Bupropion Hydrochloride

Jubilant Cadista Pharmaceuticals Inc.
Jubilant Life Sciences Limited

HIGHLIGHTS OF PRESCRIBING INFORMATION RECENT MAJOR CHANGES   Dosage and Administration (2.4, 2.5)   03/2013   Contraindications (4)   03/2013 BOXED WARNING WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC REACTIONS See full prescribing information for complete boxed warning. • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants. (5.1) • Monitor worsening and emergence of suicidal thoughts and behaviors (5.1) • Serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation. (5.2) INDICATIONS AND USAGE •Bupropion hydrochloride extended-release tablets (SR) are aminoketone antidepressant, indicated for the treatment of major depressive disorder (MDD). (1)                              DOSAGE AND ADMINISTRATION • Starting Dose: 150 mg per day. (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 150 mg twice daily at an interval of at least 8 hours. (2.1) • Usual target dose: 300 mg per day as 150 mg twice daily. (2.1) • Maximum dose: 400 mg per day, given as 200 mg twice daily, for patients not responding to 300 mg per day. (2.1) • Periodically reassess the dose and need for maintenance treatment. (2.1) • Moderate to severe hepatic impairment: 100 mg daily or 150 mg every other day. (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) DOSAGE FORMS AND STRENGTHS   Tablets: 100 mg, 150 mg, 200 mg. (3) CONTRAINDICATIONS • 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 extended-release tablets (SR) or within 14 days of stopping treatment with bupropion hydrochloride extended-release tablets (SR). Do not use bupropion hydrochloride extended-release tablets (SR) within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start bupropion hydrochloride extended-release tablets (SR) in a patient who is being treated with linezolid or intravenous methylene blue. (4, 7.6) • Known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (SR). (4, 5.7) WARNINGS AND PRECAUTIONS • Seizure risk: The risk is dose-related. Can minimize risk by gradually increasing the dose and limiting daily dose to 400 mg. Discontinue if seizure occurs. (4, 5.3, 7.3) • Hypertension: Bupropion hydrochloride extended-release tablets (SR) 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) Side EffectsMost common adverse reactions (incidence ≥5% and ≥2% more than placebo rate) are: headache, dry mouth, nausea, insomnia, dizziness, pharyngitis, constipation, agitation, anxiety, abdominal pain, tinnitus, tremor, palpitation, myalgia, sweating, rash, and anorexia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Jubilant Cadista Pharmaceuticals Inc., at 1-800-313-4623 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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 bupropion hydrochloride extended-release tablets (SR) with caution. (5.3, 7.3) • Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with bupropion hydrochloride extended-release tablets (SR). (7.4) • MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with bupropion hydrochloride extended-release tablets (SR). (7.6) • Drug-laboratory test interactions: Bupropion hydrochloride extended-release tablets (SR) can cause false-positive urine test results for amphetamines. (7.7) USE IN SPECIFIC POPULATIONS • Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: SUICIDAL THOUGHTS AND BEHAVIORS; AND NEUROPSYCHIATRIC REACTIONS
• 1 BUPROPION HYDROCHLORIDE INDICATIONS AND USAGE
• 2 BUPROPION HYDROCHLORIDE DOSAGE AND ADMINISTRATION
  • 2.1 General Instructions for Use
  • 2.2 Dose Adjustment in Patients With Hepatic Impairment
  • 2.3 Dose Adjustment in Patients With Renal Impairment
  • 2.4 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant                    
  • 2.5 Use of Bupropion Hydrochloride Extended-Release Tablets (SR) With Reversible MAOIs Such as Linezolid or Methylene Blue            
• 3 DOSAGE FORMS AND STRENGTHS
• 4 BUPROPION HYDROCHLORIDE CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
  • 5.2 Neuropsychiatric Symptoms 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 Hypersensitivity Reactions
• 6 BUPROPION HYDROCHLORIDE ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (SR)
  • 7.2 Potential for Bupropion Hydrochloride Extended-Release Tablets (SR) 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
  • 8.3 Nursing Mothers
  • 8.4 Pediatric Use
  • 8.5 Geriatric Use
  • 8.6 Renal Impairment
  • 8.7 Hepatic 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 BUPROPION HYDROCHLORIDE 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
• 16 HOW SUPPLIED/STORAGE AND HANDLING
• 17 PATIENT COUNSELING INFORMATION
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Bupropion hydrochloride extended-release tablets (SR) are indicated for the treatment of major depressive disorder (MDD), as defined by the Diagnostic and Statistical Manual (DSM).

The efficacy of bupropion in the treatment of a major depressive episode was established in two 4-week controlled inpatient trials and one 6-week controlled outpatient trial of adult subjects with MDD [see Clinical Studies (14)].

The efficacy of bupropion hydrochloride extended-release tablets (SR) in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial [see Clinical Studies (14)].

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 hydrochloride extended-release tablets (SR) should be swallowed whole and not crushed, divided, or chewed. Bupropion hydrochloride extended-release tablets (SR) may be taken with or without food.

The usual adult target dose for bupropion hydrochloride extended-release tablets (SR) is 300 mg per day, given as 150 mg twice daily. Initiate dosing with 150 mg per day given as a single daily dose in the morning. After 3 days of dosing, the dose may be increased to the 300-mg-per-day target dose, given as 150 mg twice daily. There should be an interval of at least 8 hours between successive doses. A maximum of 400 mg per day, given as 200 mg twice daily, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg per day. To avoid high peak concentrations of bupropion and/or its metabolites, do not exceed 200 mg in any single dose.

It is generally agreed that acute episodes of depression require several months or longer of antidepressant drug treatment beyond the response in the acute episode. It is unknown whether the dose of bupropion hydrochloride extended-release tablets (SR) needed for maintenance treatment is identical to the dose that provided an initial response. Periodically reassess the need for maintenance treatment and the appropriate dose for such treatment.

2.2 Dose Adjustment in Patients With Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride extended-release tablets (SR) is 100 mg per day or 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)].                       

