Drug Name

Zyban (Bupropion)

Generic Name

Bupropion (byoo PRO pee on)

Looks like

• Zyban 150 mg-purple, round, biconvex, film-coated tablets

Dosage Form

Tablets

Route Of Administration

ORAL

Imprint Code

Zyban;150

Size

14mm

Alternatives

Smoking Cessation
Wellbutrin SR

Drug Uses

Bupropion is used to treat major depressive disorder and seasonal affective disorder. At least one brand of bupropion (Zyban) is used to help people stop smoking by reducing cravings and other withdrawal effects.

Drug class

Bupropion is an antidepressant medication.

Contains

Zyban Tablets are supplied for oral administration as 150-mg (purple), film-coated, sustained-release tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients carnauba wax, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline cellulose, polyethylene glycol, polysorbate 80 and titanium dioxide and is printed with edible black ink. In addition, the 150-mg tablet contains FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake.

Chemical formula

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 (±) - 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:

Mechanism of Action

Bupropion is a relatively weak inhibitor of the neuronal uptake of norepinephrine and dopamine, and does not inhibit monoamine oxidase or the re-uptake of serotonin. The mechanism by which Zyban enhances the ability of patients to abstain from smoking is unknown. However, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.

How Taken

Take zyban exactly as it was prescribed for you. Do not take it in larger doses or for longer than recommended by your doctor. Follow the directions on your prescription label.

Zyban can be taken with or without food.

Do not crush, chew, or break the extended-release tablet (Wellbutrin SR, Wellbutrin XL, Zyban SR). Swallow the pill whole. It is specially made to release medicine slowly in the body. Breaking the pill would cause too much of the drug to be released at one time.
If you take Zyban to help you stop smoking, you may continue to smoke for about 1 week after you start the medicine. Set a date to quit smoking during the second week of Zyban treatment. By that time you will have enough of the medicine in your blood stream to help you quit smoking. Talk to your doctor if you are having trouble quitting after you have used Zyban for at least 7 weeks.

Your doctor may prescribe nicotine patches or gum to help support your smoking cessation treatment. Be sure you read all directions and safety information for the nicotine product. Using nicotine with Zyban may raise your blood pressure and your doctor may want to check your blood pressure regularly. Do not smoke at any time if you are using a nicotine product along with Zyban. Too much nicotine can cause serious side effects.

Do not stop taking zyban without first talking to your doctor. You may have unpleasant side effects if you stop taking this medication suddenly.
If you use the zyban extended-release tablet, the tablet shell may pass into your stools (bowel movements). This is normal and does not mean that you are not receiving enough of the medicine.

Dosage and Administration

Usual Dosage for Adults
The recommended and maximum dose of Zyban is 300 mg/day, given as 150 mg twice daily. Dosing should begin at 150 mg/day given every day for the first 3 days, followed by a dose increase for most patients to the recommended usual dose of 300 mg/day. There should be an interval of at least 8 hours between successive doses. Doses above 300 mg/day should not be used (see WARNINGS). Zyban should be swallowed whole and not crushed, divided, or chewed. Treatment with Zyban should be initiated while the patient is still smoking, since approximately 1 week of treatment is required to achieve steady-state blood levels of bupropion. Patients should set a "target quit date" within the first 2 weeks of treatment with Zyban, generally in the second week. Treatment with Zyban should be continued for 7 to 12 weeks; longer treatment should be guided by the relative benefits and risks for individual patients. If a patient has not made significant progress towards abstinence by the seventh week of therapy with Zyban, it is unlikely that he or she will quit during that attempt, and treatment should probably be discontinued. Conversely, a patient who successfully quits after 7 to 12 weeks of treatment should be considered for ongoing therapy with Zyban. Dose tapering of Zyban is not required when discontinuing treatment. It is important that patients continue to receive counseling and support throughout treatment with Zyban, and for a period of time thereafter.

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 information for patients at the end of the package insert.

The goal of therapy with Zyban is complete abstinence. If a patient has not made significant progress towards abstinence by the seventh week of therapy with Zyban, it is unlikely that he or she will quit during that attempt, and treatment should probably be discontinued.

