PRECAUTIONS

General

Agitation and Insomnia

Patients in placebo-controlled trials with bupropion hydrochloride extended- release tablets (SR) experienced agitation, anxiety and insomnia as shown in Table 2.

Table 2: Incidence of Agitation, Anxiety and Insomnia in Placebo- Controlled Trials

Adverse Event Term	Bupropion Hydrochloride Extended-Release Tablets (SR) 300 mg/day (n=376)	Bupropion Hydrochloride Extended-Release Tablets (SR) 400 mg/day (n=114)	Placebo (n=385)
Agitation Anxiety Insomnia	3% 5% 11%	9% 6% 16%	2% 3% 6%

In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs.

Symptoms were sufficiently severe to require discontinuation of treatment in 1% and 2.6% of patients treated with 300 mg/day and 400 mg/day, respectively, of bupropion hydrochloride extended-release tablets (SR) and 0.8% of patients treated with placebo.

Psychosis, Confusion and Other Neuropsychiatric Phenomena

Depressed patients treated with an immediate-release formulation of bupropion or with bupropion hydrochloride extended-release tablets (SR) 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 patients. Bupropion hydrochloride extended-release tablets (SR) are expected to pose similar risks.

Altered Appetite and Weight

In placebo-controlled studies, patients experienced weight gain or weight loss as shown in Table 3.

Table 3: Incidence of Weight Gain and Weight Loss in Placebo- Controlled Trials

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

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

Allergic Reactions

Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. 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 bupropion hydrochloride extended-release tablets (SR) 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.

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 the extended-release formulation of bupropion (ZYBAN® Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of extended-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 extended-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of extended-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6% and 3.1% of patients treated with extended-release bupropion, 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 one 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 bupropion hydrochloride extended-release tablets (SR) 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

Bupropion hydrochloride extended-release tablets (SR) should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced frequency and/or dose is required. Bupropion hydrochloride extended- release tablets (SR) should be used with caution in patients with hepatic impairment (including mild-to-moderate hepatic cirrhosis) and reduced frequency and/or dose 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 (see CLINICAL PHARMACOLOGY**,**WARNINGSandDOSAGE AND ADMINISTRATION).

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. A second study, comparing normal subjects and patients with moderate-to-severe renal impairment (GFR 30.9 ± 10.8 mL/min) showed that exposure to a single 150-mg dose of sustained-release bupropion was approximately 2-fold higher in patients with impaired renal function while levels of the hydroxybupropion and threo/erythrohydrobupropion (combined) metabolites were similar in the 2 groups. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. Bupropion hydrochloride extended-release tablets (SR) should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered 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

Prescribers or other health professionals should inform patients, their families, and their caregivers about the benefits and risks associated with treatment with bupropion hydrochloride extended-release tablets (SR) and should counsel them in its appropriate use. A patient Medication Guide about “Antidepressant Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts or Actions,” “Quitting Smoking, Quit-Smoking Medication, Changes in Thinking and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What other important information should I know about bupropion hydrochloride extended-release tablets (SR)?” is available for bupropion hydrochloride extended-release tablets (SR). The prescriber or health professional should instruct patients, their families, and their caregivers to read the Medication Guide and should assist them in understanding its contents. Patients should be given the opportunity to discuss the contents of the Medication Guide and to obtain answers to any questions they may have. The complete text of the Medication Guide is reprinted at the end of this document.

Patients should be advised of the following issues and asked to alert their prescriber if these occur while taking bupropion hydrochloride extended- release tablets (SR).

Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders

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

Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment

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

Bupropion-Containing Products

Patients should be made aware that bupropion hydrochloride extended-release tablets (SR) contain the same active ingredient found in ZYBAN**®, used as an aid to smoking cessation treatment and that bupropion hydrochloride extended-release tablets (SR) should not be used in combination with ZYBAN®** or any other medications that contain bupropion hydrochloride, such as WELLBUTRIN (bupropion hydrochloride tablets), the immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride extended-release tablets (XL)), the extended-release formulation.

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

Patients should be told that bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted if they experience a seizure while on treatment.

Patients should be told that any CNS-active drug like bupropion hydrochloride extended-release tablets (SR) may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion hydrochloride extended-release tablets (SR) do not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.

Patients should be told that the excessive use or abrupt discontinuation of alcohol or sedatives (including benzodiazepines) may alter the seizure threshold. Some patients have reported lower alcohol tolerance during treatment with bupropion hydrochloride extended-release tablets (SR). Patients should be advised that the consumption of alcohol should be minimized or avoided.

Patients should be advised to inform their physicians if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because bupropion hydrochloride extended-release tablets (SR) and other drugs may affect each other’s metabolism.

Patients should be advised to notify their physicians if they become pregnant or intend to become pregnant during therapy.

Patients should be advised to swallow bupropion hydrochloride extended-release tablets (SR) whole so that the release rate is not altered. Do not chew, divide or crush tablets, as this may lead to an increased risk of adverse effects, including seizures.

Laboratory Tests

There are no specific laboratory tests recommended.

Drug Interactions

Few systemic data have been collected on the metabolism of bupropion following concomitant administration with other drugs or, alternatively, the effect of concomitant administration of bupropion on the metabolism of other drugs.

