WELLBUTRIN

REMEDYREPACK INC.

These highlights do not include all the information needed to use WELLBUTRIN safely and effectively. See full prescribing information for WELLBUTRIN. WELLBUTRIN (bupropion hydrochloride) Tablets, for oral useInitial U.S. Approval: 1985

FULL PRESCRIBING INFORMATION: CONTENTS*

• RECENT MAJOR CHANGES
• Boxed Warning section
• INDICATIONS & USAGE
• DOSAGE & ADMINISTRATION
• DOSAGE FORMS & STRENGTHS
• WELLBUTRIN CONTRAINDICATIONS
• WARNINGS AND PRECAUTIONS
• WELLBUTRIN ADVERSE REACTIONS
• DRUG INTERACTIONS
• USE IN SPECIFIC POPULATIONS
• DRUG ABUSE AND DEPENDENCE
• OVERDOSAGE
• WELLBUTRIN DESCRIPTION
• CLINICAL PHARMACOLOGY
• NONCLINICAL TOXICOLOGY
• CLINICAL STUDIES
• HOW SUPPLIED
• INFORMATION FOR PATIENTS
• SPL MEDGUIDE
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

FULL PRESCRIBING INFORMATION

INDICATIONS & 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)].

DOSAGE & ADMINISTRATION

•Starting Dose: 200 mg per 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 per 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 per day as 100 mg 3 times daily. (2.1) •Maximum dose: 450 mg per 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)

To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions (5.3)]. Increases in dose should not exceed 100 mg per day in a 3‑day period. WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN may be taken with or without food.

The recommended starting dose is 200 mg per day, given as 100 mg twice daily. After 3 days of dosing, the dose may be increased to 300 mg per day, given as 100 mg 3 times daily, with at least 6 hours between successive doses. Dosing above 300 mg per day may be accomplished using the 75- or 100-mg tablets.

A maximum of 450 mg per 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 per 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 WELLBUTRIN 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.

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to15), the maximum dose of WELLBUTRIN is 75 mg per 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)].

Consider reducing the dose and/or frequency of WELLBUTRIN in patients with renal impairment (Glomerular Filtration Rate <90 mL/min) [see Use in Specific Populations (8.6) and Clinical Pharmacology (12.3)].

At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of therapy with WELLBUTRIN. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.6)].

Do not start WELLBUTRIN 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 WELLBUTRIN 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, WELLBUTRIN 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 WELLBUTRIN 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 WELLBUTRIN 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)].

DOSAGE FORMS & STRENGTHS

•75 mg – yellow‑gold, round, biconvex tablets printed with “WELLBUTRIN 75”. •100 mg – red, round, biconvex tablets printed with “WELLBUTRIN 100”.

WELLBUTRIN 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) and 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), and Drug Interactions (7.6)].

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)

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.

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.

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 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.

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) 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 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

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 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 1 subject (0.4%) treated with NTS had study medication discontinued due to hypertension compared with none of the subjects treated with sustained-release bupropion or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure (N = 36), bupropion was associated with an exacerbation of pre-existing hypertension in 2 subjects, leading to discontinuation of bupropion treatment. There are no controlled trials assessing the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac disease.

Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to initiating WELLBUTRIN, 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.

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.

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.

WELLBUTRIN 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 and Warnings and Precautions (5.1)]

•Neuropsychiatric symptoms and suicide risk in smoking cessation treatment

[see Boxed Warning and 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)]

•Hypersensitivity reactions

[see Warnings and Precautions (5.7)]

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.

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, formal thought disorder, and frigidity; 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.

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.

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, restlessness, suicide attempt, unmasking of tardive dyskinesia.

Skin and Appendages: Stevens‑Johnson syndrome, angioedema, exfoliative dermatitis, urticaria.

Special Senses: Tinnitus, increased intraocular pressure.

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)

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.

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 seeClinical Pharmacology (12.3).

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) and Warnings and Precautions (5.3)].

Bupropion, levodopa, and amantadine have dopamine agonist effects. CNS toxicity has been reported when bupropion was coadministered with levodopa or amantadine. Adverse reactions have included restlessness, agitation, tremor, ataxia, gait disturbance, vertigo, and dizziness. It is presumed that the toxicity results from cumulative dopamine agonist effects. Use caution when administering WELLBUTRIN concomitantly with these drugs.