2.3 Dose Adjustment in Patients With Renal Impairment

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

2.4 Switching a Patient To or From a Monoamine Oxidase Inhibitor (MAOI) Antidepressant                    

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

2.5 Use of Bupropion Hydrochloride Extended-Release Tablets (SR) With Reversible MAOIs Such as Linezolid or Methylene Blue            

Do not start bupropion hydrochloride extended-release tablets (SR) in a patient who is being treated with a reversible MAOI such as linezolid or intravenous methylene blue. Drug interactions can increase the risk of hypertensive reactions. In a patient who requires more urgent treatment of a psychiatric condition, non-pharmacological interventions, including hospitalization, should be considered [see Contraindications (4) and Drug Interactions (7.6)].                       

In some cases, a patient already receiving therapy with bupropion hydrochloride extended-release tablets (SR) 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 (SR) 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 (SR) may be resumed 24 hours after the last dose of linezolid or intravenous methylene blue.                       

The risk of administering methylene blue by non-intravenous routes (such as oral tablets or by local injection) or in intravenous doses much lower than 1 mg/kg with bupropion hydrochloride extended-release tablets (SR) 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 (SR) for oral administration are available as:

100 mg: Maroon, round, biconvex film-coated tablets debossed with ‘315’ on one side and ‘C’ on other side.

150 mg: Maroon, round, biconvex film-coated tablets debossed with ‘316’ on one side and ‘C’ on other side.

200 mg: Maroon, round, biconvex film-coated tablets debossed with ‘317’ on one side and ‘C’ on other side.

4 CONTRAINDICATIONS

• Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder.  
• Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with the immediate-release formulation of bupropion [see Warnings and Precautions (5.3)]. 
• Bupropion hydrochloride extended-release tablets (SR) are 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 bupropion hydrochloride extended-release tablets (SR) or within 14 days of discontinuing treatment with bupropion hydrochloride extended-release tablets (SR) is contraindicated. There is an increased risk of hypertensive reactions when bupropion hydrochloride extended-release tablets (SR) are used concomitantly with MAOIs. The use of bupropion hydrochloride extended-release tablets (SR) within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting bupropion hydrochloride extended-release tablets (SR) 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)].
• Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with known hypersensitivity to bupropion or other ingredients of bupropion hydrochloride extended-release tablets (SR). Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.7)].

5 WARNINGS AND PRECAUTIONS

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

Patients with MDD, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin reuptake inhibitors [SSRIs] and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with MDD and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short‑term trials of 9 antidepressant drugs in over 4,400 subjects. The pooled analyses of placebo‑controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short‑term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 subjects. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger subjects for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs. placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 subjects treated) are provided in Table 1.

Table 1. Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects

Age Range	Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Subjects Treated
Increases Compared With Placebo
<18	14 additional cases
18-24	5 additional cases
Decreases Compared With Placebo
25-64	1 fewer case
≥65	6 fewer cases

No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases [see Boxed Warning].

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

Families and caregivers of patients being treated with antidepressants for MDD or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for bupropion hydrochloride extended-release tablets (SR) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.2 Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment

Bupropion hydrochloride extended-release tablets (SR) are not approved for smoking cessation treatment; however, ZYBAN^® is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking bupropion for smoking cessation. These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide [see Boxed Warning and Adverse Reactions (6.2)]. Observe patients for the occurrence of neuropsychiatric reactions. Instruct patients to contact a healthcare professional if such reactions occur.

In many of these cases, a causal relationship to bupropion treatment is not certain, because depressed mood can be a symptom of nicotine withdrawal. However, some of the cases occurred in patients taking bupropion who continued to smoke.

5.3 Seizure

Bupropion hydrochloride extended-release tablets (SR) can cause seizure. The risk of seizure is dose-related. The dose should not exceed 400 mg per day. Increase the dose gradually. Discontinue bupropion hydrochloride extended-release tablets (SR) 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 extended-release tablets (SR). Bupropion hydrochloride extended-release tablets (SR) are 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: When bupropion hydrochloride extended-release tablets (SR) are dosed up to 300 mg per day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg per day.

The risk of seizure can be reduced if the dose of bupropion hydrochloride extended-release tablets (SR) does not exceed 400 mg per day, given as 200 mg twice daily, and the titration rate is gradual.

5.4 Hypertension

Treatment with bupropion hydrochloride extended-release tablets (SR) can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with bupropion hydrochloride extended-release tablets (SR), and monitor periodically during treatment. The risk of hypertension is increased if bupropion hydrochloride extended-release tablets (SR) are 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.

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 extended-release tablets (SR), 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 extended-release tablets (SR) are not approved for use in treating bipolar depression.

5.6 Psychosis and Other Neuropsychiatric Reactions

Depressed patients treated with bupropion hydrochloride extended-release tablets (SR) have had a variety of neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Some of these patients had a diagnosis of bipolar disorder. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment. Instruct patients to contact a healthcare professional if such reactions occur.

5.7 Hypersensitivity Reactions

Anaphylactoid/anaphylactic reactions have occurred during clinical trials with bupropion. Reactions have been characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment. In addition, there have been rare, spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue bupropion hydrochloride extended-release tablets (SR) and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.

There are reports of arthralgia, myalgia, fever with rash and other serum sickness-like symptoms suggestive of delayed hypersensitivity.

6 ADVERSE REACTIONS

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

• • Suicidal thoughts and behaviors in adolescents and young adults [see Boxed Warning 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)]

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

Adverse Reactions Leading to Discontinuation of Treatment: In placebo‑controlled clinical trials, 4%, 9%, and 11% of the placebo, 300-mg-per-day, and 400-mg-per-day groups, respectively, discontinued treatment due to adverse reactions. The specific adverse reactions leading to discontinuation in at least 1% of the 300-mg-per-day or 400-mg-per-day groups and at a rate at least twice the placebo rate are listed in Table 2.

Table 2. Treatment Discontinuations Due to Adverse Reactions in Placebo‑Controlled Trials

Adverse Reaction	Placebo (n = 385)	Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day (n = 376)	Bupropion Hydrochloride Extended-Release Tablets (SR) 400 mg/day (n = 114)
Rash	0.0%	2.4%	0.9%
Nausea	0.3%	0.8%	1.8%
Agitation	0.3%	0.3%	1.8%
Migraine	0.3%	0.0%	1.8%

Commonly Observed Adverse Reactions: Adverse reactions from Table 3 occurring in at least 5% of subjects treated with bupropion hydrochloride extended-release tablets (SR) and at a rate at least twice the placebo rate are listed below for the 300-and 400-mg-per-day dose groups.

