ZYBAN

GlaxoSmithKline LLC

HIGHLIGHTS OF PRESCRIBING INFORMATIONThese highlights do not include all the information needed to use ZYBAN safely and effectively. See full prescribing information for ZYBAN. ZYBAN(bupropion hydrochloride) Sustained-Release Tablets for oral useInitial U.S. Approval: 1985RECENT MAJOR CHANGES Dosage and Administration (2.8) 03/2014  Contraindications (4)  03/2014 BOXED WARNINGWARNING: NEUROPSYCHIATRIC REACTIONS; AND SUICIDAL THOUGHTS AND BEHAVIORS See full prescribing information for complete boxed warning. • Serious neuropsychiatric events have been reported in patients taking bupropion for smoking cessation. (5.1) • Increased risk of suicidal thinking and behavior in children, adolescents, and young adults taking antidepressants (5.2) • Monitor for worsening and emergence of suicidal thoughts and behaviors. (5.2) INDICATIONS AND USAGEZYBAN is an aminoketone agent indicated as an aid to smoking cessation treatment. (1)DOSAGE AND ADMINISTRATION •Starting dose: 150 mg per day for first 3 days. (2.1) •General: Increase dose gradually to reduce seizure risk. (2.1, 5.3) •Begin dosing one week before quit day (2.1) •After 3 days, increase the dose to 300 mg per day, given as 150 mg twice daily at an interval of at least 8 hours. (2.1) •May be used with a nicotine transdermal system. (2.5) •Moderate to severe hepatic impairment: 150 mg every other day. (2.6, 8.7) •Mild hepatic impairment: Consider reducing the dose and/or frequency of dosing (2.6, 8.7) •Renal Impairment: Consider reducing the dose and/or frequency. (2.7, 8.6) DOSAGE FORMS AND STRENGTHS •Tablets: 150 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 ZYBAN or within 14 days of stopping treatment with ZYBAN. Do not use ZYBAN within 14 days of stopping an MAOI intended to treat psychiatric disorders. In addition, do not start ZYBAN in a patient who is being treated with linezolid or intravenous methylene blue. (4, 7.6) •Known hypersensitivity to bupropion or other ingredients of ZYBAN. (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 300 mg. Discontinue if seizure occurs. (4, 5.3, 7.3) •Hypertension: ZYBAN can increase blood pressure. Monitor blood pressure before initiating treatment and periodically during treatment, especially if used with nicotine replacement. (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 reactions occur. (5.6) Side EffectsMost common adverse reactions (incidence ≥5% and ≥1% more than placebo rate) are: insomnia, rhinitis, dry mouth, dizziness, nervous disturbance, anxiety, nausea, constipation, and arthralgia. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact GlaxoSmithKline at 1-888-825-5249 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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 ZYBAN with caution. (5.3, 7.3) •Dopaminergic drugs (levodopa and amantadine): CNS toxicity can occur when used concomitantly with ZYBAN. (7.4) •MAOIs: Increased risk of hypertensive reactions can occur when used concomitantly with ZYBAN. (7.6) •Drug-laboratory test interactions: ZYBAN can cause false-positive urine test results for amphetamines. (7.8) USE IN SPECIFIC POPULATIONS •Pregnancy: Use only if benefit outweighs potential risk to the fetus. (8.1)