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.

Maintenance
Nicotine dependence is a chronic condition. Some patients may need continuous treatment. Systematic evaluation of Zyban 300 mg/day for maintenance therapy demonstrated that treatment for up to 6 months was efficacious. Whether to continue treatment with Zyban for periods longer than 12 weeks for smoking cessation must be determined for individual patients.

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 also CLINICAL TRIALS for methods and dosing used in the Zyban and NTS combination trial. Monitoring for treatment-emergent hypertension in patients treated with the combination of Zyban and NTS is recommended.

Dosage Adjustment for Patients with Impaired Hepatic Function
Zyban should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 150 mg every other day in these patients. Zyban should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a reduced frequency of dosing should be considered in patients with mild to moderate hepatic cirrhosis.

Dosage Adjustment for Patients with Impaired Renal Function
Zyban should be used with caution in patients with renal impairment and a reduced frequency of dosing should be considered.

Missed Dose

Take the missed dose as soon as you remember. If it is almost time for your next dose, skip the missed dose and take the medicine at the next regularly scheduled time. Do not take extra medicine to make up the missed dose.

Overdose

Seek emergency medical attention if you think you have used too much of this medicine. Overdose symptoms may include seizures, muscle stiffness, hallucinations, fainting, fast or uneven heartbeat, shallow breathing, heart failure, or coma.

Storage

Store at room temperature in a tightly closed container. Keep out of direct sunlight.

How Supplied

Zyban Sustained-Release Tablets, 150 mg of bupropion hydrochloride, are purple, round, biconvex, film-coated tablets printed with "Zyban 150" in bottles of 60 (NDC 0173-0556-02) tablets and the Zyban Advantage Pack containing 1 bottle of 60 (NDC 0173-0556-01) tablets.

What is the most important information I should know about Zyban (Bupropion)?

You should not take zyban if you have epilepsy or a seizure disorder, an eating disorder such as anorexia or bulimia, if you are using a second form of zyban, or if you have suddenly stopped using alcohol or sedatives. Do not take zyban if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl), or tranylcypromine (Parnate) in the last 14 days.
You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.

Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.
Avoid using zyban to treat more than one condition at a time. If you take Wellbutrin for depression, do not also take Zyban to quit smoking. Too much of this medicine can increase your risk of a seizure.

Do not smoke at any time if you are using a nicotine product along with Zyban. Too much nicotine can cause serious side effects. Avoid drinking alcohol while taking zyban. Alcohol may increase your risk of a seizure while you are taking zyban. If you drink alcohol regularly, talk with your doctor before changing the amount you drink. Zyban can cause seizures in people who drink a lot of alcohol and then suddenly quit drinking when they start using the medication.

What should I discuss with my doctor before taking Zyban (Bupropion)?

Do not take zyban if you have taken a monoamine oxidase inhibitor (MAOI) such as isocarboxazid (Marplan), phenelzine (Nardil), rasagiline (Azilect), selegiline (Eldepryl), or tranylcypromine (Parnate) in the last 14 days. You should not take zyban if you have:

• epilepsy or a seizure disorder;
• an eating disorder such as anorexia or bulimia;
• if you are using a second form of zyban; or
• if you have suddenly stopped using alcohol or sedatives (such as Valium).

Zyban may cause seizures, especially in people with certain medical conditions or when using certain drugs. Tell your doctor about all of your medical conditions and the drugs you use.

Before taking zyban, tell your doctor if you have:

• heart disease or high blood pressure;
• head injury, brain or spinal cord tumor;
• kidney disease;
• liver disease (especially cirrhosis);
• bipolar disorder (manic depression);
• diabetes for which you use insulin or take oral medication;
• if you currently use steroids, theophylline (Theo-Dur, Slo-Bid, Bronkodyl Theolair, Respbid), or medicine to treat depression or mental illness; or
• if you recently used alcohol, sedatives (such as Valium), narcotic pain medicines, diet pills, or street drugs such as "speed" or cocaine.

If you have any of these conditions, you may not be able to use zyban, or you may need a dosage adjustment or special tests during treatment.