Bupropion hydrochloride extended-release tablets (SR) 300 mg per day: Anorexia, dry mouth, rash, sweating, tinnitus, and tremor.

Bupropion hydrochloride extended-release tablets (SR) 400 mg per day: Abdominal pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea, palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.

Adverse reactions reported in placebo-controlled trials are presented in Table 3. Reported adverse reactions were classified using a COSTART‑based Dictionary.

Body System/

Adverse Reaction Headache Infection Abdominal pain Asthenia Chest pain Pain Fever Palpitation Flushing Migraine Hot flashes Dry mouth Nausea Constipation Diarrhea Anorexia Vomiting Dysphagia Myalgia Arthralgia Arthritis Twitch Insomnia Dizziness Agitation Anxiety Tremor Nervousness Somnolence Irritability Memory decreased Paresthesia Central nervous system stimulation Pharyngitis Sinusitis Increased cough Sweating Rash Pruritus Urticaria Tinnitus Taste perversion Blurred vision or diplopia Urinary frequency Urinary urgency Vaginal hemorrhage^a Urinary tract infection

Table 3. Adverse Reactions Reported by at Least 1% of Subjects and at a Greater Frequency Than Placebo in Controlled Clinical Trials

Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day (n = 376)	Bupropion Hydrochloride Extended-Release Tablets (SR) 400 mg/day (n = 114)	Placebo (n = 385)
Body (General)
26%	25%	23%
8%	9%	6%
3%	9%	2%
2%	4%	2%
3%	4%	1%
2%	3%	2%
1%	2%	—
Cardiovascular
2%	6%	2%
1%	4%	—
1%	4%	1%
1%	3%	1%
Digestive
17%	24%	7%
13%	18%	8%
10%	5%	7%
5%	7%	6%
5%	3%	2%
4%	2%	2%
0%	2%	0%
Musculoskeletal
2%	6%	3%
1%	4%	1%
0%	2%	0%
1%	2%	—
Nervous system
11%	16%	6%
7%	11%	5%
3%	9%	2%
5%	6%	3%
6%	3%	1%
5%	3%	3%
2%	3%	2%
3%	2%	2%
—	3%	1%
1%	2%	1%
2%	1%	1%
Respiratory
3%	11%	2%
3%	1%	2%
1%	2%	1%
Skin
6%	5%	2%
5%	4%	1%
2%	4%	2%
2%	1%	0%
Special senses
6%	6%	2%
2%	4%	—
3%	2%	2%
Urogenital
2%	5%	2%
—	2%	0%
0%	2%	—
1%	0%	—

^aIncidence based on the number of female subjects.

— Hyphen denotes adverse events occurring in greater than 0 but less than 0.5% of subjects.

Other Adverse Reactions Observed During the Clinical Development of Bupropion: In addition to the adverse reactions noted above, the following adverse reactions have been reported in clinical trials with the sustained‑release formulation of bupropion in depressed subjects and in nondepressed smokers, as well as in clinical trials with the immediate‑release formulation of bupropion.

Adverse reaction frequencies represent the proportion of subjects who experienced a treatment-emergent adverse reaction on at least one occasion in placebo-controlled trials for depression (n = 987) or smoking cessation (n = 1,013), or subjects who experienced an adverse reaction requiring discontinuation of treatment in an open-label surveillance trial with bupropion hydrochloride extended-release tablets (SR) (n = 3,100). All treatment-emergent adverse reactions are included except those listed in Table 3, those listed in other safety-related sections of the prescribing information, those subsumed under COSTART terms that are either overly general or excessively specific so as to be uninformative, those not reasonably associated with the use of the drug, and those that were not serious and occurred in fewer than 2 subjects.

Adverse reactions are further categorized by body system and listed in order of decreasing frequency according to the following definitions of frequency: 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.

Body (General): Infrequent were chills, facial edema, and photosensitivity. Rare was malaise.

Cardiovascular: Infrequent were postural hypotension, stroke, tachycardia, and vasodilation. Rare were syncope and myocardial infarction.

Digestive: Infrequent were abnormal liver function, bruxism, gastric reflux, gingivitis, increased salivation, jaundice, mouth ulcers, stomatitis, and thirst. Rare was edema of tongue.

Hemic and Lymphatic: Infrequent was ecchymosis.

Metabolic and Nutritional: Infrequent were edema and peripheral edema.

Musculoskeletal: Infrequent were leg cramps.

Nervous System: Infrequent were abnormal coordination, decreased libido, depersonalization, dysphoria, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.

Respiratory: Rare was bronchospasm.

Special Senses: Infrequent were accommodation abnormality and dry eye.

Urogenital: Infrequent were impotence, polyuria, and prostate disorder.

Changes in Body Weight: In placebo‑controlled trials, subjects experienced weight gain or weight loss as shown in Table 4.

Table 4. Incidence of Weight Gain and Weight Loss (≥5 lbs.) in Placebo-Controlled Trials

Weight Change	Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day (n = 339)	Bupropion Hydrochloride Extended-Release Tablets (SR) 400 mg/day (n = 112)	Placebo (n = 347)
Gained >5 lbs	3%	2%	4%
Lost >5 lbs	14%	19%	6%

In clinical trials conducted with the immediate-release formulation of bupropion, 35% of subjects receiving tricyclic antidepressants gained weight, compared with 9% of subjects treated with the immediate-release formulation of bupropion. If weight loss is a major presenting sign of a patient’s depressive illness, the anorectic and/or weight-reducing potential of bupropion hydrochloride extended-release tablets (SR) should be considered.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of bupropion hydrochloride extended-release tablets (SR) and are not described elsewhere in the label. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Body (General): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness [see Warnings and Precautions (5.7)].

Cardiovascular: Complete atrioventricular block, extrasystoles, hypotension, hypertension (in some cases severe), phlebitis, and pulmonary embolism.

Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, pancreatitis, and stomach ulcer.

Endocrine: Hyperglycemia, hypoglycemia, and syndrome of inappropriate antidiuretic hormone.

Hemic and Lymphatic: Anemia, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, and thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.

Metabolic and Nutritional: Glycosuria.

Musculoskeletal: Muscle rigidity/fever/rhabdomyolysis and muscle weakness.

Nervous System: Abnormal electroencephalogram (EEG), aggression, akinesia, aphasia, coma, completed suicide, delirium, delusions, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal syndrome, hallucinations, hypokinesia, increased libido, manic reaction, neuralgia, neuropathy, paranoid ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.

Respiratory: Pneumonia.

Skin: Alopecia, angioedema, exfoliative dermatitis, hirsutism, and Stevens-Johnson syndrome.

Special Senses: Deafness, increased intraocular pressure, and mydriasis.

Urogenital: Abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.

7 DRUG INTERACTIONS

7.1 Potential for Other Drugs to Affect Bupropion Hydrochloride Extended-Release Tablets (SR)

Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (SR) and drugs that are inhibitors or inducers of CYP2B6.

Inhibitors of CYP2B6: Ticlopidine and Clopidogrel: Concomitant treatment with these drugs can increase bupropion exposure but decrease hydroxybupropion exposure. Based on clinical response, dosage adjustment of bupropion hydrochloride extended-release tablets (SR) may be necessary when coadministered with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel) [see Clinical Pharmacology (12.3)].

Inducers of CYP2B6: Ritonavir, Lopinavir, and Efavirenz: Concomitant treatment with these drugs can decrease bupropion and hydroxybupropion exposure. Dosage increase of bupropion hydrochloride extended-release tablets (SR) may be necessary when coadministered with ritonavir, lopinavir, or efavirenz [see Clinical Pharmacology (12.3)] but should not exceed the maximum recommended dose.

Carbamazepine, Phenobarbital, Phenytoin: While not systematically studied, these drugs may induce the metabolism of bupropion and may decrease bupropion exposure [see Clinical Pharmacology (12.3)]. If bupropion is used concomitantly with a CYP inducer, it may be necessary to increase the dose of bupropion, but the maximum recommended dose should not be exceeded.

7.2 Potential for Bupropion Hydrochloride Extended-Release Tablets (SR) to Affect Other Drugs

Drugs Metabolized by CYP2D6: Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of bupropion hydrochloride extended-release tablets (SR) with drugs that are metabolized by CYP2D6 can increase the exposures of drugs that are substrates of CYP2D6. Such drugs include certain antidepressants (e.g., venlafaxine, nortriptyline, imipramine, desipramine, paroxetine, fluoxetine, and sertraline), antipsychotics (e.g., haloperidol, risperidone, thioridazine), beta-blockers (e.g., metoprolol), and Type 1C antiarrhythmics (e.g., propafenone and flecainide). When used concomitantly with bupropion hydrochloride extended-release tablets (SR), it may be necessary to decrease the dose of these CYP2D6 substrates, particularly for drugs with a narrow therapeutic index.

Drugs that require metabolic activation by CYP2D6 to be effective (e.g., tamoxifen) theoretically could have reduced efficacy when administered concomitantly with inhibitors of CYP2D6 such as bupropion. Patients treated concomitantly with bupropion hydrochloride extended-release tablets (SR) and such drugs may require increased doses of the drug [see Clinical Pharmacology (12.3)].

7.3 Drugs That Lower Seizure Threshold

Use extreme caution when coadministering bupropion hydrochloride extended-release tablets (SR) with other drugs that lower seizure threshold (e.g., other bupropion products, antipsychotics, antidepressants, theophylline, or systemic corticosteroids). Use low initial doses and increase the dose gradually [see Contraindications (4) and Warnings and Precautions (5.3)].

7.4 Dopaminergic Drugs (Levodopa and Amantadine)

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

7.5 Use With Alcohol

In postmarketing experience, there have been rare reports of adverse neuropsychiatric events or reduced alcohol tolerance in patients who were drinking alcohol during treatment with bupropion hydrochloride extended-release tablets (SR). The consumption of alcohol during treatment with bupropion hydrochloride extended-release tablets (SR) should be minimized or avoided.

7.6 MAO Inhibitors

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

7.7 Drug-Laboratory Test Interactions

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

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category C

Risk Summary: Data from epidemiological studies of pregnant women exposed to bupropion in the first trimester indicate no increased risk of congenital malformations overall. All pregnancies, regardless of drug exposure, have a background rate of 2% to 4% for major malformations, and 15% to 20% for pregnancy loss. No clear evidence of teratogenic activity was found in reproductive developmental studies conducted in rats and rabbits; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at doses approximately equal to the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses twice the MRHD and greater. Bupropion hydrochloride extended-release tablets (SR) 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/m^{2 basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately equal to the MRHD on a mg/m2 basis) and greater. Decreased fetal weights were observed at 50 mg/kg and greater.}

When rats were administered bupropion at oral doses of up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/m^{2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.}

8.3 Nursing Mothers

Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when bupropion hydrochloride extended-release tablets (SR) are administered to a nursing woman.

8.4 Pediatric Use

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

8.5 Geriatric Use

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

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

8.6 Renal Impairment

Consider a reduced dose and/or dosing frequency of bupropion hydrochloride extended-release tablets (SR) 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)].

8.7 Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose of bupropion hydrochloride extended-release tablets (SR) is 100 mg per day or 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 Dosage and Administration (2.2) and Clinical Pharmacology (12.3)].

9 DRUG ABUSE AND DEPENDENCE

9.1 Controlled Substance

Bupropion is not a controlled substance.

9.2 Abuse

Humans: Controlled clinical trials of bupropion (immediate-release formulation) 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.

10 OVERDOSAGE

10.1 Human Overdose Experience

Overdoses of up to 30 grams or more of bupropion have been reported. Seizure was reported in approximately one-third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances (including QRS prolongation) or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses.

Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.

10.2 Overdosage Management

Consult a Certified Poison Control Center for up-to-date guidance and advice. Telephone numbers for certified poison control centers are listed in the Physician’s Desk Reference (PDR). Call 1-800-222-1222 or refer to www.poison.org.

