BUPROPION HYDROCHLORIDE tablet, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
BUPROPION HYDROCHLORIDE (UNII: ZG7E5POY8O) (BUPROPION - UNII:01ZG3TPX31)
Available from:
Sun Pharmaceutical Industries, Inc.
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Bupropion hydrochloride extended-release tablets, USP (XL) are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM). The efficacy of the immediate-release formulation of bupropion was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with MDD. The efficacy of the sustained-release (SR) formulation of bupropion in the maintenance treatment of MDD was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded to bupropion in an 8-week study of acute treatment [seeClinical Studies (14.1)] . Bupropion hydrochloride extended-release tablets, USP (XL) are indicated for the prevention of seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD). The efficacy of bupropion hydrochloride extended-release tablets in the prevention of seasonal major depressive episodes was established in 3 placebo-controlle
Product summary:
Bupropion Hydrochloride Extended-Release Tablets, USP (XL), 150 mg of bupropion hydrochloride, USP are white to pale yellow, round, film-coated tablets imprinted with ‘L2’ in black ink on one side and plain on the other side and are supplied as follows: Store at 20ºC to 25ºC (68ºF to 77ºF). [See USP Controlled Room Temperature.]
Authorization status:
Abbreviated New Drug Application
Authorization number:
63304-723-05, 63304-723-30, 63304-723-90

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BUPROPION HYDROCHLORIDE- bupropion hydrochloride tablet, extended release

Sun Pharmaceutical Industries, Inc.

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use BUPROPION HYDROCHLORIDE

EXTENDED-RELEASE TABLETS (XL) safely and effectively. See full prescribing information for BUPROPION

HYDROCHLORIDE EXTENDED-RELEASE TABLETS (XL).

BUPROPION HYDROCHLORIDE extended-release tablets, for oral use

Initial U.S. Approval: 1985

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

See full prescribing information for complete boxed warning.

INDICATIONS AND USAGE

Bupropion hydrochloride extended-release tablets, USP (XL) is an aminoketone antidepressant, indicated for: (1)

DOSAGE AND ADMINISTRATION

General: (2)

Seasonal Affective Disorder (2)

Hepatic Impairment (2)

Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing. (2.6, 8.7) (2)

Renal Impairment (2)

DOSAGE FORMS AND STRENGTHS

Extended-release tablets: 150 mg (3) (3)

CONTRAINDICATIONS

Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking

antidepressants. Monitor for worsening and emergence of suicidal thoughts and behaviors. (5.1)

treatment of major depressive disorder (MDD) (1.1)

prevention of seasonal affective disorder (SAD) (1.2)

Increase dose gradually to reduce seizure risk. (2.1, 5.3)

Periodically reassess the dose and need for maintenance treatment. (2.2) Major Depressive Disorder

Starting dose: 150 mg once daily. Usual target dose: 300 mg once daily (2.2)

After 4 days, may increase the dose to 300 mg once daily. (2.2)

Initiate treatment in the autumn prior to onset of seasonal depressive symptoms. (2.3)

Starting dose: 150 mg once daily. Usual target dose: 300 mg once daily. (2.3)

After one week, may increase the dose to 300 mg once daily. (2.3)

Continue treatment through the winter season. (2.3)

Moderate to severe hepatic impairment: 150 mg every other day (2.6)

Consider reducing the dose and/or frequency of dosing. (2.7, 8.6)

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 bupropion

hydrochloride (XL) or within 14 days of stopping treatment with bupropion hydrochloride (XL). Do not use bupropion

hydrochloride (XL) within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not

start bupropion hydrochloride (XL) in a patient who is being treated with linezolid or intravenous methylene blue. (4,

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

Most common adverse reactions are (incidence ≥ 5%; ≥ 2 times placebo rate): dry mouth, nausea, insomnia, dizziness,

pharyngitis, abdominal pain, agitation, anxiety, tremor, palpitation, sweating, tinnitus, myalgia, anorexia, urinary frequency,

rash. (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-406-

7984 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

See 17 for PATIENT COUNSELING INFORMATION.