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

Bupropion inhibits the reuptake of dopamine and norepinephrine. Concomitant use of MAOIs and bupropion is contraindicated because there is an increased risk of hypertensive reactions if bupropion is used concomitantly with MAOIs. Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine. At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and initiation of treatment with WELLBUTRIN. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN before starting an MAOI antidepressant [see Dosage and Administration (2.4, 2.5) and Contraindications (4)].

False-positive urine immunoassay screening tests for amphetamines have been reported in patients taking bupropion. This is due to lack of specificity of some screening tests. False-positive test results may result even following discontinuation of bupropion therapy. Confirmatory tests, such as gas chromatography/mass spectrometry, will distinguish bupropion from amphetamines.

USE IN SPECIFIC POPULATIONS

•Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1)

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/kg/day, respectively (approximately 11 and 7 times the MRHD, respectively, on a mg/m²basis). 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/m²basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

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 WELLBUTRIN is administered to a nursing woman.

Safety and effectiveness in the pediatric population have not been established [see Boxed Warning and Warnings and Precautions (5.1)].

Of the approximately 6,000 subjects who participated in clinical trials with bupropion sustained-release tablets (depression and smoking cessation trials), 275 were aged ≥65 years and 47 were aged ≥75 years. In addition, several hundred subjects aged ≥65 years participated in clinical trials using the immediate-release formulation of bupropion (depression trials). No overall differences in safety or effectiveness were observed between these subjects and younger subjects. Reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out.

Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of adverse reactions may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, it may be necessary to consider this factor in dose selection; it may be useful to monitor renal function [see Dosage and Administration (2.3), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

Consider a reduced dose and/or dosing frequency of WELLBUTRIN in patients with renal impairment (Glomerular Filtration Rate: <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) and Clinical Pharmacology (12.3)].

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) and Clinical Pharmacology (12.3)].

DRUG ABUSE AND DEPENDENCE

Bupropion is not a controlled substance.

Humans: Controlled clinical trials conducted in normal volunteers, in subjects with a history of multiple drug abuse, and in depressed subjects showed some increase in motor activity and agitation/excitement.

In a population of individuals experienced with drugs of abuse, a single dose of 400 mg of bupropion produced mild amphetamine‑like activity as compared with placebo on the Morphine‑Benzedrine Subscale of the Addiction Research Center Inventories (ARCI) and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.

Findings in clinical trials, however, are not known to reliably predict the abuse potential of drugs. Nonetheless, evidence from single‑dose trials does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be significantly reinforcing to amphetamine or CNS stimulant abusers. However, higher doses (that could not be tested because of the risk of seizure) might be modestly attractive to those who abuse CNS stimulant drugs.

Animals: Studies in rodents and primates demonstrated that bupropion exhibits some pharmacologic actions common to psychostimulants. In rodents, it has been shown to increase locomotor activity, elicit a mild stereotyped behavior response, and increase rates of responding in several schedule‑controlled behavior paradigms. In primate models assessing the positive reinforcing effects of psychoactive drugs, bupropion was self-administered intravenously. In rats, bupropion produced amphetamine-like and cocaine-like discriminative stimulus effects in drug discrimination paradigms used to characterize the subjective effects of psychoactive drugs.

OVERDOSAGE

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.

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.

WELLBUTRIN DESCRIPTION

WELLBUTRIN (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, 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:

WELLBUTRIN is supplied for oral administration as 75‑mg (yellow‑gold) and 100‑mg (red) film‑coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: 75‑mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100‑mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

CLINICAL PHARMACOLOGY

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.

Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half-life (±SD) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days.

Absorption: The absolute bioavailability of WELLBUTRIN in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.

In humans, following oral administration of WELLBUTRIN, peak plasma bupropion concentrations are usually achieved within 2 hours. Plasma bupropion concentrations are dose‑proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma level is maintained in chronic use.

Distribution: In vitro tests show that bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.

Metabolism: Bupropion is extensively metabolized in humans. Three metabolites are active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl group. In vitro findings suggest that CYP2B6 is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 enzymes are not involved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glycine conjugate of meta-chlorobenzoic acid, which is then excreted as the major urinary metabolite. The potency and toxicity of the metabolites relative to bupropion have not been fully characterized. However, it has been demonstrated in an antidepressant screening test in mice that hydroxybupropion is one‑half as potent as bupropion, while threohydrobupropion and erythrohydrobupropion are 5-fold less potent than bupropion. This may be of clinical importance because the plasma concentrations of the metabolites are as high as or higher than those of bupropion.

Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 3 hours after administration of WELLBUTRIN and are approximately 10 times the peak level of the parent drug at steady state. The elimination half‑life of hydroxybupropion is approximately 20 (±5) hours, and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion metabolites are similar to that of the hydroxybupropion metabolite. However, their elimination half‑lives are longer, 33 (±10) and 37 (±13) hours, respectively, and steady‑state AUCs are 1.5 and 7 times that of bupropion, respectively.

Bupropion and its metabolites exhibit linear kinetics following chronic administration of 300 to 450 mg per day.

Elimination: Following oral administration of 200 mg of ¹⁴C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. Only 0.5% of the oral dose was excreted as unchanged bupropion.

Population Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of bupropion. The elimination of the major metabolites of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.

Renal Impairment: There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-trial comparison between normal subjects and subjects with end-stage renal failure demonstrated that the parent drug C_max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for subjects with end-stage renal failure. A second trial, comparing normal subjects and subjects with moderate‑to‑severe renal impairment (GFR 30.9 10.8 mL/min) showed that after a single 150-mg dose of sustained-release bupropion, exposure to bupropion was approximately 2-fold higher in subjects with impaired renal function, while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. The elimination of the major metabolites of bupropion may be reduced by impaired renal function. WELLBUTRIN should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered [see Use in Specific Populations (8.6)].

Hepatic Impairment: The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose trials, one in subjects with alcoholic liver disease and one in subjects with mild-to-severe cirrhosis. The first trial demonstrated that the half‑life of hydroxybupropion was significantly longer in 8 subjects with alcoholic liver disease than in 8 healthy volunteers (32 ± 14 hours versus 21 ± 5 hours, respectively). Although not statistically significant, the AUCs for bupropion and hydroxybupropion were more variable and tended to be greater (by 53% to 57%) in volunteers with alcoholic liver disease. The differences in half‑life for bupropion and the other metabolites in the 2 groups were minimal.

The second trial demonstrated no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 subjects with mild-to-moderate hepatic cirrhosis compared with 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, C_max, and T_max) and its active metabolites (t_½) in subjects with mild-to-moderate hepatic cirrhosis. In subjects with severe hepatic cirrhosis, significant alterations in the pharmacokinetics of bupropion and its metabolites were seen (Table 3).

^a

= Difference

Left Ventricular Dysfunction: During a chronic dosing trial with bupropion in 14 depressed subjects with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), there was no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared with healthy volunteers.

Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady‑state bupropion concentrations from several depression efficacy trials involving subjects dosed in a range of 300 to 750 mg per day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single‑dose pharmacokinetic trial demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects. These data suggest there is no prominent effect of age on bupropion concentration; however, another single- and multiple-dose pharmacokinetics trial suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites [see Use in Specific Populations (8.5)].

Gender: Pooled analysis of bupropion pharmacokinetic data from 90 healthy male and 90 healthy female volunteers revealed no sex-related differences in the peak plasma concentrations of bupropion. The mean systemic exposure (AUC) was approximately 13% higher in male volunteers compared with female volunteers. The clinical significance of this finding is unknown.

Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there were no statistically significant differences in C_max, half-life, T_max, AUC, or clearance of bupropion or its active metabolites between smokers and nonsmokers.

Drug Interactions: Potential for Other Drugs to Affect WELLBUTRIN: In vitro studies indicate that 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. In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the hydroxylation of bupropion.

Inhibitors of CYP2B6: Ticlopidine, Clopidogrel: In a trial in healthy male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily increased exposures (C_max and AUC) of bupropion by 40% and 60% for clopidogrel, and by 38% and 85% for ticlopidine, respectively. The exposures (C_max and AUC) of hydroxybupropion were decreased 50% and 52%, respectively, by clopidogrel, and 78% and 84%, respectively, by ticlopidine. This effect is thought to be due to the inhibition of the CYP2B6-catalyzed bupropion hydroxylation.

Prasugrel: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel increased bupropion C_max and AUC values by 14% and 18%, respectively, and decreased C_max and AUC values of hydroxybupropion, an active metabolite of bupropion, by 32% and 24%, respectively.

Cimetidine: The threohydrobupropion metabolite of bupropion does not appear to be produced by cytochrome P450 enzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of bupropion 300 mg with and without cimetidine 800 mg, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and C_max, respectively of the combined moieties of threohydrobupropion and erythrohydrobupropion.