There are no known antidotes for bupropion. In case of an overdose, provide supportive care, including close medical supervision and monitoring. Consider the possibility of multiple drug overdose. Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. Induction of emesis is not recommended.

11 DESCRIPTION

Bupropion hydrochloride USP, 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 (±)-2-(tert-Butylamino)-3’-chloropropiophenone hydrochloride. The molecular weight is 276.21. The molecular formula is C₁₃H₁₈ClNO•HCl. Bupropion hydrochloride is white powder, soluble in water, in 0.1N HCl and in alcohol. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is:

Bupropion hydrochloride extended-release tablets, USP (SR) are supplied for oral administration as 100 mg, 150 mg, and 200 mg maroon, round, biconvex film-coated tablets debossed with ‘315’ (for 100 mg), ‘316’ (for 150 mg), and ‘317’ (for 200 mg) on one side and ‘C’ on the other side. Each extended-release tablet contains the labeled amount of bupropion hydrochloride USP and the inactive ingredients: hydrogenated castor oil, mannitol, povidone, crospovidone, magnesium stearate, hypromellose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, lecithin, FD&C blue # 2 Aluminum lake and FD&C red # 40 Aluminum lake.

Bupropion hydrochloride extended-release tablets, USP (SR) comply with USP dissolution test 7.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

The exact mechanism of the antidepressant action of bupropion is not known, but is presumed to be related to noradrenergic and/or dopaminergic mechanisms. Bupropion is a relatively weak inhibitor of the neuronal reuptake of norepinephrine and dopamine, and does not inhibit the reuptake of serotonin. Bupropion does not inhibit monoamine oxidase.

12.3 Pharmacokinetics

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 bupropion hydrochloride extended-release tablets (SR) 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 bupropion hydrochloride extended-release tablets (SR), peak plasma concentration (C_max) of bupropion is usually achieved within 3 hours.

In a trial comparing chronic dosing with bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to bupropion immediate-release formulation 100 mg 3 times daily, the steady state C_max for bupropion after bupropion hydrochloride extended-release tablets (SR) administration was approximately 85% of those achieved after bupropion immediate-release formulation administration. Exposure (AUC) to bupropion was equivalent for both formulations. Bioequivalence was also demonstrated for all three major active metabolites (i.e., hydroxybupropion, threohydrobupropion and erythrohydrobupropion) for both C_max and AUC. Thus, at steady state, bupropion hydrochloride extended-release tablets (SR) given twice daily, and the immediate-release formulation of bupropion given 3 times daily, are essentially bioequivalent for both bupropion and the 3 quantitatively important metabolites.

Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food. Bupropion C_max and AUC was increased by 11% to 35% and 16% to 19%, respectively, when bupropion hydrochloride extended-release tablets (SR) was administered with food to healthy volunteers in three trials. The food effect is not considered clinically significant.

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 administration of bupropion hydrochloride extended-release tablets (SR) in humans, C_max of hydroxybupropion occurs approximately 6 hours post-dose and is 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. Bupropion hydrochloride extended-release tablets (SR) 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 5).

Table 5. Pharmacokinetics of Bupropion and Metabolites in Patients With Severe Hepatic Cirrhosis: Ratio Relative to Healthy Matched Controls

	Cmax	AUC	t½	Tmax a
Bupropion	1.69	3.12	1.43	0.5 h
Hydroxybupropion	0.31	1.28	3.88	19 h
Threo/erythrohydrobupropion amino alcohol	0.69	2.48	1.96	20 h

^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 Bupropion Hydrochloride Extended-Release Tablets (SR): In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between bupropion hydrochloride extended-release tablets (SR) 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 Bupropion Hydrochloride Extended-Release Tablets (SR) 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.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

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.

14 CLINICAL STUDIES

The efficacy of the immediate‑release formulation of bupropion in the treatment of major depressive disorder was established in two 4‑week, placebo‑controlled trials in adult inpatients with MDD (Trials 1 and 2 in Table 6) and in one 6‑week, placebo‑controlled trial in adult outpatients with MDD (Trial 3 in Table 6). In the first trial, the dose range of bupropion was 300 mg to 600 mg per day administered in divided doses; 78% of subjects were treated with doses of 300 mg to 450 mg per day. This trial demonstrated the effectiveness of the immediate‑release formulation of bupropion 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 the immediate‑release formulation of bupropion (300 and 450 mg per day) and placebo. This trial demonstrated the effectiveness of the immediate‑release formulation of bupropion, but only at the 450‑mg-per-day dose. The efficacy results were 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 the immediate‑release formulation of bupropion. This trial demonstrated the efficacy of the immediate‑release formulation of bupropion as measured by the HDRS total score, the HDRS item 1, the Montgomery‑Asberg Depression Rating Scale (MADRS), the CGI-S score, and the CGI-Improvement Scale (CGI-I) score.

Table 6. Efficacy of Immediate-Release Bupropion for the Treatment of Major Depressive Disorder

Trial Number	Treatment Group	Primary Efficacy Measure: HDRS
		Mean Baseline Score (SD)	LS Mean Score at Endpoint Visit (SE)	Placebo-substracted Differencea (95% CI)
Trial 1	Immediate-Release Bupropion 300-600 mg/dayb (n = 48)	28.5 (5.1)	14.9 (1.3)	-4.7 (-8.8, -0.6)
	Placebo (n = 27)	29.3 (7.0)	19.6 (1.6)	--
		Mean Baseline Score (SD)	LS Mean Change from Baseline (SE)	Placebo-subtracted Differencea (95% CI)
Trial 2	Immediate-Release Bupropion 300 mg/day (n = 36)	32.4 (5.9)	-15.5 (1.7)	-4.1
	Immediate-Release Bupropion 450 mg/dayb (n = 34)	34.8 (4.6)	-17.4 (1.7)	-5.9 (-10.5, -1.4)
	Placebo (n = 39)	32.9 (5.4)	-11.5 (1.6)	--
Trial 3	Immediate-Release Bupropion 300 mg/dayb (n = 110)	26.5 (4.3)	-12.0 (NA)	-3.9 (-5.7, -1.0)
	Placebo (n = 106)	27.0 (3.5)	-8.7 (NA)	--

•  n: sample size; SD: standard deviation; SE: standard error; LS Mean: least-squares mean; CI: unadjusted confidence interval included for doses that were demonstrated to be effective; NA: not available.