FULL PRESCRIBING INFORMATION: CONTENTS*

• WARNING: NEUROPSYCHIATRIC REACTIONS; AND SUICIDAL THOUGHTS AND BEHAVIORS
• 1 ZYBAN INDICATIONS AND USAGE
• 2 ZYBAN DOSAGE AND ADMINISTRATION
  • 2.1 Usual Dosage
  • 2.2 Duration of Treatment
  • 2.3 Individualization of Therapy
  • 2.4 Maintenance
  • 2.5 Combination Treatment With ZYBAN and a Nicotine Transdermal System (NTS)
  • 2.6 Dose Adjustment in Patients With Hepatic Impairment
  • 2.7 Dose Adjustment in Patients With Renal Impairment
• 3 DOSAGE FORMS AND STRENGTHS
• 4 ZYBAN CONTRAINDICATIONS
• 5 WARNINGS AND PRECAUTIONS
  • 5.1 Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment
  • 5.2 Suicidal Thoughts and Behaviors in Children, Adolescents, and Young Adults
  • 5.3 Seizure
  • 5.4 Hypertension
  • 5.5 Activation of Mania/Hypomania
  • 5.6 Psychosis and Other Neuropsychiatric Reactions
  • 5.7 Hypersensitivity Reactions
• 6 ZYBAN ADVERSE REACTIONS
  • 6.1 Clinical Trials Experience
  • 6.2 Postmarketing Experience
• 7 DRUG INTERACTIONS
  • 7.1 Potential for Other Drugs to Affect ZYBAN
  • 7.2 Potential for ZYBAN 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 Smoking Cessation
  • 7.8 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 ZYBAN 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

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

ZYBAN is indicated as an aid to smoking cessation treatment.

2 DOSAGE AND ADMINISTRATION

2.1 Usual Dosage

Treatment with ZYBAN should be initiated before the patient’s planned quit day, while the patient is still smoking, because it takes approximately 1 week of treatment to achieve steady-state blood levels of bupropion. The patient should set a “target quit date” within the first 2 weeks of treatment with ZYBAN.

Dosing: To minimize the risk of seizure:

• •Begin dosing with one 150-mg tablet per day for 3 days.
• •Increase dose to 300 mg/day given as one 150-mg tablet twice each day with an interval of at least 8 hours between each dose.
• •Do not exceed 300 mg/day.

ZYBAN should be swallowed whole and not crushed, divided, or chewed, as this may lead to an increased risk of adverse effects including seizures [see Warnings and Precautions (5.3)].

ZYBAN may be taken with or without food [see Clinical Pharmacology (12.3)].

2.2 Duration of Treatment

Treatment with ZYBAN should be continued for 7 to 12 weeks. If the patient has not quit smoking after 7 to 12 weeks, it is unlikely that he or she will quit during that attempt so treatment with ZYBAN should probably be discontinued and the treatment plan reassessed. The goal of therapy with ZYBAN is complete abstinence.

Discuss discontinuing treatment with ZYBAN after 12 weeks if the patient feels ready but consider whether the patient may benefit from ongoing treatment. Patients who successfully quit after 12 weeks of treatment but do not feel ready to discontinue treatment should be considered for ongoing therapy with ZYBAN; longer treatment should be guided by the relative benefits and risks for individual patients.

It is important that patients continue to receive counseling and support throughout treatment with ZYBAN and for a period of time thereafter.

2.3 Individualization of Therapy

Patients are more likely to quit smoking and remain abstinent if they are seen frequently and receive support from their physicians or other healthcare professionals. It is important to ensure that patients read the instructions provided to them and have their questions answered. Physicians should review the patient’s overall smoking cessation program that includes treatment with ZYBAN. Patients should be advised of the importance of participating in the behavioral interventions, counseling, and/or support services to be used in conjunction with ZYBAN [see Medication Guide].

Patients who fail to quit smoking during an attempt may benefit from interventions to improve their chances for success on subsequent attempts. Patients who are unsuccessful should be evaluated to determine why they failed. A new quit attempt should be encouraged when factors that contributed to failure can be eliminated or reduced, and conditions are more favorable.

2.4 Maintenance

Tobacco dependence is a chronic condition. Some patients may need on-going treatment. Whether to continue treatment with ZYBAN for periods longer than 12 weeks for smoking cessation must be determined for individual patients.

2.5 Combination Treatment With ZYBAN and a Nicotine Transdermal System (NTS)

Combination treatment with ZYBAN and NTS may be prescribed for smoking cessation. The prescriber should review the complete prescribing information for both ZYBAN and NTS before using combination treatment [see Clinical Studies (14)]. Monitoring for treatment‑emergent hypertension in patients treated with the combination of ZYBAN and NTS is recommended.