Citalopram: Citalopram did not affect the pharmacokinetics of bupropion and its three metabolites.

Inducers of CYP2B6: Ritonavir and Lopinavir: In a healthy volunteer trial, ritonavir 100 mg twice daily reduced the AUC and C_max of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%. In a second healthy volunteer trial, ritonavir 600 mg twice daily decreased the AUC and the C_max of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%.

In another healthy volunteer trial, lopinavir 400 mg/ritonavir 100 mg twice daily decreased bupropion AUC and C_max by 57%. The AUC and C_max of hydroxybupropion were decreased by 50% and 31%, respectively.

Efavirenz: In a trial in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and C_max of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas C_max of hydroxybupropion was increased by 50%.

Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion.

Potential for WELLBUTRIN to Affect Other Drugs

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

Drugs Metabolized by CYP2D6: In vitro, bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. In a clinical trial of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of CYP2D6, bupropion 300 mg per day followed by a single dose of 50 mg desipramine increased the C_max, AUC, and t_1/2 of desipramine by an average of approximately 2-, 5-, and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

Citalopram: Although citalopram is not primarily metabolized by CYP2D6, in one trial bupropion increased the C_max and AUC of citalopram by 30% and 40%, respectively.

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

NONCLINICAL TOXICOLOGY

Lifetime carcinogenicity studies were performed in rats and mice at bupropion doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 7 and 2 times the MRHD, respectively, on a mg/m² basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 2 to 7 times the MRHD on a mg/m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.

Bupropion produced a positive response (2 to 3 times control mutation rate) in 2 of 5 strains in the Ames bacterial mutagenicity assay. Bupropion produced an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenetic studies.

A fertility study in rats at doses up to 300 mg/kg/day revealed no evidence of impaired fertility.

CLINICAL STUDIES

The efficacy of WELLBUTRIN 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 WELLBUTRIN was 300 mg to 600 mg per day administered in 3 divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. The trial demonstrated the efficacy of WELLBUTRIN 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 WELLBUTRIN (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness of WELLBUTRIN for only the 450‑mg-per-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 per day of WELLBUTRIN. This trial demonstrated the efficacy of WELLBUTRIN 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 WELLBUTRIN in long‑term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials.

Table 4. Efficacy of WELLBUTRIN for the Treatment of Major Depressive Disorder

HOW SUPPLIED

WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride, are yellow‑gold, round, biconvex tablets printed with “WELLBUTRIN 75” in bottles of 100 (NDC 0173-0177-55).

WELLBUTRIN Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex tablets printed with “WELLBUTRIN 100” in bottles of 100 (NDC 0173-0178-55).

Store at room temperature, 20° to 25°C (68° to 77°F); excursions permitted between 15°C and 30°C (59°F and 86°F) [See USP Controlled Room Temperature]. Protect from light and moisture.

INFORMATION FOR PATIENTS

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 WELLBUTRIN 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 WELLBUTRIN?” is available for WELLBUTRIN. 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 WELLBUTRIN.

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 WELLBUTRIN is 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 WELLBUTRIN if they have a severe allergic reaction.

Seizure: Instruct patients to discontinue and not restart WELLBUTRIN 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 WELLBUTRIN contains the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that WELLBUTRIN 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 WELLBUTRIN may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that WELLBUTRIN does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. WELLBUTRIN 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 WELLBUTRIN 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 WELLBUTRIN is present in human milk in small amounts.

Storage Information: Instruct patients to store WELLBUTRIN at room temperature, between 59°F and 86°F (15°C to 30°C) and keep the tablets dry and out of the light.

Administration Information: Instruct patients to take WELLBUTRIN 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 WELLBUTRIN Tablets should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN can be taken with or without food.

 WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered trademarks of the GlaxoSmithKline group of companies. The other brands listed are trademarks of their respective owners and are not trademarks of the GlaxoSmithKline group of companies. The makers of these brands are not affiliated with and do not endorse the GlaxoSmithKline group of companies or its products. Manufactured for: GlaxoSmithKline Research Triangle Park, NC 27709 ©2013, GlaxoSmithKline group of companies. All rights reserved.