•   ^a Difference (drug minus placebo) in least-squares estimates with respect to the primary efficacy parameter. For Trial 1, it refers to the mean score at the endpoint visit; for Trials 2 and 3, it refers to the mean change from baseline to the endpoint visit.
•   ^bDoses that are demonstrated to be statistically significantly superior to placebo.

Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the sustained‑release formulation of bupropion, trials have demonstrated the bioequivalence of the immediate‑release and sustained‑release forms of bupropion under steady‑state conditions, i.e., bupropion sustained‑release 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the immediate‑release formulation of bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.

In a longer-term trial, outpatients meeting DSM-IV criteria for major depressive disorder, recurrent type, who had responded during an 8-week open trial on bupropion hydrochloride extended-release tablets (SR) (150 mg twice daily) were randomized to continuation of their same dose of bupropion hydrochloride extended-release tablets (SR) or placebo for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving continued treatment with bupropion hydrochloride extended-release tablets (SR) experienced significantly lower relapse rates over the subsequent 44 weeks compared with those receiving placebo.

16 HOW SUPPLIED/STORAGE AND HANDLING

Bupropion hydrochloride extended-release tablets USP (SR) for oral administration are available as:

100 mg: Maroon, round, biconvex film-coated tablets debossed with ‘315’ on one side and ‘C’ on other side.

Bottles of 60               NDC 59746-315-60
Bottles of 100             NDC 59746-315-01

150 mg: Maroon, round, biconvex film-coated tablets debossed with ‘316’ on one side and ‘C’ on other side.

Bottles of 60               NDC 59746-316-60
Bottles of 100             NDC 59746-316-01

200 mg: Maroon, round, biconvex film-coated tablets debossed with ‘317’ on one side and ‘C’ on other side.

Bottles of 60               NDC 59746-317-60
Bottles of 100             NDC 59746-317-01

STORAGE: Store at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light resistant container as defined in USP.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets (SR) and counsel them in its appropriate use.

A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other Important Information Should I Know About Bupropion Hydrochloride Extended-Release Tablets (SR)?” is available for bupropion hydrochloride extended-release tablets (SR). Instruct patients, their families, and their caregivers to read the Medication Guide and assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Advise patients regarding the following issues and to alert their prescriber if these occur while taking bupropion hydrochloride extended-release tablets (SR).

Suicidal Thoughts and Behaviors: Instruct patients, their families, and/or their caregivers to be alert to the emergence of anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, other unusual changes in behavior, worsening of depression, and suicidal ideation, especially early during antidepressant treatment and when the dose is adjusted up or down. Advise families and caregivers of patients to observe for the emergence of such symptoms on a day-to-day basis, since changes may be abrupt. Such symptoms should be reported to the patient’s prescriber or healthcare professional, especially if they are severe, abrupt in onset, or were not part of the patient’s presenting symptoms. Symptoms such as these may be associated with an increased risk for suicidal thinking and behavior and indicate a need for very close monitoring and possibly changes in the medication.

Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: Although bupropion hydrochloride extended-release tablets (SR) are not indicated for smoking cessation treatment, it contains the same active ingredient as ZYBAN which is approved for this use. Advise patients, families and caregivers that quitting smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g., including depression or agitation), or worsen pre-existing psychiatric illness. Some patients have experienced changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide when attempting to quit smoking while taking ZYBAN. If patients develop agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for them, or if patients develop suicidal ideation or behavior, they should be urged to report these symptoms to their healthcare provider immediately.

Severe Allergic Reactions: Educate patients on the symptoms of hypersensitivity and to discontinue bupropion hydrochloride extended-release tablets (SR) if they have a severe allergic reaction.

Seizure:  Instruct patients to discontinue and not restart bupropion hydrochloride extended-release tablets (SR) 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.

As the dose is increased during initial titration to doses above 150 mg per day, instruct patients to take bupropion hydrochloride extended-release tablets (SR) in 2 divided doses, preferably with at least 8 hours between successive doses, to minimize the risk of seizures.

Bupropion-Containing Products: Educate patients that bupropion hydrochloride extended-release tablets (SR) contains the same active ingredient (bupropion hydrochloride) found in ZYBAN, which is used as an aid to smoking cessation treatment, and that bupropion hydrochloride extended-release tablets (SR) should not be used in combination with ZYBAN or any other medications that contain bupropion (such as WELLBUTRIN^®, the immediate-release formulation and WELLBUTRIN XL^® or FORFIVO XL^TM, the extended-release formulations, and APLENZIN^®, the extended-release formulation of bupropion hydrobromide). In addition, there are a number of generic bupropion HCl products for the immediate-, sustained-, and extended-release formulations.

Potential for Cognitive and Motor Impairment: Advise patients that any CNS-active drug like bupropion hydrochloride extended-release tablets (SR) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Advise patients that until they are reasonably certain that bupropion hydrochloride extended-release tablets (SR) do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery. Bupropion hydrochloride extended-release tablets (SR) may lead to decreased alcohol tolerance.

Concomitant Medications: Counsel patients to notify their healthcare provider if they are taking or plan to take any prescription or over-the-counter drugs because bupropion hydrochloride extended-release tablets (SR) and other drugs may affect each others’ metabolisms.

Pregnancy: Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during therapy. 

Precautions for Nursing Mothers: Advise patients that bupropion hydrochloride is present in human milk in small amounts. 

Storage Information: Instruct patients to store bupropion hydrochloride extended-release tablets (SR) 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 swallow bupropion hydrochloride extended-release tablets (SR) whole so that the release rate is not altered. Do not chew, divide, or crush tablets; they are designed to slowly release drug in the body. When patients take more than 150 mg per day, instruct them to take bupropion hydrochloride extended-release tablets (SR) in 2 doses at least 8 hours apart, to minimize the risk of seizures. Instruct patients if they miss a dose, not to take an extra tablet to make up for the missed dose and to take the next tablet at the regular time because of the dose-related risk of seizure. Instruct patients that bupropion hydrochloride extended-release tablets (SR) may have an odor. Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food.