You may have thoughts about suicide when you first start taking an antidepressant, especially if you are younger than 24 years old. Tell your doctor if you have worsening symptoms of depression or suicidal thoughts during the first several weeks of treatment, or whenever your dose is changed.

Your family or other caregivers should also be alert to changes in your mood or symptoms. Your doctor will need to check you at regular visits for at least the first 12 weeks of treatment.

FDA pregnancy category C. This medication may be harmful to an unborn baby. Tell your doctor if you are pregnant or plan to become pregnant during treatment. Zyban passes into breast milk and could be harmful to a nursing baby. Do not take zyban without telling your doctor if you are breast-feeding a baby. Do not give this medication to anyone younger than 18 years old without the advice of a doctor.

Absorption

Bupropion has not been administered intravenously to humans; therefore, the absolute bioavailability of Zyban Sustained-Release Tablets in humans has not been determined. In rat and dog studies, the bioavailability of bupropion ranged from 5% to 20%.

Following oral administration of Zyban to healthy volunteers, peak plasma concentrations of bupropion are achieved within 3 hours. The mean peak concentration (Cmax) values were 91 and 143 ng/mL from 2 single-dose (150-mg) studies. At steady state, the mean Cmax following a 150-mg dose every 12 hours is 136 ng/mL.

In a single-dose study, food increased the Cmax of bupropion by 11% and the extent of absorption as defined by area under the plasma concentration-time curve (AUC) by 17%. The mean time to peak concentration (Tmax) was prolonged by 1 hour. This effect was of no clinical significance.

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. The volume of distribution (Vss/F) estimated from a single 150-mg dose given to 17 subjects is 1,950 L (20% CV).

Metabolism

Bupropion is extensively metabolized in humans. Three metabolites have been shown to be 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 cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 isoenzymes 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 or higher than those of bupropion.

Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6 (CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is coadministered with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions).

Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 6 hours after administration of Zyban Tablets. Peak plasma concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug at steadystate. The elimination half-life of hydroxybupropion is approximately 20 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/day.

Elimination

The mean apparent clearance (Cl/F) estimated from 2 single-dose (150-mg) studies are 135 and 209 L/hr. Following chronic dosing of 150 mg of Zyban every 12 hours for 14 days (n = 34), the mean Cl/F at steady state was 160 L/hr. The mean elimination half-life of bupropion estimated from a series of studies is approximately 21 hours. Estimates of the half-lives of the metabolites determined from a multiple-dose study were 20 hours for hydroxybupropion, 37 hours for threohydrobupropion, and 33 hours for erythrohydrobupropion. Steady-state plasma concentrations of bupropion and metabolites are reached within 5 and 8 days, respectively.

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. The fraction of the oral dose of bupropion excreted unchanged was only 0.5%.

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 Zyban, there was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of bupropion or its major metabolites between smokers and nonsmokers.

In a study comparing the treatment combination of Zyban and nicotine transdermal system (NTS) versus Zyban alone, no statistically significant differences were observed between the 2 treatment groups of combination Zyban and NTS (n = 197) and Zyban alone (n = 193) in the plasma concentrations of bupropion or its active metabolites at weeks 3 and 6.

Special Populations

Hepatic

The effect of hepatic impairment on the pharmacokinetics of bupropion was characterized in 2 single-dose studies, one in patients with alcoholic liver disease and one in patients with mild to severe cirrhosis. The first study showed that the half-life of hydroxybupropion was significantly longer in 8 patients 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 patients with alcoholic liver disease. The differences in half-life for bupropion and the other metabolites in the 2 patient groups were minimal.

The second study showed that there were no statistically significant differences in the pharmacokinetics of bupropion and its active metabolites in 9 patients with mild to moderate hepatic cirrhosis compared to 8 healthy volunteers. However, more variability was observed in some of the pharmacokinetic parameters for bupropion (AUC, Cmax, and Tmax) and its active metabolites (t1/2) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion Cmax and AUC were substantially increased (mean difference: by approximately 70% and 3-fold, respectively) and more variable when compared to values in healthy volunteers; the mean bupropion half-life was also longer (29 hours in patients with severe hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite hydroxybupropion, the mean Cmax was approximately 69% lower.For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cmax was approximately 31% lower. The mean AUC increased by 28% for hydroxybupropion and 50% for threo/erythrohydrobupropion.The median Tmax was observed 19 hours later for hydroxybupropion and 21 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 2- and 4-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers.