2.6 Dose Adjustment in Patients With Hepatic Impairment

In patients with moderate to severe hepatic impairment (Child-Pugh score: 7 to 15), the maximum dose should not exceed 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Use in Specific Populations (8.7) and Clinical Pharmacology (12.3)].

2.7 Dose Adjustment in Patients With Renal Impairment

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

Do not start ZYBAN 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 [see Contraindications (4) and Drug Interactions (7.6)].

In some cases, a patient already receiving therapy with ZYBAN 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, ZYBAN 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 ZYBAN 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 ZYBAN 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

150 mg – purple, round, biconvex, film‑coated, sustained-release tablets printed with “ZYBAN 150”.

4 CONTRAINDICATIONS

• •ZYBAN is contraindicated in patients with a seizure disorder.
• •ZYBAN is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence of seizures was observed in such patients treated with the immediate‑release formulation of bupropion [see Warnings and Precautions (5.3)].
• •ZYBAN is contraindicated in patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Warnings and Precautions (5.3) and Drug Interactions (7.3)].
• • The use of MAOIs (intended to treat psychiatric disorders) concomitantly with ZYBAN or within 14 days of discontinuing treatment with ZYBAN is contraindicated. There is an increased risk of hypertensive reactions when ZYBAN is used concomitantly with MAOIs. The use of ZYBAN within 14 days of discontinuing treatment with an MAOI is also contraindicated. Starting ZYBAN in a patient treated with reversible MAOIs such as linezolid or intravenous methylene blue is contraindicated [see Dosage and Administration (2.8), Warnings and Precautions (5.4), and Drug Interactions (7.6)].
• •ZYBAN is contraindicated in patients with a known hypersensitivity to bupropion or other ingredients of ZYBAN. Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported [see Warnings and Precautions (5.7)].

5 WARNINGS AND PRECAUTIONS

5.1 Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment

Serious neuropsychiatric symptoms have been reported in patients taking ZYBAN 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 ZYBAN who continued to smoke.

The risks of ZYBAN should be weighed against the benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking for as long as 6 months compared with treatment with placebo. The health benefits of quitting smoking are immediate and substantial.

5.2 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.

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 ZYBAN should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

5.3 Seizure

ZYBAN can cause seizure. The risk of seizure is dose-related. The dose of ZYBAN should not exceed 300 mg per day [see Dosage and Administration (2.1)]. Discontinue ZYBAN 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 ZYBAN. ZYBAN is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs [see Contraindications (4) and Drug Interactions (7.3)]. The following conditions can also increase the risk of seizure: severe head injury; arteriovenous malformation; CNS tumor or CNS infection; severe stroke; concomitant use of other medications that lower the seizure threshold (e.g., other bupropion products, antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), use of illicit drugs (e.g., cocaine), or abuse or misuse of prescription drugs such as CNS stimulants. Additional predisposing conditions include diabetes mellitus treated with oral hypoglycemic drugs or insulin; use of anorectic drugs; and excessive use of alcohol, benzodiazepines, sedative/hypnotics, or opiates.

Incidence of Seizure With Bupropion Use: Doses for smoking cessation should not exceed 300 mg per day. The seizure rate associated with doses of sustained‑release bupropion in depressed patients up to 300 mg per day is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1000) at doses up to 400 mg per day.

The risk of seizure can be reduced if the dose of ZYBAN for smoking cessation does not exceed 300 mg per day, given as 150 mg twice daily, and titration rate is gradual.

5.4 Hypertension

Treatment with ZYBAN can result in elevated blood pressure and hypertension. Assess blood pressure before initiating treatment with ZYBAN, and monitor periodically during treatment. The risk of hypertension is increased if ZYBAN is used concomitantly with MAOIs or other drugs that increase dopaminergic or noradrenergic activity [see Contraindications (4)].

