WARNING. Suicidality and Antidepressant Drugs. Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared to.
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PRESCRIBING INFORMATION WELLBUTRIN® (bupropion hydrochloride) Tablets WARNING Suicidality and Antidepressant Drugs Use in Treating Psychiatric Disorders: Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive di sorder (MDD) and other psychiatric disorders. Anyone considering the use of WELLBUTRIN or any other antidepre ssant in a child, adolescent, or young adult must balance this risk with the clin ical need. 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 in risk with antidepressan ts compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of a ll ages who are started on antidepressant therapy should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregive rs should be advised of the need for close observation and communication with the prescriber. WELLBUT RIN is not approved for use in pediatric patients. (See WARN INGS: Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders, PRECAUTIONS: Info rmation for Patients, and PRECAUTIONS: Pediatric Use.) Use in Smoking Cessation Treatment: WELLBUTRIN®, WELLBUTRIN SR®, and WELLBUTRIN XL® are not approved for smoking cessation treatment, but bupropion under the name ZYBAN ® is approved for this use. Serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide have been reported in patients taking bupropion for sm oking cessation. Some cases may have been complicated by the symptoms of nicotine wi thdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotin e withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms ha ve occurred in patients taking bupropion who continued to smoke. All patients being treated with bupropion for smoking cessation treatment should be observed for neuropsychiatric symptoms including change s in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of pre-existing psychiatric illness and completed suicide have been reported in some patients attempting to quit smoking while taking ZYBAN in the postmarketing experience. When symptoms were reported, most were during treatment with ZYBAN, but some were following disc ontinuation of treatment with ZYBAN. These events have occurred in patients with and without pre-existi ng psychiatric disease; some have experienced 1 Reference ID: 2978172
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worsening of their psychiatric illnesses. Patien ts with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depr essive disorder did not participate in the premarketing studies of ZYBAN. Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion and contact a healthcare provider immediately if agitation, hostility, depressed mood, or changes in thinki ng or behavior that are not typical for the patient are observed, or if the patient develo ps suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symp toms after discontinuation of ZYBAN was reported, although in some cases the symptoms persisted; therefore, ongoing monitoring and supportive care should be provided until symptoms resolve. The risks of using bupropion for smoking cessati on should be weighed against the benefits of its use. ZYBAN has been demonstrated to in crease the likelihood of abstinence from smoking for as long as 6 months compared to treatment with placebo. The health benefits of quitting smoking are immediate and substantial. (See WARNINGS: Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment and PRECAUTIONS: Information for Patients.) DESCRIPTION WELLBUTRIN (bupropion hydrochloride), an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, se lective serotonin re-uptak e 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)ami propanone hydrochloride. The molecular weight is 276.2. The empirical formula is C13H18ClNOŁHCl. Bupropion hydrochloride powder is wh ite, 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: WELLBUTRIN is supplied for oral administra tion as 75-mg (yellow-gold) and 100-mg (red) film-coated tablets. Each tablet contains th e labeled amount of bupropion hydrochloride and the inactive ingredients: 75-mg tablet Œ D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystal line cellulose, polyethylene glycol, talc, and titanium dioxide; 100-mg tablet Œ FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hypromellose, microcrystal line cellulose, polyethylene glycol, talc, and titanium dioxide. 2 Reference ID: 2978172
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CLINICAL PHARMACOLOGY Pharmacodynamics: The neurochemical mechanism of the antidepressant effect of bupropion is not known. 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. Bupropion produces dose-related central nervous system (CNS) s timulant effects in animals, as evidenced by increased locomotor activit y, increased rates of responding in various schedule-controlled operant behavior tasks, and, at high doses, induction of mild stereotyped behavior. Bupropion causes convulsions in rodents and dogs at doses approximately tenfold the dose recommended as the human antidepressant dose. Pharmacokinetics: Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers ha ve not been studied. In humans, following oral administration of WELLBUTRIN, peak plasma bupropion concentrations are usually achieved within 2 hours, followed by a biphasic decline. The terminal phase has a mean half-life of 14 hours, with a range of 8 to 24 hours. The distribution phase has a mean half-life of 3 to 4 hours. The mean elimination half-life (±SD ) of bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of bupropion are reached within 8 days. Plasma bupropion concentrations are dose-proportional following single doses of 100 to 250 mg; however, it is not known if the proportionality between dose and plasma level is maintained in chronic use. Absorption: The absolute bioavailability of WELLBUTRIN in humans has not been determined because an intravenous formulation for human use is not available. However, it appears likely that only a small proportion of any orally administered dose reaches the systemic circulation intact. Distribution: In vitro tests show that bupropion is 84% bound to human plasma protein at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxybupropion metabolite is similar to that for bupropion, wh ereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion. Metabolism: Bupropion is extensively metabolized in humans. Three metabolites have been shown to be active: hydroxybupropion, which is formed via hydroxylation of the tert-butyl group of bupropion, and the amino-alcohol isom ers threohydrobupropion and erythrohydrobupropion, which are formed via reduction of the carbonyl gr oup. In vitro findings suggest that cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450 isoenzymes are not i nvolved in the formation of threohydrobupropion. Oxidation of the bupropion side chain results in the formation of a glyc ine conjugate of me 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 eryt3 Reference ID: 2978172
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fold less potent than bupropion. This may be of clinical importance because their plasma concentrations are as high or higher than those of bupropion. Because bupropion is extensively metabo lized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by or which inhibit/induce the cytochrome P450IIB6 (CYP2B6) isoenzyme, such as ritonavir or efavirenz. In a healthy volunteer study, ritonavir at a dose of 100 mg twice daily reduced the AUC and C max of bupropion by 22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 23%, the threohydrobupropion decreased by 38%, and the erythrohydrobupropion decreased by 48%. In a second healthy volunteer study, ritonavir at a dose of 600 mg twice daily decreased the AUC and the Cmax of bupropion by 66% and 62%, respectively. The exposure of the hydroxybupropion metabolite was decreased by 78%, the threohydrobupropion decreased by 50%, and the erythrohydrobupropion decreased by 68%. In another healthy volunteer study, KALETRA® (lopinavir 400 mg/ritonavir 100 mg twice daily) decreased bupropion AUC and Cmax by 57%. The AUC and Cmax of hydroxybupropion were decreased by 50% and 31%, respectively (see PRECAUTIONS: Drug Interactions). In a study in healthy volunteers, efavirenz 600 mg once daily for 2 weeks reduced the AUC and Cmax of bupropion by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was unchanged, whereas Cmax of hydroxybupropion was increased by 50%. Although bupropion is not metabolized by cyto chrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is coadminist ered with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions). Following a single dose in humans, peak pl asma concentrations of hydroxybupropion occur approximately 3 hours after administration of WE LLBUTRIN. Peak plasma concentrations of hydroxybupropion are approximately 10 times the peak level of the parent drug at steady state. The elimination half-life of hydroxybupropion is approximately 20 (± 5) hours, and its AUC at steady state is about 17 times that of bupropion. The times to peak concentrations for the erythrohydrobupropion and threohydrobupropion meta bolites are similar to that of the hydroxybupropion metabolite. However, their elimin ation 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 chroni c administration of 300 to 450 mg/day. Elimination: Following oral administration of 200 mg of 14C-bupropion in humans, 87% and 10% of the radioactive dose were recovered in the urine and feces, respectively. However, the fraction of the oral dose of WELLBUTRIN excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion. Populations Subgroups: Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, c oncomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of 4 Reference ID: 2978172
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bupropion. The elimination of the major metabolite s of bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in th e liver prior to urinary excretion. 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 volunteers 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 metabol ites 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, C max , and Tmax ) and its active metabolites (t ½) in patients with mild-to-moderate hepa tic 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, resp ectively) 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 C max was approximately 69% lower. For the combined amino- alcohol isomers threohydrobupropion a nd erythrohydrobupropion, the mean C max was approximately 31% lower. The mean AUC increased by about 1½-fold for hydroxybupropion and about 2½-fold for threo/erythrohydrobupropion. The median Tmax was observed 19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion. The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion were increased 5- and 2-fold, respectively, in patients with severe hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). Renal: There is limited information on the pharm acokinetics of bupropion in patients with renal impairment. An inter-study comparison be tween normal subjects and patients with end-stage renal failure demonstrated that the parent drug C max and AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for 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. The elimination of bupropion an d/or the major metabolit es of bupropion may be reduced by impaired renal function (see PRECAUTIONS: Renal Impairment). 5 Reference ID: 2978172