Renal

There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug Cmax 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 patients with end-stage renal failure. The elimination of the major metabolites of bupropion may be reduced by impaired renal function.

Left Ventricular Dysfunction

During a chronic dosing study with bupropion in 14 depressed patients with left ventricular dysfunction (history of CHF or an enlarged heart on x-ray), no apparent effect on the pharmacokinetics of bupropion or its metabolites, compared to healthy normal volunteers, was revealed.

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 studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times a day schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of bupropion. A single-dose pharmacokinetic study 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 pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites.

Gender

A single-dose study involving 12 healthy male and 12 healthy female volunteers revealed no sex-related differences in the pharmacokinetic parameters of bupropion.

Possible side effects

Get emergency medical help if you have any of these signs of an allergic reaction: hives; difficulty breathing; swelling of your face, lips, tongue, or throat.

Call your doctor at once if you have any new or worsening symptoms such as: mood or behavior changes, anxiety, panic attacks, trouble sleeping, or if you feel impulsive, irritable, agitated, hostile, aggressive, restless, hyperactive (mentally or physically), more depressed, or have thoughts about suicide or hurting yourself.

Less serious side effects may be more likely to occur, such as:

• headache or migraine;
• nausea, vomiting, constipation, dry mouth;
• confusion, dizziness, tremors (shaking);
• appetite changes, weight loss or gain;
• mild itching or skin rash, increased sweating; or
• loss of interest in sex.

This is not a complete list of side effects and others may occur. Tell your doctor about any unusual or bothersome side effect.

What other drugs will affect Zyban (Bupropion)?

There are many other drugs that can interact with zyban. Tell your doctor about all the prescription and over-the-counter medications you use. This includes vitamins, minerals, herbal products, and drugs prescribed by other doctors. Do not start using a new medication without telling your doctor.

What should I avoid while taking Zyban (Bupropion)?

Avoid drinking alcohol while taking zyban. Alcohol may increase your risk of a seizure while you are taking zyban. If you drink alcohol regularly, talk with your doctor before changing the amount you drink. Zyban can cause seizures in people who drink a lot of alcohol and then suddenly quit drinking when they start using the medication.
Avoid using zyban to treat more than one condition at a time. If you take Wellbutrin for depression, do not also take Zyban to quit smoking. Too much of this medicine can increase your risk of a seizure.

Zyban can cause side effects that may impair your thinking or reactions. Be careful if you drive or do anything that requires you to be awake and alert.

Contraindications

Zyban is contraindicated in patients with a seizure disorder.

Zyban is contraindicated in patients treated with WELLBUTRIN (bupropion hydrochloride), the immediate-release formulation; WELLBUTRIN SR (bupropion hydrochloride), the sustained-release formulation; WELLBUTRIN XL (bupropion hydrochloride), the extended-release formulation; or any other medications that contain bupropion because the incidence of seizure is dose dependent.

Zyban is contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in patients treated for bulimia with the immediate-release formulation of bupropion.

Zyban is contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines).

The concurrent administration of Zyban and a monoamine oxidase (MAO) inhibitor is contraindicated. At least 14 days should elapse between discontinuation of an MAO inhibitor and initiation of treatment with Zyban.

Zyban is contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up Zyban.

Warnings

Clinical Worsening and Suicide Risk
Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, 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 (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older.

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

No suicides occurred in any of these 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.

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 major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Zyban should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

Screening Patients for Bipolar Disorder
A major depressive episode may be the initial presentation of bipolar disorder. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. Whether any of the symptoms described above represent such a conversion is unknown. However, prior to initiating treatment with an antidepressant, patients with depressive symptoms should be adequately screened to determine if they are at risk for bipolar disorder; such screening should include a detailed psychiatric history, including a family history of suicide, bipolar disorder, and depression. It should be noted that Zyban is not approved for use in treating bipolar depression.