Revised: 12/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder (MDD)

1.2 Seasonal Affective Disorder (SAD)

2 DOSAGE AND ADMINISTRATION

2.1 General Instructions for Use

2.2 Dosage for Major Depressive Disorder (MDD)

2.3 Dosage for Seasonal Affective Disorder (SAD)

7.6)

Known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride (XL) (4, 5.8)

Neuropsychiatric Adverse Events During Smoking Cessation: Postmarketing reports of serious or clinically

significant neuropsychiatric adverse events have included changes in mood (including depression and mania),

psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as

well as suicidal ideation, suicide attempt, and completed suicide. Observe patients attempting to quit smoking with

bupropion hydrochloride (XL) for the occurrence of such symptoms and instruct them to discontinue bupropion

hydrochloride (XL) and contact a healthcare provider if they experience such adverse events. (5.2)

Seizure Risk: The risk is dose-related. Can minimize risk by limiting daily dose to 450 mg and gradually increasing the

dose. Discontinue if seizure occurs. (4, 5.3, 7.3)

Hypertension: bupropion hydrochloride (XL) 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)

CYP2B6 inducers: Dose increase may be necessary if coadministered with CYP2B6 inducers (e.g., ritonavir,

lopinavir, efavirenz, carbamazepine, phenobarbital, and phenytoin) based on clinical exposure, but should not exceed

the maximum recommended dose. (7.1)

Drugs metabolized by CYP2D6: Bupropion inhibits CYP2D6 and can increase concentrations of: antidepressants

(e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, sertraline), antipsychotics (e.g.,

haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g.,

propafenone, flecainide). Consider dose reduction when using with bupropion. (7.2)

Drugs that lower seizure threshold: Dose bupropion hydrochloride (XL) with caution. (5.3, 7.3)

Dopaminergic Drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with bupropion

hydrochloride (XL). (7.4)

MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with bupropion hydrochloride

(XL). (7.6)

Drug-laboratory test interactions: bupropion hydrochloride (XL) can cause false-positive urine test results for

amphetamines. (7.7)

2.4 Switching Patients from Bupropion Hydrochloride Tablets or from Bupropion Hydrochloride

SR Sustained-Release Tablets

2.5 To Discontinue Bupropion Hydrochloride (XL), Taper the Dose

2.6 Dosage Adjustment in Patients with Hepatic Impairment

2.7 Dose Adjustment in Patients with Renal Impairment

2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

2.9 Use of Bupropion Hydrochloride Extended-Release Tablets (XL) with Reversible MAOIs such

as Linezolid or Methylene Blue

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

5.2 Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment

5.3 Seizure

5.4 Hypertension

5.5 Activation of Mania/Hypomania

5.6 Psychosis and Other Neuropsychiatric Reactions

5.7 Angle-Closure Glaucoma

5.8 Hypersensitivity Reactions

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride (XL)

7.2 Potential for Bupropion Hydrochloride (XL) to Affect Other Drugs

7.3 Drugs That Lower Seizure Threshold

7.4 Dopaminergic Drugs (Levodopa and Amantadine)

7.5 Use with Alcohol

7.6 MAO Inhibitors

7.7 Drug-Laboratory Test Interactions

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

9.2 Abuse

10 OVERDOSAGE

10.1 Human Overdose Experience

10.2 Overdosage Management

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Major Depressive Disorder

14.2 Seasonal Affective Disorder

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

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 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)].

1 INDICATIONS AND USAGE

1.1 Major Depressive Disorder (MDD)

Bupropion hydrochloride extended-release tablets, USP (XL) are indicated for the treatment of major

depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).

The efficacy of the immediate-release formulation of bupropion was established in two 4-week

controlled inpatient trials and one 6-week controlled outpatient trial of adult patients with MDD. The

efficacy of the sustained-release (SR) formulation of bupropion in the maintenance treatment of MDD

was established in a long-term (up to 44 weeks), placebo-controlled trial in patients who had responded

to bupropion in an 8-week study of acute treatment [seeClinical Studies (14.1)].

1.2 Seasonal Affective Disorder (SAD)

Bupropion hydrochloride extended-release tablets, USP (XL) are indicated for the prevention of

seasonal major depressive episodes in patients with a diagnosis of seasonal affective disorder (SAD).

The efficacy of bupropion hydrochloride extended-release tablets in the prevention of seasonal major

depressive episodes was established in 3 placebo-controlled trials in adult outpatients with a history of

MDD with an autumn-winter seasonal pattern as defined in the DSM [see Clinical Studies (14.2)].

2 DOSAGE AND ADMINISTRATION

2.1 General Instructions for Use

To minimize the risk of seizure, increase the dose gradually [see Warnings and Precautions (5.3)].