Because bupropion is extensively metabolized, the co-administration of other drugs may affect its clinical activity. In vitro studies indicate that bupropion is primarily metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore, the potential exists for a drug interaction between bupropion hydrochloride extended-release tablets (SR) and drugs that are substrates of or inhibitors/inducers of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, cyclophosphamide, ticlopidine and clopidogrel). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine and fluvoxamine as well as nelfinavir and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this finding. The threohydrobupropion metabolite of bupropion does not appear to be produced by the cytochrome P450 isoenzymes. The effects of concomitant administration of cimetidine on the pharmacokinetics of bupropion and its active metabolites were studied in 24 healthy young male volunteers. Following oral administration of two 150 mg bupropion hydrochloride extended-release tablets (SR) with and without 800 mg of cimetidine, the pharmacokinetics of bupropion and hydroxybupropion were unaffected. However, there were 16% and 32% increases in the AUC and Cmax, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion.

In a series of studies in healthy volunteers, ritonavir (100 mg twice daily or 600 mg twice daily) or ritonavir 100 mg plus lopinavir 400 mg (KALETRA) twice daily reduced the exposure of bupropion and its major metabolites in a dose dependent manner by approximately 20% to 80%. This effect is thought to be due to the induction of bupropion metabolism. Patients receiving ritonavir may need increased doses of bupropion, but the maximum recommended dose of bupropion should not be exceeded (see**CLINICAL PHARMACOLOGY, **Metabolism).

While not systematically studied, certain drugs may induce the metabolism of bupropion (e.g., carbamazepine, phenobarbital, phenytoin).

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

Animal data indicated that bupropion may be an inducer of drug-metabolizing enzymes in humans. In one study, following chronic administration of bupropion, 100 mg 3 times daily to 8 healthy male volunteers for 14 days, there was no evidence of induction of its own metabolism. Nevertheless, there may be the potential for clinically important alterations of blood levels of co-administered drugs.

Drugs Metabolized By Cytochrome P450IID6 (CYP2D6)

Many drugs, including most antidepressants (SSRIs, many tricyclics), beta- blockers, antiarrhythmics and antipsychotics are metabolized by the CYP2D6 isoenzyme. Although bupropion is not metabolized by this isoenzyme, bupropion and hydroxybupropion are inhibitors of CYP2D6 isoenzyme in vitro. In a study of 15 male subjects (ages 19 to 35 years) who were extensive metabolizers of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg twice daily followed by a single dose of 50 mg desipramine increased the Cmax, AUC and t1/2 of desipramine by an average of approximately 2-, 5- and 2-fold, respectively. The effect was present for at least 7 days after the last dose of bupropion. Concomitant use of bupropion with other drugs metabolized by CYP2D6 has not been formally studied.

Therefore, co-administration of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including certain antidepressants (e.g., 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), should be approached with caution and should be initiated at the lower end of the dose range of the concomitant medication. If bupropion is added to the treatment regimen of a patient already receiving a drug metabolized by CYP2D6, the need to decrease the dose of the original medication should be considered, particularly for those concomitant medications with a narrow therapeutic index.

Although citalopram is not primarily metabolized by CYP2D6, in one study bupropion increased the Cmax and AUC of citalopram by 30% and 40%, respectively. Citalopram did not affect the pharmacokinetics of bupropion and its 3 metabolites.

MAO Inhibitors

Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine (seeCONTRAINDICATIONS).

Levodopa and Amantadine

Limited clinical data suggest a higher incidence of adverse experiences in patients receiving bupropion concurrently with either levodopa or amantadine. Administration of bupropion hydrochloride extended-release tablets (SR) to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and gradual dose increases.

Drugs That Lower Seizure Threshold

Concurrent administration of bupropion hydrochloride extended-release tablets (SR) and agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution (seeWARNINGS). Low initial dosing and gradual dose increases should be employed.

Nicotine Transdermal System:(see**PRECAUTIONS,**Cardiovascular Effects).

Alcohol

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

Carcinogenesis, Mutagenesis, Impairment of Fertility

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

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

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

Pregnancy

Teratogenic Effects

Pregnancy Category C: In studies conducted in rats and rabbits, bupropion was administered orally at doses up to 450 mg/kg/day and 150 mg/kg/day, respectively (approximately 11 and 7 times the 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 equal to 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 7 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 the first trimester. This study included 7,005 infants with antidepressant exposure during pregnancy, 1,213 of whom were exposed to bupropion in the first trimester. The study showed no greater risk for congenital malformations overall or cardiovascular malformations specifically, following first trimester bupropion exposure compared to exposure to all other antidepressants in the first trimester or bupropion outside of the first trimester. The results of this study have not been corroborated. Bupropion hydrochloride extended-release tablets (SR) should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Labor and Delivery

The effect of bupropion hydrochloride extended-release tablets (SR) on labor and delivery in humans is unknown.

Nursing Mothers

Like many other drugs, bupropion and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from bupropion hydrochloride extended-release tablets (SR), a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness in the pediatric population have not been established (seeBOX WARNING and**WARNINGS,**Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders). Anyone considering the use of bupropion hydrochloride extended-release tablets (SR) in a child or adolescent must balance the potential risks with the clinical need.

Geriatric Use

Of the approximately 6,000 patients who participated in clinical trials with bupropion extended-release tablets (SR) (depression and smoking cessation studies), 275 were 65 and over and 47 were 75 and over. In addition, several hundred patients 65 and over participated in clinical trials using the immediate-release formulation of bupropion (depression studies). No overall differences in safety or effectiveness were observed between these subjects and younger subjects and other 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.

A single-dose pharmacokinetic study demonstrated that the disposition of bupropion and its metabolites in elderly subjects was similar to that of younger subjects; however, another pharmacokinetic study, single and multiple dose, has suggested that the elderly are at increased risk for accumulation of bupropion and its metabolites (seeCLINICAL PHARMACOLOGY).

Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and excreted by the kidneys. The risk of toxic reaction to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection and it may be useful to monitor renal function (seePRECAUTIONS,****Renal ImpairmentandDOSAGE AND ADMINISTRATION).