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Left Ventricular Dysfunction: During a chronic dosing study 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 was revealed, compared to healthy volunteers. Age: The effects of age on the pharmacokinetic s 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 daily schedule, revealed no relations hip 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 el derly 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 (see PRECAUTIONS: Geriatric Use). 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. Smokers: The effects of cigarette smoking on the pharmacokinetics of bupropion were studied in 34 healthy male and female volunteers; 17 were chronic cigarette smokers and 17 were nonsmokers. Following oral administration of a single 150-mg dose of bupropion, there were no statistically significant differences in C max , half-life, Tmax , AUC or clearance of bupropion or its active metabolites be tween smokers and nonsmokers. INDICATIONS AND USAGE WELLBUTRIN is indicated for the treatment of major depressive disorder. A physician considering WELLBUTRIN for the management of a patient™s firs t episode of depression should be aware that the drug may cause generalized se izures in a dose-dependent manner with an approximate incidence of 0.4% (4/1,000). This in cidence of seizures may exceed that of other marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted (see WARNINGS). The efficacy of WELLBUTRIN has been established in 3 placebo-controlled trials, including 2 of approximately 3 weeks™ duration in depresse d inpatients and one of approximately 6 weeks™ duration in depressed outpatients. The depressive disorder of the patients studied corresponds most closely to the Major Depression category of the APA Diagnostic and Statistical Manual III. Major Depression implies a prominent and rela tively persistent depressed or dysphoric mood that usually interferes with daily functioning (nearly every day for at least 2 weeks); it should include at least 4 of the following 8 symptoms: ch ange in appetite, change in sleep, psychomotor agitation or retardation, loss of interest in usual activities or decrease in sexual drive, increased fatigability, feelings of guilt or worthlessness, slowed thinking or impaired concentration, and suicidal ideation or attempts. 6 Reference ID: 2978172
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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 disorder s included a total of 295 short-term trials (median duration of 2 months) of 11 antidepre ssant 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 acr oss the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, we re relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 1. Table 1 Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated Increases Compared to Placebo <18 14 additional cases 18-24 5 additional cases Decreases Compared to Placebo 25-64 1 fewer case 65 6 fewer cases No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach a ny conclusion about drug effect on suicide. It is unknown whether the suicidality risk ex tends 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 antidepressa nts for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few mont hs of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, pani c attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomot or 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 in dications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of su ch symptoms and either the worsening of depression and/or the emergence of suicidal impul ses 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 suicidalit y or symptoms that might be pr ecursors to worsening depression 8 Reference ID: 2978172
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or suicidality, especially if thes e 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 emergen ce of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report su ch symptoms immediately to healthcare providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for WELLBUTRIN shoul d be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment: WELLBUTRIN, WELLBUTRIN SR , and WELLBUTRIN XL ar e not approved for smoking cessation treatment, but bupropion under the name ZYBAN is approved for this use. Serious neuropsychiatric symptoms have been repor ted in patients taking bupropion for smoking cessation (see BOXED WARNING, ADVERSE RE ACTIONS). These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitati on, aggression, anxiety, and panic, as well as suicidal ideation, suicide a ttempt, and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine wi thdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotin e withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms ha ve occurred in patients taking bupropion who continued to smoke. When sympto ms were reported, most were during bupropion treatment, but some were following discontinuation of bupropion therapy. These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychi atric illnesses. All