Bupropion hydrochlorideextended-release tablets (XL) should be swallowed whole and not crushed,

divided, or chewed. Bupropion hydrochloride extended-release tablets (XL) should be administered in

the morning and may be taken with or without food.

2.2 Dosage for Major Depressive Disorder (MDD)

The recommended starting dose for MDD is 150 mg once daily in the morning. After 4 days of dosing,

the dose may be increased to the target dose of 300 mg once daily in the morning.

Sections or subsections omitted from the full prescribing information are not listed.

It is generally agreed that acute episodes of depression require several months or longer of

antidepressant treatment beyond the response in the acute episode. It is unknown whether the bupropion

hydrochloride (XL) dose needed for maintenance treatment is identical to the dose that provided an

initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for

such treatment.

2.3 Dosage for Seasonal Affective Disorder (SAD)

The recommended starting dose for SAD is 150 mg once daily. After 7 days of dosing, the dose may be

increased to the target dose of 300 mg once daily in the morning. Doses above 300 mg of bupropion

hydrochloride extended-release were not assessed in the SAD trials.

For the prevention of seasonal MDD episodes associated with SAD, initiate bupropion hydrochloride

(XL) in the autumn, prior to the onset of depressive symptoms. Continue treatment through the winter

season. Taper and discontinue bupropion hydrochloride (XL) in early spring. For patients treated with

300 mg per day, decrease the dose to 150 mg once daily before discontinuing bupropion hydrochloride

(XL). Individualize the timing of initiation, and duration of treatment should be individualized, based on

the patient’s historical pattern of seasonal MDD episodes.

2.4 Switching Patients from Bupropion Hydrochloride Tablets or from Bupropion Hydrochloride

SR Sustained-Release Tablets

When switching patients from bupropion hydrochloride Tablets to bupropion hydrochloride extended-

release tablets, USP (XL) or from bupropion hydrochloride SR Sustained-Release Tablets to bupropion

hydrochloride extended-release tablets, USP (XL), give the same total daily dose when possible.

2.5 To Discontinue Bupropion Hydrochloride (XL), Taper the Dose

When discontinuing treatment in patients treated with bupropion hydrochloride (XL) 300 mg once daily,

decrease the dose to 150 mg once daily prior to discontinuation.

2.6 Dosage Adjustment in Patients with Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose is

150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider

reducing the dose and/or frequency of dosing [see Use in Specific Populations (8.7) and Clinical

Pharmacology (12.3)].

2.7 Dose Adjustment in Patients with Renal Impairment

Consider reducing the dose and/or frequency of bupropion hydrochloride in patients with renal

impairment (glomerular filtration rate less than 90 mL/min) [see Use in Specific Populations (8.6) and

Clinical Pharmacology (12.3)].

2.8 Switching a Patient to or from a Monoamine Oxidase Inhibitor (MAOI) Antidepressant

At least 14 days should elapse between discontinuation of an MAOI intended to treat depression and

initiation of therapy with bupropion hydrochloride extended-release tablets (XL). Conversely, at least

14 days should be allowed after stopping bupropion hydrochloride extended-release tablets (XL)

before starting an MAOI antidepressant [see Contraindications (4) and Drug Interactions (7.6)].

2.9 Use of Bupropion Hydrochloride Extended-Release Tablets (XL) with Reversible MAOIs

such as Linezolid or Methylene Blue

Do not start bupropion hydrochloride extended-release tablets (XL) in a patient who is being treated

with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase

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)].

In some cases, a patient already receiving therapy with bupropion hydrochloride extended-release

tablets (XL) may require urgent treatment with linezolid or intravenous methylene blue. If acceptable

alternatives to linezolid or intravenous methylene blue treatment are not available and the potential

benefits of linezolid or intravenous methylene blue treatment are judged to outweigh the risks of

hypertensive reactions in a particular patient, bupropion hydrochloride extended-release tablets (XL)

should be stopped promptly, and linezolid or intravenous methylene blue can be administered. The

patient should be monitored for 2 weeks or until 24 hours after the last dose of linezolid or intravenous

methylene blue, whichever comes first. Therapy with bupropion hydrochloride extended-release

tablets (XL) 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 per kg with bupropion hydrochloride extended-

release tablets (XL) 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)].