Data from a comparative trial of ZYBAN, nicotine transdermal system (NTS), the combination of ZYBAN 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 ZYBAN and NTS. In this trial, 6.1% of subjects treated with the combination of ZYBAN and NTS had treatment‑emergent hypertension compared to 2.5%, 1.6%, and 3.1% of subjects treated with ZYBAN, NTS, and placebo, respectively. The majority of these subjects had evidence of pre-existing hypertension. Three subjects (1.2%) treated with the combination of ZYBAN 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 ZYBAN 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 episode. The risk appears to be increased in patients with bipolar disorder or who have risk factors for bipolar disorder. There were no reports of activation of psychosis or mania in clinical trials with ZYBAN conducted in nondepressed smokers. Bupropion is not approved for use in treating bipolar depression.

5.6 Psychosis and Other Neuropsychiatric Reactions

Depressed patients treated with bupropion in depression trials 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.

In clinical trials with ZYBAN conducted in nondepressed smokers, the incidence of neuropsychiatric side effects was generally comparable to placebo. However, in the postmarketing experience, patients taking ZYBAN to quit smoking have reported similar types of neuropsychiatric symptoms to those reported by patients in the clinical trials of bupropion for depression.

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 ZYBAN 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:

• •Neuropsychiatric symptoms and suicide risk in smoking cessation treatment [see Boxed Warning and Warnings and Precautions (5.1)]
• •Suicidal thoughts and behaviors in adolescents and young adults [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: Adverse reactions were sufficiently troublesome to cause discontinuation of treatment in 8% of the 706 subjects treated with ZYBAN and 5% of the 313 patients treated with placebo. The more common events leading to discontinuation of treatment with ZYBAN included nervous system disturbances (3.4%), primarily tremors, and skin disorders (2.4%), primarily rashes.

Commonly Observed Adverse Reactions: The most commonly observed adverse reactions consistently associated with the use of ZYBAN were dry mouth and insomnia. The incidence of dry mouth and insomnia may be related to the dose of ZYBAN. The occurrence of these adverse reactions may be minimized by reducing the dose of ZYBAN. In addition, insomnia may be minimized by avoiding bedtime doses.

Adverse reactions reported in the dose-response and comparator trials are presented in Table 2 and Table 3, respectively. Reported adverse reactions were classified using a COSTART‑based dictionary.

%

%

^aSubjects randomized to ZYBAN or placebo received placebo patches.

Adverse reactions in a 1-year maintenance trial and a 12-week COPD trial with ZYBAN were quantitatively and qualitatively similar to those observed in the dose‑response and comparator trials.

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 sustained‑release tablets (n = 3,100). All treatment‑emergent adverse reactions are included except those listed in Tables 2 and 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): Frequent were asthenia, fever, and headache. Infrequent were chills, inguinal hernia, and photosensitivity.Rare was malaise.

Cardiovascular: Infrequent were flushing, migraine, postural hypotension, stroke, tachycardia, and vasodilation. Rare was syncope.

Digestive: Frequent were dyspepsia and vomiting. Infrequent were abnormal liver function, bruxism, dysphagia, gastric reflux, gingivitis, jaundice, and stomatitis.

Hemic and Lymphatic: Infrequent was ecchymosis.

Metabolic and Nutritional: Infrequent were edema and peripheral edema.

Musculoskeletal: Infrequent were leg cramps and twitching.

Nervous System: Frequent were agitation, depression, and irritability. Infrequent were abnormal coordination, CNS stimulation, confusion, decreased libido, decreased memory, depersonalization, emotional lability, hostility, hyperkinesia, hypertonia, hypesthesia, paresthesia, suicidal ideation, and vertigo. Rare were amnesia, ataxia, derealization, and hypomania.

Respiratory: Rare was bronchospasm.

Skin: Frequent was sweating.