All brands mentioned are trademarks of their respective owners and are not trademarks of Jubilant Life Sciences Limited.

Rx Only

Manufactured by:
Jubilant Life Sciences Limited
Roorkee-247661, India

Marketed by:
Jubilant Cadista Pharmaceuticals Inc.
Salisbury, MD-21801, USA

Revised: January /201 4

BuPROPion Hydrochloride Extended-Release Tablets, USP (SR)

(bue proe' pee on hye" droe klor' ide)                 

Read this Medication Guide carefully before you start taking bupropion hydrochloride extended-release tablets (SR) 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 bupropion hydrochloride extended-release tablets (SR), 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 Bupropion Hydrochloride Extended-Release Tablets (SR)?”

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?

• 1. Antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment.
• 2. 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.
• 3. 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:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling very agitated or restless

panic attackstrouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

•

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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 bupropion hydrochloride extended-release tablets (SR) are 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 bupropion hydrochloride extended-release tablets (SR) are 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:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

panic attacks

feeling very agitated or restless

acting aggressive, being angry, or violent

acting on dangerous impulsesan extreme increase in activity and talking (mania)

abnormal thoughts or sensations

seeing or hearing things that are not there (hallucinations)

feeling people are against you (paranoia)

feeling confused

other unusual changes in behavior or mood

•

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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 Bupropion Hydrochloride Extended-Release Tablets (SR)?                 

• Seizures: There is a chance of having a seizure (convulsion, fit) with bupropion hydrochloride extended-release tablets (SR), especially in people:
  o   with certain medical problems.
  o   who take certain medicines.

The chance of having seizures increases with higher doses of bupropion hydrochloride extended-release tablets (SR). For more information, see the sections “Who should not take bupropion hydrochloride extended-release tablets (SR)?” and “What should I tell my healthcare provider before taking bupropion hydrochloride extended-release tablets (SR)?” 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 bupropion hydrochloride extended-release tablets (SR) unless your healthcare provider has said it is okay to take them.                 

If you have a seizure while taking bupropion hydrochloride extended-release tablets (SR), stop taking the tablets and call your healthcare provider right away. Do not take bupropion hydrochloride extended-release tablets (SR) again if you have a seizure.

• • High blood pressure (hypertension). Some people get high blood pressure, that can be severe, while taking bupropion hydrochloride extended-release tablets (SR). 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 bupropion hydrochloride extended-release tablets (SR), 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 bupropion hydrochloride extended-release tablets (SR). Stop taking bupropion hydrochloride extended-release tablets (SR) 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 are bupropion hydrochloride extended-release tablets (SR)?                  

Bupropion hydrochloride extended-release tablets (SR) are a prescription medicine used to treat adults with a certain type of depression called major depressive disorder.

Who should not take bupropion hydrochloride extended-release tablets (SR)?                  

Do not take bupropion hydrochloride extended-release tablets (SR) 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, ZYBAN (used to help people stop smoking) APLENZIN^®, FORFIVO XL^™, WELLBUTRIN^®, or WELLBUTRIN XL^®. Bupropion is the same active ingredient that is in bupropion hydrochloride extended-release tablets (SR).
• • 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.
• odo not take an MAOI within 2 weeks of stopping bupropion hydrochloride extended-release tablets (SR) unless directed to do so by your healthcare provider.                              
• odo not start bupropion hydrochloride extended-release tablets (SR) if you stopped taking an MAOI in the last 2 weeks unless directed to do so by your healthcare provider.

What should I tell my healthcare provider before taking bupropion hydrochloride extended-release tablets (SR)?                 

•  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. Bupropion hydrochloride 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 bupropion hydrochloride extended-release tablets (SR).

How should I take bupropion hydrochloride extended-release tablets (SR)?                  

• Take bupropion hydrochloride extended-release tablets (SR) exactly as prescribed by your healthcare provider. 
• Swallow bupropion hydrochloride extended-release tablets (SR) whole. Do not chew, cut, or crush bupropion hydrochloride extended-release tablets (SR). If you do, the medicine will be released into your body too quickly. If this happens you may be more likely to get side effects including seizures. Tell your healthcare provider if you cannot swallow tablets. 
• Take bupropion hydrochloride extended-release tablets (SR) at the same time each day. 
• Take your doses of bupropion hydrochloride extended-release tablets (SR) at least 8 hours apart. 
• You may take bupropion hydrochloride extended-release tablets (SR) 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 bupropion hydrochloride extended-release tablets (SR) can increase your chance of having a seizure. 
• If you take too much bupropion hydrochloride extended-release tablets (SR), or overdose, call your local emergency room or poison control center right away. 
• Do not take any other medicines while taking bupropion hydrochloride extended-release tablets (SR) unless your healthcare provider has told you it is okay. 
• If you are taking bupropion hydrochloride extended-release tablets (SR) for the treatment of major depressive disorder, it may take several weeks for you to feel that bupropion hydrochloride extended-release tablets (SR) are working. Once you feel better, it is important to keep taking bupropion hydrochloride extended-release tablets (SR) exactly as directed by your healthcare provider. Call your healthcare provider if you do not feel bupropion hydrochloride extended-release tablets (SR) are working for you.
• Do not change your dose or stop taking bupropion hydrochloride extended-release tablets (SR) without talking with your healthcare provider first.

What should I avoid while taking bupropion hydrochloride extended-release tablets (SR)?                  

• • Limit or avoid using alcohol during treatment with bupropion hydrochloride extended-release tablets (SR). 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 chance of having seizures.
• • Do not drive a car or use heavy machinery until you know how bupropion hydrochloride extended-release tablets (SR) affect you. Bupropion hydrochloride extended-release tablets (SR) can affect your ability to do these things safely.

What are possible side effects of bupropion hydrochloride extended-release tablets (SR)? 

See “What Other Important Information Should I Know About Bupropion Hydrochloride Extended-Release Tablets (SR)?”                                    

Bupropion hydrochloride extended-release tablets (SR) can cause serious side effects.