WLT:10PI

SPL MEDGUIDE

Medication Guide

WELLBUTRIN^® (WELL byu-trin)

(bupropion hydrochloride) Tablets

Read this Medication Guide carefully before you start taking WELLBUTRIN and each time you get a refill. There may be new information. This information does not take the place of talking with your healthcare provider about your medical condition or your treatment. If you have any questions about WELLBUTRIN, ask your healthcare provider or pharmacist.

IMPORTANT: Be sure to read the three sections of this Medication Guide. The first section is about the risk of suicidal thoughts and actions with antidepressant medicines; the second section is about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with medicines used to quit smoking; and the third section is entitled “What Other Important Information Should I Know About WELLBUTRIN?”

Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions

This section of the Medication Guide is only about the risk of suicidal thoughts and actions with antidepressant medicines. Talk to your healthcare provider or your family member’s healthcare provider about:

•all risks and benefits of treatment with antidepressant medicines•all treatment choices for depression or other serious mental illness

What is the most important information I should know about antidepressant medicines, depression and other serious mental illnesses, and suicidal thoughts or actions?

•

Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment.

•

Depression or other serious mental illnesses are the most important causes of suicidal thoughts and actions. Some people may have a particularly high risk of having suicidal thoughts or actions.

These include people who have (or have a family history of) bipolar illness (also called manic-depressive illness) or suicidal thoughts or actions. •

How can I watch for and try to prevent suicidal thoughts and actions in myself or a family member?

•Pay close attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings. This is very important when an antidepressant medicine is started or when the dose is changed.•Call your healthcare provider right away to report new or sudden changes in mood, behavior, thoughts, or feelings.•Keep all follow-up visits with your healthcare provider as scheduled. Call the healthcare provider between visits as needed, especially if you have concerns about symptoms.

Call your healthcare provider right away if you or your family member has any of the following symptoms, especially if they are new, worse, or worry you:

What else do I need to know about antidepressant medicines?

•

Never stop an antidepressant medicine without first talking to a healthcare provider.

Stopping an antidepressant medicine suddenly can cause other symptoms.•

Antidepressants are medicines used to treat depression and other illnesses

. It is important to discuss all the risks of treating depression and also the risks of not treating it. Patients and their families or other caregivers should discuss all treatment choices with the healthcare provider, not just the use of antidepressants.•

Antidepressant medicines have other side effects.

Talk to the healthcare provider about the side effects of the medicine prescribed for you or your family member.•

Antidepressant medicines can interact with other medicines.

Know all of the medicines that you or your family member takes. Keep a list of all medicines to show the healthcare provider. Do not start new medicines without first checking with your healthcare provider.

It is not known if WELLBUTRIN is safe and effective in children under the age of 18.

Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions

This section of the Medication Guide is only about the risk of changes in thinking and behavior, depression and suicidal thoughts or actions with drugs used to quit smoking.

Although WELLBUTRIN is not a treatment for quitting smoking, it contains the same active ingredient (bupropion hydrochloride) as ZYBAN^® which is used to help patients quit smoking.

Some people have had changes in behavior, hostility, agitation, depression, suicidal thoughts or actions while taking bupropion to help them quit smoking. These symptoms can develop during treatment with bupropion or after stopping treatment with bupropion.

If you, your family member, or your caregiver notice agitation, hostility, depression, or changes in thinking or behavior that are not typical for you, or you have any of the following symptoms, stop taking bupropion and call your healthcare provider right away:

When you try to quit smoking, with or without bupropion, you may have symptoms that may be due to nicotine withdrawal, including urge to smoke, depressed mood, trouble sleeping, irritability, frustration, anger, feeling anxious, difficulty concentrating, restlessness, decreased heart rate, and increased appetite or weight gain. Some people have even experienced suicidal thoughts when trying to quit smoking without medication. Sometimes quitting smoking can lead to worsening of mental health problems that you already have, such as depression.

Before taking bupropion, tell your healthcare provider if you have ever had depression or other mental illnesses. You should also tell your healthcare provider about any symptoms you had during other times you tried to quit smoking, with or without bupropion.

What Other Important Information Should I Know About WELLBUTRIN?

•

Seizures: There is a chance of having a seizure (convulsion, fit) with WELLBUTRIN, especially in people:

∘with certain medical problems.∘who take certain medicines.