3 DOSAGE FORMS AND STRENGTHS

Bupropion Hydrochloride Extended-Release Tablets, USP (XL), 150 mg of bupropion hydrochloride,

are white to pale yellow, round, film-coated tablets imprinted with ‘‘L2’’ in black ink on one side and

plain on the other side.

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults

Patients with major depressive disorder (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

Bupropion hydrochloride (XL) is contraindicated in patients with seizure disorder.

B upropion hydrochloride (XL) 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 bupropion hydrochloride (XL) [see Warnings and Precautions (5.3)].

B upropion hydrochloride (XL) 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 b upropion

hydrochloride (XL) or within 14 days of discontinuing treatment with b upropion hydrochloride

(XL) is contraindicated. There is an increased risk of hypertensive reactions when b upropion

hydrochloride (XL) is used concomitantly with MAOIs. The use of b upropion hydrochloride

(XL) within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting b

upropion hydrochloride (XL) in a patient treated with reversible MAOIs such as linezolid or

intravenous methylene blue is contraindicated [see Dosage and Administration (2.9), Warnings and

Precautions (5.4) and Drug Interactions (7.6)] .

B upropion hydrochloride extended-release tablets (XL) are contraindicated in patients with

known hypersensitivity to bupropion or other ingredients of b upropion hydrochloride extended-

release tablets (XL). Anaphylactoid/anaphylactic reactions and Stevens-Johnson Syndrome have

been reported [see Warnings and Precautions (5.8)].

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 major depressive

disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk

of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction

with antidepressants compared to 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 4400 patients. 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 patients. There was considerable variation in risk of

suicidality among drugs, but a tendency toward an increase in the younger patients 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 1000 patients treated) are provided in Table 1.

Age Range

Drug-Placebo Difference in Number of Cases

of Suicidality per 1000 Patients Treated

Increases Compared to Placebo

< 18 years

14 additional cases

18 to 24 years

5 additional cases

Decreases Compared to Placebo

25 to 64 years

1 fewer case

≥ 65 years

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 and Use in Specific Populations (8.4)].

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

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 Patients

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 major depressive

disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the

need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior,

and the other symptoms described above, as well as the emergence of suicidality, and to report

such symptoms immediately to healthcare providers. Such monitoring should include daily

observation by families and caregivers. Prescriptions for bupropion hydrochloride extended-

release tablets (XL) 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 Adverse Events and Suicide Risk in Smoking Cessation Treatment

Bupropion hydrochloride (XL) is not approved for smoking cessation treatment; however, bupropion

HCl sustained-release (SR) is approved for this use. Serious neuropsychiatric adverse events have

been reported in patients taking bupropion for smoking cessation. These postmarketing reports have

included changes in mood (including depression and mania), psychosis, hallucinations, paranoia,

delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and panic, as well as suicidal

ideation, suicide attempt, and completed suicide [see Adverse Reactions (6.2)]. Some patients who

stopped smoking may have been experiencing symptoms of nicotine withdrawal, including depressed

mood. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a

smoking cessation attempt without medication. However, some of these adverse events occurred in

patients taking bupropion who continued to smoke.

Neuropsychiatric adverse events occurred in patients without and with pre-existing psychiatric disease;

some patients experienced worsening of their psychiatric illnesses. Observe patients for the

occurrence of neuropsychiatric adverse events. Advise patients and caregivers that the patient should

stop taking bupropion hydrochloride(XL) and contact a healthcare provider immediately if agitation,

depressed mood, or changes in behavior or thinking that are not typical for the patient are observed, or

if the patient develops suicidal ideation or suicidal behavior. The healthcare provider should evaluate

the severity of the adverse events and the extent to which the patient is benefiting from treatment, and

consider options including continued treatment under closer monitoring, or discontinuing treatment. In

many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported.

However, the symptoms persisted in some cases; therefore, ongoing monitoring and supportive care

should be provided until symptoms resolve.

5.3 Seizure

Bupropion hydrochloride (XL) can cause seizure. The risk of seizure is dose-related. The dose should

not exceed 300 mg once daily. Increase the dose gradually. Discontinue bupropion hydrochloride (XL)

and do not restart treatment if the patient experiences a seizure.

