medications during pregnancy and postpartum.
Human Data 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.
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% (nine 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 and a case-control study (6,853 infants with cardiovascular malformations and 5,763 with non-cardiovascular malformations) 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.
Animal Data In studies conducted in 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).
No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences 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/m2 basis) and greater.
Decreased fetal weights were observed at 50 mg/kg and greater.
When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.
8.3 Nursing Mothers Bupropion and its metabolites are present in human milk.
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.
Exercise caution when bupropion is administered to a nursing woman.
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC REACTIONS SUICIDALITY AND ANTIDEPRESSANT DRUGS 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 [see Warnings and Precautions (5.1)].
In patients of all ages who are started on antidepressant therapy, monitor closely for worsening, and for emergence of suicidal thoughts and behaviors.
Advise families and caregivers of the need for close observation and communication with the prescriber [see Warnings and Precautions (5.1)].
NEUROPSYCHIATRIC REACTIONS IN PATIENTS TAKING BUPROPION FOR SMOKING CESSATION Serious neuropsychiatric reactions have occurred in patients taking bupropion for smoking cessation [see Warnings and Precautions (5.2)].
The majority of these reactions occurred during bupropion treatment, but some occurred in the context of discontinuing treatment.
In many cases, a causal relationship to bupropion treatment is not certain, because depressed mood may be a symptom of nicotine withdrawal.
However, some of the cases occurred in patients taking bupropion who continued to smoke.
Although bupropion hydrochloride tablets are not approved for smoking cessation, observe all patients for neuropsychiatric reactions.
Instruct the patient to contact a healthcare provider if such reactions occur [see Warnings and Precautions (5.2)].
WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC REACTIONS See full prescribing information for complete boxed warning.
• Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants.
(5.1) • Monitor for worsening and emergence of suicidal thoughts and behaviors.
(5.1) • Serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation.
WARNING AND CAUTIONS
5 WARNINGS AND PRECAUTIONS •Seizure risk: The risk is dose-related.
Can minimize risk by gradually increasing the dose and limiting daily dose to 450 mg.
Discontinue if seizure occurs.
(4, 5.3, 7.3) •Hypertension: Bupropion can increase blood pressure.
Monitor blood pressure before initiating treatment and periodically during treatment.
(5.4) •Activation of mania/hypomania: Screen patients for bipolar disorder and monitor for these symptoms.
(5.5) •Psychosis and other neuropsychiatric reactions: Instruct patients to contact a healthcare professional if such reactions occur.
(5.6) 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults 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 nine 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.
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 Patients 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.
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 bupropion should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
5.2 Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment Bupropion is not approved for smoking cessation treatment; however, bupropion HCl sustained-release is approved for this use.
Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation.
These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Boxed Warning and Adverse Reactions (6.2)].
Observe patients for the occurrence of neuropsychiatric reactions.
Instruct patients to contact a healthcare professional if such reactions occur.
In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal.
However, some of the cases occurred in patients taking bupropion who continued to smoke.
5.3 Seizure Bupropion can cause seizure.
The risk of seizure is dose-related.
The dose should not exceed 450 mg/day.
Increase the dose gradually.
Discontinue bupropion 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.
Bupropion 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) and 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 increases almost 10-fold between 450 and 600 mg/day.
The risk of seizure can be reduced if the dose of bupropion does not exceed 450 mg/day, given as 150 mg 3 times daily, and the titration rate is gradual.
5.4 Hypertension Treatment with bupropion can result in elevated blood pressure and hypertension.
Assess blood pressure before initiating treatment with bupropion, and monitor periodically during treatment.
The risk of hypertension is increased if bupropion 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 to 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 one 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.
5.5 Activation of Mania/Hypomania 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 bupropion, 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).
Bupropion is not approved for use in treating bipolar depression.
5.6 Psychosis and Other Neuropsychiatric Reactions Depressed patients treated with bupropion 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.
5.7 Hypersensitivity Reactions 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 bupropion 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.