Patients should be made aware that Zyban contains the same active ingredient found in WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL used to treat depression, and that Zyban should not be used in combination with WELLBUTRIN (bupropion hydrochloride), the immediate release formulation; WELLBUTRIN SR (bupropion hydrochloride), the sustained-release formulation; WELLBUTRIN XL (bupropion hydrochloride), the extended-release formulation; or any other medications that contain bupropion.

Seizures
Because the use of bupropion is associated with a dose-dependent risk of seizures, clinicians should not prescribe doses over 300 mg/day for smoking cessation. The risk of seizures is also related to patient factors, clinical situation, and concomitant medications, which must be considered in selection of patients for therapy with Zyban. Zyban should be discontinued and not restarted in patients who experience a seizure while on treatment.

• Dose: For smoking cessation, doses above 300 mg/day should not be used. The seizure rate associated with doses of sustained-release bupropion up to 300 mg/day is approximately 0.1% (1/1,000). This incidence was prospectively determined during an 8-week treatment exposure in approximately 3,100 depressed patients.

Data for the immediate-release formulation of bupropion revealed a seizure incidence of approximately 0.4% (4/1,000) in depressed patients treated at doses in a range of 300 to 450 mg/day. In addition, the estimated seizure incidence increases almost tenfold between 450 and 600 mg/day.

• Patient factors: Predisposing factors that may increase the risk of seizure with bupropion use include history of head trauma or prior seizure, central nervous system (CNS) tumor, the presence of severe hepatic cirrhosis, and concomitant medications that lower seizure threshold.
• Clinical situations: Circumstances associated with an increased seizure risk include, among others, excessive use of alcohol or sedatives (including benzodiazepines); addiction to opiates, cocaine, or stimulants; use of over-the-counter stimulants and anorectics; and diabetes treated with oral hypoglycemics or insulin.
• Concomitant medications: Many medications (e.g., antipsychotics, antidepressants, theophylline, systemic steroids) are known to lower seizure threshold.

Recommendations for Reducing the Risk of Seizure
Retrospective analysis of clinical experience gained during the development of bupropion suggests that the risk of seizure may be minimized if

• the total daily dose of Zyban does not exceed 300 mg (the maximum recommended dose for smoking cessation), and
• the recommended daily dose for most patients (300 mg/day) is administered in divided doses (150 mg twice daily).
• No single dose should exceed 150 mg to avoid high peak concentrations of bupropion and/or its metabolites.

Zyban should be administered with extreme caution to patients with a history of seizure, cranial trauma, or other predisposition(s) toward seizure, or patients treated with other agents (e.g., antipsychotics, antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold.

Hepatic Impairment
Zyban should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced frequency of dosing is required, as peak bupropion levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 150 mg every other day in these patients.

Potential for Hepatotoxicity
In rats receiving large doses of bupropion chronically, there was an increase in incidence of hepatic hyperplastic nodules and hepatocellular hypertrophy. In dogs receiving large doses of bupropion chronically, various histologic changes were seen in the liver, and laboratory tests suggesting mild hepatocellular injury were noted.

Precautions

Allergic Reactions
Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported at a rate of about 1 to 3 per thousand in clinical trials of Zyban. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. A patient should stop taking Zyban and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic reactions (e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath) during treatment.

Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.

Insomnia
In the dose-response smoking cessation trial, 29% of patients treated with 150 mg/day of Zyban and 35% of patients treated with 300 mg/day of Zyban experienced insomnia, compared to 21% of placebo-treated patients. Symptoms were sufficiently severe to require discontinuation of treatment in 0.6% of patients treated with Zyban and none of the patients treated with placebo.

In the comparative trial, 40% of the patients treated with 300 mg/day of Zyban, 28% of the patients treated with 21 mg/day of NTS, and 45% of the patients treated with the combination of Zyban and NTS experienced insomnia compared to 18% of placebo-treated patients. Symptoms were sufficiently severe to require discontinuation of treatment in 0.8% of patients treated with Zyban and none of the patients in the other 3 treatment groups.