patients being treated with bupropion as part of smoking cessation treatment should be observed for neuropsychiatric symptoms or worsening of pre- existing psychiatric illness. Patients with serious psychiatric illness such as schizophrenia, bipolar disorder, and major depressive disorder did not participate in the pre-marketing studies of ZYBAN. Advise patients and caregivers that the patient using bupropion for smoking cessation should stop taking bupropion and contact a healthcare provider immediately if agitation, depressed mood, or changes in behavior or thin king that are not typical for the patient are observed, or if the patient develops su icidal ideation or suicidal behavior. In many postmarketing cases, resolution of symp toms after discontinuation of ZYBAN was reported, although in some cases the symptoms persisted, therefore, ongoing monitoring and supportive care should be pr ovided until symptoms resolve. The risks of using bupropion for smoking cessati on should be weighed against the benefits of its use. ZYBAN has been demonstrated to in crease the likelihood of abstinence from smoking 9 Reference ID: 2978172
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for as long as six months compared to treatmen t with placebo. The health benefits of quitting smoking are immediate and substantial. 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 conv ersion is unknown. However, prior to initiating treatment with an antidepressant, patients wi th 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 WELLBUTRIN is not approved for use in treating bipolar depression. Bupropion-Containing Products: Patients should be made aware that WELLBUTRIN contains the same active ingredient found in ZYBAN, used as an aid to smoking cessation treatment, and that WELLBUTRIN should not be used in combination with ZYBAN, or any other medications that contain bupro pion, such as WELLBUTRIN SR (bupropion hydrochloride), the sustained-release formulation or WELLBUTRIN XL (bupropion hydrochloride), the extended-release formulation. Seizures: Bupropion is associated with seizures in approximately 0.4% (4/1,000) of patients treated at doses up to 450 mg/day. This incidence of seizures may exceed that of other marketed antidepressants by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted. The estimated seizure incidence for WELLBUTRIN increases almost tenfold between 450 and 600 mg/day, which is twice the usually require d daily dose (300 mg) and one and one-third the maximum recommended daily dose (450 mg). Given the wide variability among individuals and their capacity to metabolize and eliminate drugs this disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing. During the initial development, 25 among approximately 2,400 patients treated with WELLBUTRIN experienced seizures. At the time of seizure, 7 patients were receiving daily doses of 450 mg or below for an incidence of 0.33% (3/1,000) within the recommended dose range. Twelve patients experienced seizures at 600 mg/day (2.3% incidence); 6 additional patients had seizures at daily doses between 600 and 900 mg (2.8% incidence). A separate, prospective study was conducte d to determine the incidence of seizure during an 8-week treatment exposure in a pproximately 3,200 additional patients who received daily doses of up to 450 mg. Patients were permitted to continue treatment beyond 8 weeks if clinically indicated. Eight seizu res occurred during the initial 8-week treatment period and 5 seizures were rep orted in patients continuing treatment beyond 8 weeks, resulting in a total seizure incidence of 0.4%. 10 Reference ID: 2978172
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The risk of seizure appears to be stro ngly associated with dose. Sudden and large increments in dose may contribute to increased ri sk. While many seizures occurred early in the course of treatment, some seizures di d occur after several weeks at fixed dose. WELLBUTRIN should be discontinued and not restarted in patients who experience a seizure while on treatment. The risk of seizure is also related to patien t factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with WELLBUTRIN. 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 hepati c 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 wi th 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 developm ent of WELLBUTRIN suggests that the risk of seizure may be minimized if the total daily dose of WELLBUTRIN does not exceed 450 mg, the daily dose is administered 3 times daily, with each single dose not to exceed 150 mg to avoid high peak concentrations of bupropion and/or its metabolites, and the rate of incrementation of dose is very gradual. WELLBUTRIN should be administered with ex treme caution to patients with a history of seizure, cranial trauma, or other predisposi tion(s) toward seizure, or patients treated with other agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold. Hepatic Impairment: WELLBUTRIN should be used wi th extreme caution in patients with severe hepatic cirrhosis. In these patients a reduced dose and/or frequency is required, as peak bupropion, as well as AUC, levels are substantially increase d and accumulation is likely to occur in such patien ts to a greater extent than us ual. The dose should not exceed 75 mg once a day in these patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION). 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. 11 Reference ID: 2978172
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