INFORMATION FOR PATIENTS
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).
Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion and counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions”, “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions”, and “What Other Important Information Should I Know About Bupropion Hydrochloride Tablets?” is available for bupropion hydrochloride tablets.
Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents.
Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have.
The complete text of the Medication Guide is reprinted at the end of this document.
Advise patients regarding the following issues and to alert their prescriber if these occur while taking bupropion.
Suicidal Thoughts and Behaviors: Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down.
Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt.
Such symptoms should be reported to the patient’s prescriber or healthcare professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.
Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Although bupropion hydrochloride tablets are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN® which is approved for this use.
Advise patients, families and caregivers that quitting smoking, with or without ZYBAN®, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness.
Some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN®.
If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.
Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and to discontinue bupropion if they have a severe allergic reaction.
Seizure: Instruct patients to discontinue and not restart bupropion if they experience a seizure while on treatment.
Advise patients that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure.
Advise patients to minimize or avoid use of alcohol.
Bupropion-Containing Products: Educate patients that bupropion hydrochloride tablets contain the same active ingredient (bupropion hydrochloride) found in ZYBAN®, which is used as an aid to smoking cessation treatment, and that bupropion hydrochloride tablets should not be used in combination with ZYBAN® or any other medications that contain bupropion (such as WELLBUTRIN SR®, the sustained-release formulation and WELLBUTRIN XL® or FORFIVO XL™, the extended-release formulations, and APLENZIN®, the extended-release formulation of bupropion hydrobromide).
In addition, there are a number of generic bupropion HCl products for the immediate-, sustained-, and extended-release formulations.
Potential for Cognitive and Motor Impairment: Advise patients that any CNS-active drug like bupropion may impair their ability to perform tasks requiring judgment or motor and cognitive skills.
Advise patients that until they are reasonably certain that bupropion does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Bupropion may lead to decreased alcohol tolerance.
Concomitant Medications: Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs because bupropion and other drugs may affect each others’ metabolisms.
Pregnancy: Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy.
Precautions for Nursing Mothers: Advise patients that bupropion is present in human milk in small amounts.
Storage Information: Instruct patients to store bupropion at room temperature, between 20° to 25°C (68° to 77°F) and keep the tablets dry and out of the light.
Administration Information: Instruct patients to take bupropion in equally divided doses 3 or 4 times a day, with doses separated by least 6 hours to minimize the risk of seizure.
Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure.
Instruct patients that bupropion hydrochloride tablets should be swallowed whole and not crushed, divided, or chewed.
Bupropion hydrochloride tablets can be taken with or without food.
DOSAGE AND ADMINISTRATION
2 •Starting Dose: 200 mg/day given as 100 mg twice daily (2.1) •General: Increase dose gradually to reduce seizure risk.
(2.1, 5.3) •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) •Usual target dose: 300 mg/day as 100 mg 3 times daily.
(2.1) •Maximum dose: 450 mg/day given as 150 mg 3 times daily.
(2.1) •Periodically reassess the dose and need for maintenance treatment.
(2.1) •Moderate to severe hepatic impairment: 75 mg once daily.
(2.2, 8.7) •Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing.
(2.2, 8.7) •Renal Impairment: Consider reducing the dose and/or frequency.
(2.3, 8.6) 2.1 General Instructions for Use To 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 mg 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.
2.2 Dose Adjustment in Patients with Hepatic Impairment In 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) and Clinical Pharmacology (12.3)].
2.3 Dose Adjustment in Patients with Renal Impairment Consider reducing the dose and/or frequency of bupropion hydrochloride tablets in patients with renal impairment (Glomerular Filtration Rate < 90 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].
2.4 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant At 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) and Drug Interactions (7.6)].
2.5 Use of Bupropion Hydrochloride Tablets with Reversible MAOIs such as Linezolid or Methylene Blue Do 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) and 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 is unclear.
The clinician should, nevertheless, be aware of the possibility of a drug interaction with such use [see Contraindications (4) and Drug Interactions (7.6)].