Insomnia may be minimized by avoiding bedtime doses and, if necessary, reduction in dose.

Psychosis, Confusion, and Other Neuropsychiatric Phenomena
In clinical trials with Zyban conducted in nondepressed smokers, the incidence of neuropsychiatric side effects was generally comparable to placebo. Depressed patients treated with bupropion in depression trials have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.

In clinical trials with Zyban conducted in nondepressed smokers, the incidence of neuropsychiatric side effects was generally comparable to placebo. Depressed patients treated with bupropion in depression trials have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. In some cases, these symptoms abated upon dose reduction and/or withdrawal of treatment.

Activation of Psychosis and/or Mania
Antidepressants can precipitate manic episodes in bipolar disorder patients during the depressed phase of their illness and may activate latent psychosis in other susceptible individuals. The sustained-release formulation of bupropion is expected to pose similar risks. There were no reports of activation of psychosis or mania in clinical trials with Zyban conducted in nondepressed smokers.

Depression and Nicotine Withdrawal
Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in patients undergoing a smoking cessation attempt.

Cardiovascular Effects
In clinical practice, hypertension, in some cases severe, requiring acute treatment, has been reported in patients receiving bupropion alone and in combination with nicotine replacement therapy. These events have been observed in both patients with and without evidence of preexisting hypertension.

Data from a comparative study of Zyban, 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 Zyban and NTS. In this study, 6.1% of patients treated with the combination of Zyban and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with Zyban, NTS, and placebo, respectively. The majority of these patients had evidence of preexisting hypertension.Three patients (1.2%) treated with the combination of Zyban and NTS and 1 patient (0.4%) treated with NTS had study medication discontinued due to hypertension compared to none of the patients treated with Zyban or placebo. Monitoring of blood pressure is recommended in patients who receive the combination of bupropion and nicotine replacement.

There is no clinical experience establishing the safety of Zyban in patients with a recent history of myocardial infarction or unstable heart disease. Therefore, care should be exercised if it is used in these groups. Bupropion was well tolerated in depressed patients who had previously developed orthostatic hypotension while receiving tricyclic antidepressants, and was also generally well tolerated in a group of 36 depressed inpatients with stable congestive heart failure (CHF). However, bupropion was associated with a rise in supine blood pressure in the study of patients with CHF, resulting in discontinuation of treatment in 2 patients for exacerbation of baseline hypertension.

Hepatic Impairment
Zyban should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency of dosing is required. Zyban should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and reduced frequency of dosing should be considered in patients with mild to moderate hepatic cirrhosis.

All patients with hepatic impairment should be closely monitored for possible adverse effects that could indicate high drug and metabolite levels.

Renal Impairment
There is limited information on the pharmacokinetics of bupropion in patients with renal impairment. An inter-study comparison between normal subjects and patients with end-stage renal failure demonstrated that the parent drug Cmax 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 patients with end-stage renal failure. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. Zyban should be used with caution in patients with renal impairment and a reduced frequency of dosing should be considered as bupropion and the metabolites of bupropion may accumulate in such patients to a greater extent than usual. The patient should be closely monitored for possible adverse effects that could indicate high drug or metabolite levels.

Information For Patients

Carcinogenesis/ Mutagenesis/ Impairment of Fertility

Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg per day, respectively. These doses are approximately 10 and 2 times the maximum recommended human dose (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 per day (approximately 3 to 10 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 test and an increase in chromosomal aberrations in 1 of 3 in vivo rat bone marrow cytogenic studies.

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

Pregnancy

Teratogenic Effects
Pregnancy Category C: In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 and 150 mg/kg/day, respectively (approximately 14 and 10 times the maximum recommended human dose [MRHD], respectively, on a mg/m2 basis), during the period of organogenesis. 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 seen 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.

One study has been conducted in pregnant women. This retrospective, managed-care database study assessed the risk of congenital malformations overall, and cardiovascular malformations specifically, following exposure to bupropion in the first trimester compared to the risk of these malformations following exposure to other antidepressants in the first trimester and bupropion outside of th