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 WELLBUTRIN® is 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. (5.2)
1 INDICATIONS AND USAGE WELLBUTRIN (bupropion hydrochloride) is indicated for the treatment of major depressive disorder(MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of WELLBUTRIN 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)]. WELLBUTRIN is an aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD). (1)
3 DOSAGE FORMS AND STRENGTHS •75 mg – yellow‑gold, round, biconvex tablets printed with “WELLBUTRIN 75”. •100 mg – red, round, biconvex tablets printed with “WELLBUTRIN 100”. Tablets: 75 mg and 100 mg. (3)
4 CONTRAINDICATIONS •WELLBUTRIN is contraindicated in patients with a seizure disorder. •WELLBUTRIN is 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 WELLBUTRIN [see Warnings and Precautions (5.3)]. •WELLBUTRIN is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3), Drug Interactions (7.3)]. •The use of MAOIs (intended to treat psychiatric disorders) concomitantly with WELLBUTRIN or within 14 days of discontinuing treatment with WELLBUTRIN is contraindicated. There is an increased risk of hypertensive reactions when WELLBUTRIN is used concomitantly with MAOIs. The use of WELLBUTRIN within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting WELLBUTRIN in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration (2.4, 2.5), Warnings and Precautions (5.4), Drug Interactions (7.6)]. •WELLBUTRIN is contraindicated in patients with known hypersensitivity to bupropion or other ingredients of WELLBUTRIN. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.8)]. •Seizure disorder. (4, 5.3) •Current or prior diagnosis of bulimia or anorexia nervosa. (4, 5.3) •Abrupt discontinuation of alcohol, benzodiazepines, barbiturates, antiepileptic drugs. (4, 5.3) •Monoamine Oxidase Inhibitors (MAOIs): Do not use MAOIs intended to treat psychiatric disorders with WELLBUTRIN or within 14 days of stopping treatment with WELLBUTRIN. Do not use WELLBUTRIN within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start WELLBUTRIN in a patient who is being treated with linezolid or intravenous methylene blue. (4, 7.6) •Known hypersensitivity to bupropion or other ingredients of WELLBUTRIN. (4, 5.8)
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: WELLBUTRIN 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) •Angle-closure glaucoma: Angle-closure glaucoma has occurred in patients with untreated anatomically narrow angles treated with antidepressants. (5.7) 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 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 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 WELLBUTRIN 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, 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 WELLBUTRIN can cause seizure. The risk of seizure is dose-related. The dose should not exceed 450 mg per day. Increase the dose gradually. Discontinue WELLBUTRIN 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. WELLBUTRIN 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 per day. The estimated seizure incidence for WELLBUTRIN increases almost 10-fold between 450 and 600 mg per day. The risk of seizure can be reduced if the dose of WELLBUTRIN does not exceed 450 mg per day, given as 150 mg 3 times daily, and the titration rate is gradual. 5.4 Hypertension Treatment with WELLBUTRIN can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with WELLBUTRIN, and monitor periodically during treatment. The risk of hypertension is increased if WELLBUTRIN 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. 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 WELLBUTRIN, 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 is not approved for use in treating bipolar depression. 5.6 Psychosis and Other Neuropsychiatric Reactions Depressed patients treated with WELLBUTRIN 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 Angle-Closure Glaucoma The pupillary dilation that occurs following use of many antidepressant drugs including WELLBUTRIN may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy. 5.8 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 WELLBUTRIN 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.
6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: •Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning, Warnings and Precautions (5.1)] •Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Boxed Warning, Warnings and Precautions (5.2)] •Seizure [see Warnings and Precautions (5.3)] •Hypertension [see Warnings and Precautions (5.4)] •Activation of mania or hypomania [see Warnings and Precautions (5.5)] •Psychosis and other neuropsychiatric reactions [see Warnings and Precautions (5.6)] •Angle-closure glaucoma [see Warnings and Precautions (5.7)] •Hypersensitivity reactions [see Warnings and Precautions (5.8)] Most common adverse reactions (incidence ≥5% and ≥1% more than placebo rate) are: agitation, dry mouth, constipation, headache/migraine, nausea/vomiting, dizziness, excessive sweating, tremor, insomnia, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmias, and auditory disturbance. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. Adverse Reactions Leading to Discontinuation of Treatment Adverse reactions were sufficiently troublesome to cause discontinuation of treatment with WELLBUTRIN in approximately 10% of the 2,400 subjects and healthy volunteers who participated in clinical trials during the product’s initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose. Commonly Observed Adverse Reactions Adverse reactions commonly encountered in subjects treated with WELLBUTRIN are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, tremor, dizziness, excessive sweating, blurred vision, tachycardia, confusion, rash, hostility, cardiac arrhythmia, and auditory disturbance. Table 2 summarizes the adverse reactions that occurred in placebo-controlled trials at an incidence of at least 1% of subjects receiving WELLBUTRIN and more frequently in these subjects than in the placebo group. Table 2. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency than Placebo in Controlled Clinical Trials Adverse Reaction WELLBUTRIN (n = 323) % Placebo (n = 185) % Cardiovascular Cardiac arrhythmias 5.3 4.3 Dizziness 22.3 16.2 Hypertension 4.3 1.6 Hypotension 2.5 2.2 Palpitations 3.7 2.2 Syncope 1.2 0.5 Tachycardia 10.8 8.6 Dermatologic Pruritus 2.2 0.0 Rash 8.0 6.5 Gastrointestinal Appetite increase 3.7 2.2 Constipation 26.0 17.3 Dyspepsia 3.1 2.2 Nausea/vomiting 22.9 18.9 Genitourinary Impotence 3.4 3.1 Menstrual complaints 4.7 1.1 Urinary frequency 2.5 2.2 Musculoskeletal Arthritis 3.1 2.7 Neurological Akathisia 1.5 1.1 Cutaneous temperature disturbance 1.9 1.6 Dry mouth 27.6 18.4 Excessive sweating 22.3 14.6 Headache/migraine 25.7 22.2 Impaired sleep quality 4.0 1.6 Insomnia 18.6 15.7 Sedation 19.8 19.5 Sensory disturbance 4.0 3.2 Tremor 21.1 7.6 Neuropsychiatric Agitation 31.9 22.2 Anxiety 3.1 1.1 Confusion 8.4 4.9 Decreased libido 3.1 1.6 Delusions 1.2 1.1 Euphoria 1.2 0.5 Hostility 5.6 3.8 Nonspecific Fever/chills 1.2 0.5 Special Senses Auditory disturbance 5.3 3.2 Blurred vision 14.6 10.3 Gustatory disturbance 3.1 1.1 Other Adverse Reactions Observed during the Clinical Development of WELLBUTRIN The conditions and duration of exposure to WELLBUTRIN varied greatly, and a substantial proportion of the experience was gained in open and uncontrolled clinical settings. During this experience, numerous adverse events were reported; however, without appropriate controls, it is impossible to determine with certainty which events were or were not caused by WELLBUTRIN. The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the database. The following definitions of frequency are used: 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. Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG) abnormalities (premature beats and nonspecific ST‑T changes), and shortness of breath/dyspnea; rare were flushing, and myocardial infarction. Dermatologic: Infrequent was alopecia. Endocrine: Infrequent was gynecomastia; rare was glycosuria. Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice; rare was intestinal perforation. Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were enuresis, and urinary incontinence. Neurological: Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram (EEG) abnormality, and impaired attention. Neuropsychiatric: Frequent were mania/hypomania, increased libido, hallucinations, decrease in sexual function, and depression; infrequent were memory impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, and formal thought disorder; rare was suicidal ideation. Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum irritation, and oral edema. Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare was pulmonary embolism. Special Senses: Infrequent was visual disturbance; rare was diplopia. Nonspecific: Frequent were flu‑like symptoms; infrequent was nonspecific pain; rare was overdose. Altered Appetite and Weight A weight loss of greater than 5 lbs occurred in 28% of subjects receiving WELLBUTRIN. This incidence is approximately double that seen in comparable subjects treated with tricyclics or placebo. Furthermore, while 35% of subjects receiving tricyclic antidepressants gained weight, only 9.4% of subjects treated with WELLBUTRIN did. Consequently, if weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight-reducing potential of WELLBUTRIN should be considered. 6.2 Postmarketing Experience The following adverse reactions have been identified during post-approval use of WELLBUTRIN 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 Hypertension (in some cases severe), orthostatic hypotension, third degree heart block. Endocrine Syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia, hypoglycemia. Gastrointestinal Esophagitis, hepatitis. Hemic and Lymphatic Ecchymosis, leukocytosis, leukopenia, thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin. Musculoskeletal Muscle rigidity/fever/rhabdomyolysis, muscle weakness. Nervous System Aggression, coma, completed suicide, delirium, dream abnormalities, paranoid ideation, paresthesia, parkinsonism, restlessness, suicide attempt, unmasking of tardive dyskinesia. Skin and Appendages Stevens‑Johnson syndrome, angioedema, exfoliative dermatitis, urticaria. Special Senses Tinnitus, increased intraocular pressure.
7 DRUG INTERACTIONS •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 WELLBUTRIN with caution. (5.3, 7.3) •Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with WELLBUTRIN. (7.4) •MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with WELLBUTRIN. (7.6) •Drug-laboratory test interactions: WELLBUTRIN can cause false-positive urine test results for amphetamines. (7.7) 7.1 Potential for Other Drugs to Affect WELLBUTRIN Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between WELLBUTRIN 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 WELLBUTRIN 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 WELLBUTRIN 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 WELLBUTRIN to Affect Other Drugs Drugs Metabolized by CYP2D6 Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of WELLBUTRIN 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, 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 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 WELLBUTRIN 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)]. 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 WELLBUTRIN 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 WELLBUTRIN. The consumption of alcohol during treatment with WELLBUTRIN 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 WELLBUTRIN. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN before starting an MAOI antidepressant [see Dosage and Administration (2.4, 2.5), 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.
8 USE IN SPECIFIC POPULATIONS •Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1) 8.1 Pregnancy 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. WELLBUTRIN 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% (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 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 per kg per day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg per 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 per kg per day, approximately equal to the MRHD on a mg per m2 basis) and greater. Decreased fetal weights were observed at 50 mg per kg and greater. When rats were administered bupropion at oral doses of up to 300 mg per kg per day (approximately 7 times the MRHD on a mg per 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 per kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when WELLBUTRIN is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness in the pediatric population have not been established [see Boxed Warning, Warnings and Precautions (5.1)]. 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 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)]. 8.6 Renal Impairment Consider a reduced dose and/or dosing frequency of WELLBUTRIN in patients with renal impairment (Glomerular Filtration Rate: less than 90 mL per 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)]. 8.7 Hepatic Impairment In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of WELLBUTRIN 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)].