The risk of seizures is also related to patient factors, clinical situations, and concomitant medications

that lower the seizure threshold. Consider these risks before initiating treatment with bupropion

hydrochloride (XL). Bupropion hydrochloride (XL) is contraindicated in patients with a seizure

disorder or conditions that increase the risk of seizure (e.g., severe head injury, arteriovenous

malformation, CNS tumor or CNS infection, severe stroke, anorexia nervosa or bulimia, or abrupt

discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications

(4)]. The following conditions can also increase the risk of seizure: 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), or 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, excessive

use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Incidence of Seizure with Bupropion Use

The incidence of seizure with bupropion hydrochloride (XL) has not been formally evaluated in clinical

trials. In studies using bupropion HCl sustained-release (SR) up to 300 mg per day the incidence of

seizure was approximately 0.1% (1/1000 patients). In a large prospective, follow-up study, the seizure

incidence was approximately 0.4% (13/3200) with bupropion HCl immediate-release in the range of

300 mg to 450 mg per day.

Additional data accumulated for bupropion immediate-release suggests that the estimated seizure

incidence increases almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced if

the bupropion hydrochloride (XL) dose does not exceed 450 mg once daily and the titration rate is

gradual.

5.4 Hypertension

Treatment with bupropion hydrochloride (XL) can result in elevated blood pressure and hypertension.

Assess blood pressure before initiating treatment with bupropion hydrochloride (XL), and monitor

periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride (XL) 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 (SR) of bupropion HCl, nicotine

transdermal system (NTS), the combination of sustained-release bupropion (SR) 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 (SR) and NTS. In this trial, 6.1% of

subjects treated with the combination of sustained-release bupropion (SR) and NTS had treatment-

emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release

bupropion (SR), 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 (SR) 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 (SR) or

placebo. Monitoring of blood pressure is recommended in patients who receive the combination of

bupropion and nicotine replacement.

In the 3 trials of bupropion HCl extended-release in seasonal affective disorder, there were significant

elevations in blood pressure. Hypertension was reported as an adverse reaction for 2% of the

bupropion group (11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients treated

with bupropion discontinued from the study because they developed hypertension. None of the placebo

group discontinued because of hypertension. The mean increase in systolic blood pressure was 1.3

mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference was statistically

significant (p = 0.013). The mean increase in diastolic blood pressure was 0.8 mmHg in the bupropion

group and 0.1 mmHg in the placebo group. The difference was not statistically significant (p = 0.075).

In the SAD trials, 82% of patients were treated with 300 mg per day, and 18% were treated with 150 mg

per day. The mean daily dose was 270 mg per day. The mean duration of bupropion exposure was 126

days.

In a clinical trial of bupropion immediate-release in MDD subjects with stable congestive heart failure

(CHF) (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 studies assessing

the safety of bupropion in patients with a recent history of myocardial infarction or unstable cardiac

disease.

5.5 Activation of Mania/Hypomania

Antidepressant treatment can precipitate a manic, mixed, or hypomanic manic episode. The risk appears

to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. Prior to

initiating bupropion hydrochloride (XL), screen patients for a history of bipolar disorder and the

presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or

depression). Bupropion hydrochloride (XL) is not approved for the treatment of bipolar depression.

5.6 Psychosis and Other Neuropsychiatric Reactions

Depressed patients treated with bupropion have had a variety of neuropsychiatric signs and symptoms,

including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some

of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose

reduction and/or withdrawal of treatment. Discontinue bupropion hydrochloride (XL) if these reactions

occur.

5.7 Angle-Closure Glaucoma

Angle-Closure Glaucoma: The pupillary dilation that occurs following use of many antidepressant

drugs including bupropion hydrochloride (XL) 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

bupropion hydrochloride (XL) 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 symptoms of serum sickness

suggestive of delayed hypersensitivity.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

6.1 Clinical Trials Experience

Adverse Reaction

Term

Placebo

(n = 385)

Bupropion HCl

Sustained-Release (SR)

300 mg/day

Bupropion HCl

Sustained-Release (SR)

400 mg/day

Suicidal thoughts and behaviors in children, adolescents, and young adults [see Warnings and

Precautions (5.1)]

Neuropsychiatric adverse events and suicide risk in smoking cessation treatment [see 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 events [see Warnings and Precautions (5.6)]

Angle-Closure Glaucoma [see Warnings and Precautions (5.7)]

Hypersensitivity reactions [see Warnings and Precautions (5.8)]

Because clinical trials are conducted under widely varying conditions, adverse reaction rates

observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials

of another drug and may not reflect the rates observed in practice.

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