The chance of having seizures increases with higher doses of WELLBUTRIN. For more information, see the sections “Who should not take WELLBUTRIN?” and “What should I tell my healthcare provider before taking WELLBUTRIN?” Tell your healthcare provider about all of your medical conditions and all the medicines you take. Do not take any other medicines while you are taking WELLBUTRIN unless your healthcare provider has said it is okay to take them.

If you have a seizure while taking WELLBUTRIN, stop taking the tablets and call your healthcare provider right away. Do not take WELLBUTRIN again if you have a seizure.

•

High blood pressure (hypertension). Some people get high blood pressure that can be severe, while taking WELLBUTRIN

. The chance of high blood pressure may be higher if you also use nicotine replacement therapy (such as a nicotine patch) to help you stop smoking.•

Manic episodes.

Some people may have periods of mania while taking WELLBUTRIN, including:∘Greatly increased energy∘Severe trouble sleeping∘Racing thoughts∘Reckless behavior∘Unusually grand ideas∘Excessive happiness or irritability∘Talking more or faster than usual

If you have any of the above symptoms of mania, call your healthcare provider.

•

Unusual thoughts or behaviors.

Some patients have unusual thoughts or behaviors while taking WELLBUTRIN, including delusions (believe you are someone else), hallucinations (seeing or hearing things that are not there), paranoia (feeling that people are against you), or feeling confused. If this happens to you, call your healthcare provider.•

Severe allergic reactions. Some people can have severe allergic reactions to WELLBUTRIN. Stop taking WELLBUTRIN and call your healthcare provider right away

if you get a rash, itching, hives, fever, swollen lymph glands, painful sores in the mouth or around the eyes, swelling of the lips or tongue, chest pain, or have trouble breathing. These could be signs of a serious allergic reaction.

What is WELLBUTRIN?

WELLBUTRIN is a prescription medicine used to treat adults with a certain type of depression called major depressive disorder.

Who should not take WELLBUTRIN?

Do not take WELLBUTRIN if you

•have or had a seizure disorder or epilepsy.•have or had an eating disorder such as anorexia nervosa or bulimia.•

are taking any other medicines that contain bupropion, including ZYBAN (used to help people stop smoking) APLENZIN^®, FORFIVO XL^™, WELLBUTRIN SR^®, or WELLBUTRIN XL^®

. Bupropion is the same active ingredient that is in WELLBUTRIN.•drink a lot of alcohol and abruptly stop drinking, or use medicines called sedatives (these make you sleepy), benzodiazepines, or anti-seizure medicines, and you stop using them all of a sudden.•take a monoamine oxidase inhibitor (MAOI). Ask your healthcare provider or pharmacist if you are not sure if you take an MAOI, including the antibiotic linezolid.∘do not take an MAOI within 2 weeks of stopping WELLBUTRIN unless directed to do so by your healthcare provider.∘do not start WELLBUTRIN if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider.•are allergic to the active ingredient in WELLBUTRIN, bupropion, or to any of the inactive ingredients. See the end of this Medication Guide for a complete list of ingredients in WELLBUTRIN.

What should I tell my healthcare provider before taking WELLBUTRIN?

Tell your healthcare provider if you have ever had depression, suicidal thoughts or actions, or other mental health

problems. See “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions.”

Tell your healthcare provider about your other medical conditions including if you:

•have liver problems, especially cirrhosis of the liver. •have kidney problems.•have, or have had, an eating disorder, such as anorexia nervosa or bulimia.•have had a head injury.•have had a seizure (convulsion, fit).•have a tumor in your nervous system (brain or spine).•have had a heart attack, heart problems, or high blood pressure.•are a diabetic taking insulin or other medicines to control your blood sugar.•drink alcohol.•abuse prescription medicines or street drugs.•are pregnant or plan to become pregnant.•are breastfeeding. WELLBUTRIN passes into your milk in small amounts.

Tell your healthcare provider about all the medicines you take, including prescription, over-the-counter medicines, vitamins, and herbal supplements. Many medicines increase your chances of having seizures or other serious side effects if you take them while you are taking WELLBUTRIN.

How should I take WELLBUTRIN?

•Take WELLBUTRIN exactly as prescribed by your healthcare provider.•Take WELLBUTRIN at the same time each day.•Take your doses of WELLBUTRIN at least 6 hours apart.•

Do not chew, cut, or crush WELLBUTRIN tablets.

•You may take WELLBUTRIN with or without food.•If you miss a dose, do not take an extra dose to make up for the dose you missed. Wait and take your next dose at the regular time.

This is very important.

Too much WELLBUTRIN can increase your chance of having a seizure.•If you take too much WELLBUTRIN, or overdose, call your local emergency room or poison control center right away.•

Do not take any other medicines while taking WELLBUTRIN unless your healthcare provider has told you it is okay.

•If you are taking WELLBUTRIN for the treatment of major depressive disorder, it may take several weeks for you to feel that WELLBUTRIN is working. Once you feel better, it is important to keep taking WELLBUTRIN exactly as directed by your healthcare provider. Call your healthcare provider if you do not feel WELLBUTRIN is working for you.•Do not change your dose or stop taking WELLBUTRIN without talking with your healthcare provider first.

What should I avoid while taking WELLBUTRIN?

•Limit or avoid using alcohol during treatment with WELLBUTRIN. If you usually drink a lot of alcohol, talk with your healthcare provider before suddenly stopping. If you suddenly stop drinking alcohol, you may increase your risk of having seizures.•Do not drive a car or use heavy machinery until you know how WELLBUTRIN affects you. WELLBUTRIN can affect your ability to do these things safely.

What are possible side effects of WELLBUTRIN?

See “What Other Important Information Should I Know About WELLBUTRIN?”

WELLBUTRIN can cause serious side effects.

The most common side effects of WELLBUTRIN include:

•Nervousness•Dry mouth•Constipation•Headache•Nausea or vomiting•Dizziness•Heavy sweating•Shakiness (tremor)•Trouble sleeping•Blurred vision•Fast heartbeat

If you have nausea, take your medicine with food. If you have trouble sleeping, do not take your medicine too close to bedtime.

Tell your healthcare provider right away about any side effects that bother you.

These are not all the possible side effects of WELLBUTRIN. For more information, ask your healthcare provider or pharmacist.

Call your healthcare provider for medical advice about side effects. You may report side effects to FDA at 1‑800-FDA-1088.

You may also report side effects to GlaxoSmithKline at 1-888-825-5249.

How should I store WELLBUTRIN?

•Store WELLBUTRIN at room temperature between 59°F and 86°F (15°C to 30°C). •Keep WELLBUTRIN Tablets dry and out of the light.

Keep WELLBUTRIN and all medicines out of the reach of children.

General Information about WELLBUTRIN.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use WELLBUTRIN for a condition for which it was not prescribed. Do not give WELLBUTRIN to other people, even if they have the same symptoms you have. It may harm them.

If you take a urine drug screening test, WELLBUTRIN may make the test result positive for amphetamines. If you tell the person giving you the drug screening test that you are taking WELLBUTRIN, they can do a more specific drug screening test that should not have this problem.

This Medication Guide summarizes important information about WELLBUTRIN. If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about WELLBUTRIN that is written for healthcare professionals.

For more information about WELLBUTRIN, go to www.wellbutrin.com or call 1-888-825-5249.

What are the ingredients in WELLBUTRIN?

Active ingredient: bupropion hydrochloride.

Inactive ingredients: 75‑mg tablet – D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100‑mg tablet – FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and ZYBAN are registered trademarks of the GlaxoSmithKline group of companies.

The other brands listed are trademarks of their respective owners and are not trademarks of the GlaxoSmithKline group of companies. The makers of these brands are not affiliated with and do not endorse the GlaxoSmithKline group of companies or its products.

Manufactured for:

 GlaxoSmithKline Research Triangle Park, NC 27709 ©2013, GlaxoSmithKline group of companies. All rights reserved. December 2013

WLT: 9MG

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

DRUG: WELLBUTRIN

GENERIC: bupropion hydrochloride

DOSAGE: TABLET, FILM COATED

ADMINSTRATION: ORAL

NDC: 52125-825-02

ACTIVE INGREDIENT(S):

• BUPROPION HYDROCHLORIDE 100mg in 1

INACTIVE INGREDIENT(S):

• FD&C RED NO. 40
• TITANIUM DIOXIDE
• FD&C YELLOW NO. 6
• TALC
• CELLULOSE, MICROCRYSTALLINE
• HYPROMELLOSES
• HYDROXYPROPYL CELLULOSE (TYPE H)
• POLYETHYLENE GLYCOLS

COLOR: red

SHAPE: ROUND

SCORE: No score

SIZE: 12 mm

IMPRINT: WELLBUTRIN;100

PACKAGING: 30 in 1 BLISTER PACK