The most common side effects of bupropion hydrochloride extended-release tablets (SR) include:

• •Headache
• •Dry mouth
• •Nausea
• •Trouble sleeping
• •Dizziness
• •Sore throat
• •Constipation

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 bupropion hydrochloride extended-release tablets (SR). For more information, ask your healthcare provider or pharmacist.

Call your doctor 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 Jubilant Cadista Pharmaceuticals Inc., at 1-800-313-4623.

How should I store bupropion hydrochloride extended-release tablets (SR)?

• •Store bupropion hydrochloride extended-release tablets (SR) at 20°C-25°C (68°F-77°F), excursions permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]. Dispense in tight, light resistant container as defined in USP.
• •Bupropion hydrochloride extended-release tablets (SR) may have an odor.

Keep bupropion hydrochloride extended-release tablets (SR) and all medicines out of the reach of children.                  

General Information about Bupropion Hydrochloride Extended-Release Tablets (SR).                  

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use bupropion hydrochloride extended-release tablets (SR) for a condition for which it was not prescribed. Do not give bupropion hydrochloride extended-release tablets (SR) to other people, even if they have the same symptoms you have. It may harm them.

If you take a urine drug screening test, bupropion hydrochloride extended-release tablets (SR) may make the test result positive for amphetamines. If you tell the person giving you the drug screening test that you are taking bupropion hydrochloride extended-release tablets (SR), they can do a more specific drug screening test that should not have this problem.

This Medication Guide summarizes important information about bupropion hydrochloride extended-release tablets (SR). If you would like more information, talk with your healthcare provider. You can ask your healthcare provider or pharmacist for information about bupropion hydrochloride extended-release tablets (SR) that is written for healthcare professionals.

For more information about bupropion hydrochloride extended-release tablets (SR), call 1-800-313-4623.

What are the ingredients in bupropion hydrochloride extended-release tablets (SR)?                  

Active ingredient: bupropion hydrochloride, USP.

Inactive ingredients: hydrogenated castor oil, mannitol, povidone, crospovidone, magnesium stearate, hypromellose, polyethylene glycol, polyvinyl alcohol, talc, titanium dioxide, lecithin, FD&C blue # 2 Aluminum lake and FD&C red # 40 Aluminum lake.

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

All brands mentioned are trademarks of their respective owners and are not trademarks of Jubilant Life Sciences Limited.

Rx Only

Manufactured by:
Jubilant Life Sciences Limited
Roorkee-247661, India

Marketed by:
Jubilant Cadista Pharmaceuticals Inc.
Salisbury, MD-21801, USA

Revised: January/2014

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC      59746-315-60

Twice-A-Day
(After Initial Titration)

BuPROPion Hydrochloride Extended-Release Tablets (SR)

100 mg

WARNING: Do not use in combination with Zyban^® or any other medicines that contain bupropion hydrochloride.

60 Tablets                         Rx Only

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

CADISTA^TM

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC      59746-316-60

Twice-A-Day
(After Initial Titration)

BuPROPion Hydrochloride Extended-Release Tablets (SR)

150 mg

WARNING: Do not use in combination with Zyban^® or any other medicines that contain bupropion hydrochloride.

60 Tablets                         Rx Only

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

CADISTA^TM

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL

NDC      59746-317-60

Twice-A-Day
(After Initial Titration)

BuPROPion Hydrochloride Extended-Release Tablets (SR)

200 mg

WARNING: Do not use in combination with Zyban^® or any other medicines that contain bupropion hydrochloride.

60 Tablets                         Rx Only

PHARMACIST: Dispense the Medication Guide provided separately to each patient.

CADISTA^TM

Bupropion Hydrochloride bupropion hydrochloride TABLET, FILM COATED, EXTENDED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:59746-315 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BUPROPION HYDROCHLORIDE BUPROPION 100 mg Inactive Ingredients Ingredient Name Strength HYDROGENATED CASTOR OIL mannitol POVIDONES CROSPOVIDONE MAGNESIUM STEARATE HYPROMELLOSES polyethylene glycol 400 POLYVINYL ALCOHOL talc titanium dioxide FD&C RED NO. 40 FD&C BLUE NO. 2 LECITHIN, SOYBEAN POLYETHYLENE GLYCOL 3350 Product Characteristics Color Size Imprint Code Shape RED (Maroon) 9 mm 315;C ROUND Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59746-315-60 60 in 1 BOTTLE 2 NDC:59746-315-01 100 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202774 2013-10-11

Bupropion Hydrochloride bupropion hydrochloride TABLET, FILM COATED, EXTENDED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:59746-316 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BUPROPION HYDROCHLORIDE BUPROPION 150 mg Inactive Ingredients Ingredient Name Strength HYDROGENATED CASTOR OIL mannitol POVIDONES CROSPOVIDONE MAGNESIUM STEARATE HYPROMELLOSES polyethylene glycol 400 POLYVINYL ALCOHOL talc titanium dioxide FD&C RED NO. 40 FD&C BLUE NO. 2 LECITHIN, SOYBEAN POLYETHYLENE GLYCOL 3350 Product Characteristics Color Size Imprint Code Shape RED (Maroon) 11 mm 316;C ROUND Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59746-316-60 60 in 1 BOTTLE 2 NDC:59746-316-01 100 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202774 2013-10-11

Bupropion Hydrochloride bupropion hydrochloride TABLET, FILM COATED, EXTENDED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:59746-317 Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength BUPROPION HYDROCHLORIDE BUPROPION 200 mg Inactive Ingredients Ingredient Name Strength HYDROGENATED CASTOR OIL mannitol POVIDONES CROSPOVIDONE MAGNESIUM STEARATE HYPROMELLOSES polyethylene glycol 400 POLYVINYL ALCOHOL talc titanium dioxide FD&C RED NO. 40 FD&C BLUE NO. 2 LECITHIN, SOYBEAN POLYETHYLENE GLYCOL 3350 Product Characteristics Color Size Imprint Code Shape RED (Maroon) 12 mm 317;C ROUND Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:59746-317-60 60 in 1 BOTTLE 2 NDC:59746-317-01 100 in 1 BOTTLE Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA202774 2013-10-11