Special Senses: Frequent was blurred vision or diplopia. Infrequent were accommodation abnormality and dry eye.

Urogenital: Frequent was urinary frequency. Infrequent were impotence, polyuria, and urinary urgency.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of ZYBAN 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 relationship to drug exposure.

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

Cardiovascular: Cardiovascular disorder, complete AV block, extrasystoles, hypotension, myocardial infarction, phlebitis, and pulmonary embolism.

Digestive: Colitis, esophagitis, gastrointestinal hemorrhage, gum hemorrhage, hepatitis, increased salivation, intestinal perforation, liver damage, pancreatitis, stomach ulcer, and stool abnormality.

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: Arthritis and 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, prostate disorder, salpingitis, urinary incontinence, urinary retention, urinary tract disorder, and vaginitis.

7 DRUG INTERACTIONS

7.1 Potential for Other Drugs to Affect ZYBAN

Bupropion is primarily metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for drug interactions between ZYBAN 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 ZYBAN 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 ZYBAN 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 ZYBAN to Affect Other Drugs

Drugs Metabolized by CYP2D6: Bupropion and its metabolites (erythrohydrobupropion, threohydrobupropion, hydroxybupropion) are CYP2D6 inhibitors. Therefore, coadministration of ZYBAN 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 ZYBAN, 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 ZYBAN 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 ZYBAN 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 ZYBAN 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 ZYBAN. The consumption of alcohol during treatment with ZYBAN 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 and initiation of treatment with ZYBAN. Conversely, at least 14 days should be allowed after stopping ZYBAN before starting an MAOI intended to treat psychiatric disorders [see Dosage and Administration (2.8) and Contraindications (4)].

7.7 Smoking Cessation

Physiological changes resulting from smoking cessation, with or without treatment with ZYBAN, may alter the pharmacokinetics or pharmacodynamics of certain drugs (e.g., theophylline, warfarin, insulin) for which dosage adjustment may be necessary.

7.8 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 2 times the maximum recommended human dose (MRHD) and greater and decreased fetal weights were seen at doses three times the MRHD and greater. ZYBAN should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Clinical Considerations: Pregnant smokers should be encouraged to attempt cessation using educational and behavioral interventions before pharmacological approaches are used.

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 15 and 10 times the MRHD respectively, on a mg/m2 basis). No clear evidence of teratogenic activity was found in either species; however, in rabbits, slightly increased incidences of fetal malformations and skeletal variations were observed at the lowest dose tested (25 mg/kg/day, approximately 2 times 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 10 times the MRHD on a mg/m2 basis) prior to mating and throughout pregnancy and lactation, there were no apparent adverse effects on offspring development.

8.3 Nursing Mothers

Bupropion and its metabolites are present in human milk. In a lactation study of 10 women, levels of orally dosed bupropion and its active metabolites were measured in expressed milk. The average daily infant exposure (assuming 150 mL/kg daily consumption) to bupropion and its active metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when ZYBAN is 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 (5.2)].

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 (2.7), Use in Specific Populations (8.6), and Clinical Pharmacology (12.3)].

8.6 Renal Impairment

Consider a reduced dose and/or dosing frequency of ZYBAN 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 (2.7) 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 ZYBAN is 150 mg every other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider reducing the dose and/or frequency of dosing [see Dosage and Administration (2.6) 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.

The possibility that bupropion may induce dependence should be kept in mind when evaluating the desirability of including the drug in smoking cessation programs of individual patients.

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 Physicians’ 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

ZYBAN (bupropion hydrochloride) Sustained‑Release Tablets are a non‑nicotine aid to smoking cessation. ZYBAN is chemically unrelated to nicotine or other agents currently used in the treatment of nicotine addiction. Initially developed and marketed as an antidepressant (WELLBUTRIN [bupropion hydrochloride] Tablets and WELLBUTRIN SR [bupropion hydrochloride] Sustained‑Release Tablets), ZYBAN is also chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C₁₃H₁₈ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is: