Generic Name: Bupropion hydrochloride
Dosage Form: tablet, extended release
Bupropion Hydrochloride Extended-Release Tablets USP (SR)
Rx only
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 disorder (MDD) and other psychiatric disorders. Anyone considering the use of Bupropion hydrochloride extended-release tablets (SR) or any other antidepressant in a child, adolescent, or young adult must balance this risk with the clinical 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 antidepressants 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 all 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 caregivers should be advised of the need for close observation and communication with the prescriber. Bupropion hydrochloride extended-release tablets (SR) is not approved for use in pediatric patients (see WARNINGS, Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders , PRECAUTIONS, Information for Patients and PRECAUTIONS, Pediatric Use).
Use in Smoking Cessation Treatment: WELLBUTRIN®, Bupropion hydrochloride extended-release tablets (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 smoking cessation. Some cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have 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 changes 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 post-marketing experience. When symptoms were reported, most were during treatment with ZYBAN, but some were following discontinuation of treatment with ZYBAN. These events have occurred in patients with and without pre-existing psychiatric disease; some have experienced worsening of their psychiatric illnesses. 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, hostility, depressed mood, or changes in thinking or behavior that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing cases, resolution of symptoms 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 cessation should be weighed against the benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking for as long as 6 months compared 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).
Bupropion Description
Bupropion hydrochloride extended-release tablets USP (SR), antidepressants of the aminoketone class, are chemically unrelated to tricyclic, tetracyclic, selective serotonin re-uptake inhibitor, or other known antidepressant agents. Its structure closely resembles that of diethylpropion; it is related to phenylethylamines. It is designated as (±)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone hydrochloride. The molecular weight is 276.2. The molecular formula is C13H18ClNO•HCl. Bupropion hydrochloride powder is white, crystalline, and highly soluble in water. It has a bitter taste and produces the sensation of local anesthesia on the oral mucosa. The structural formula is:
- M.W. 276.2
Each tablet for oral administration contains either 100 mg, 150 mg or 200 mg of Bupropion hydrochloride and the following inactive ingredients: carnauba wax, hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, hypromellose, titanium dioxide, polyethylene glycol and polysorbate. In addition, the 100 mg tablet contains FD&C blue No. 1 lake and 150 mg tablet contains FD&C red No. 40 lake and FD&C blue No. 2 lake and the 200 mg tablet contains FD&C red No. 40 lake and FD&C yellow No. 6 lake.
This product meets USP Drug Release Test #2.
Bupropion - Clinical Pharmacology
Pharmacodynamics
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. While the mechanism of action of Bupropion, as with other antidepressants, is unknown, it is presumed that this action is mediated by noradrenergic and/or dopaminergic mechanisms.
Pharmacokinetics
Bupropion is a racemic mixture. The pharmacologic activity and pharmacokinetics of the individual enantiomers have not been studied. The mean elimination half-life (±SD) of Bupropion after chronic dosing is 21 (±9) hours, and steady-state plasma concentrations of Bupropion are reached within 8 days. In a study comparing chronic dosing with Bupropion hydrochloride extended-release tablets (SR) 150 mg twice daily to the immediate-release formulation of Bupropion at 100 mg 3 times daily, peak plasma concentrations of Bupropion at steady state for Bupropion hydrochloride extended-release tablets (SR) were approximately 85% of those achieved with the immediate-release formulation. There was equivalence for Bupropion AUCs, as well as equivalence for both peak plasma concentration and AUCs for all 3 of the detectable Bupropion metabolites. Thus, at steady state, Bupropion hydrochloride extended-release tablets (SR), given twice daily, and the immediate-release formulation of Bupropion, given 3 times daily, are essentially bioequivalent for both Bupropion and the 3 quantitatively important metabolites.
Absorption
Exposure following oral administration of Bupropion hydrochloride extended-release tablets (SR) may be increased when Bupropion hydrochloride extended-release tablets (SR) are taken with food. Three studies in healthy volunteers demonstrated, peak plasma concentrations of Bupropion are achieved within 3 hours. Food increased Cmax and AUC of Bupropion increased by 11% to 35% when administered with food, while overall exposure (AUC) to Bupropion increased by 16% to 19%. The food effect and 17%, respectively, indicating that there is not considered clinically significant and Bupropion hydrochloride extended-release tablets (SR) can be taken with or without food effect.
Distribution
In vitro tests show that Bupropion is 84% bound to human plasma proteins at concentrations up to 200 mcg/mL. The extent of protein binding of the hydroxyBupropion metabolite is similar to that for Bupropion, whereas the extent of protein binding of the threohydroBupropion metabolite is about half that seen with Bupropion.
Metabolism
Bupropion is extensively metabolized in humans. Three metabolites 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 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 Cmax 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 cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when Bupropion is co-administered 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 Bupropion hydrochloride extended-release tablets (SR). 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 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 mg/day 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 Bupropion excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of Bupropion.
Population Subgroups
Factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure [CHF], age, concomitant medications, etc.) or elimination may be expected to influence the degree and extent of accumulation of the active metabolites of Bupropion. The elimination of the major metabolites of Bupropion may be affected by reduced renal or hepatic function because they are moderately polar compounds and are likely to undergo further metabolism or conjugation in the liver prior to urinary excretion.
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 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 (t½) 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 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 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. The elimination of Bupropion and/or the major metabolites of Bupropion may be reduced by impaired renal function (see PRECAUTIONS, Renal Impairment).
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 was revealed, compared to healthy volunteers.
Age
The effects of age on the pharmacokinetics of Bupropion and its metabolites have not been fully characterized, but an exploration of steady-state Bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 mg/day to 750 mg/day, on a 3 times daily schedule, revealed no relationship between age (18 to 83 years) and plasma concentration of Bupropion. A single-dose pharmacokinetic 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 (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 was no statistically significant difference in Cmax, half-life, Tmax, AUC, or clearance of Bupropion or its active metabolites between smokers and nonsmokers.
Clinical Trials
The efficacy of the immediate-release formulation of Bupropion as a treatment for depression was established in two 4-week, placebo-controlled trials in adult inpatients with depression and in one 6-week, placebo-controlled trial in adult outpatients with depression. In the first study, patients were titrated in a Bupropion dose range of 300 mg/day to 600 mg/day on a 3 times daily schedule; 78% of patients received maximum doses of 450 mg/day or less. This trial demonstrated the effectiveness of the immediate-release formulation of Bupropion on the Hamilton Depression Rating Scale (HDRS) total score, the depressed mood item (item 1) from that scale, and the Clinical Global Impressions (CGI) severity score. A second study included 2 fixed doses of the immediate-release formulation of Bupropion (300 mg/day and 450 mg/day) and placebo. This trial demonstrated the effectiveness of the immediate-release formulation of Bupropion, but only at the 450-mg/day dose; the results were positive for the HDRS total score and the CGI severity score, but not for HDRS item 1. In the third study, outpatients received 300 mg/day of the immediate-release formulation of Bupropion. This study demonstrated the effectiveness of the immediate-release formulation of Bupropion on the HDRS total score, HDRS item 1, the Montgomery-Asberg Depression Rating Scale, the CGI severity score, and the CGI improvement score.
Although there are not as yet independent trials demonstrating the antidepressant effectiveness of the extended-release formulation of Bupropion, studies have demonstrated the bioequivalence of the immediate-release and extended-release forms of Bupropion under steady-state conditions, i.e., Bupropion extended-release (SR) 150 mg twice daily was shown to be bioequivalent to 100 mg 3 times daily of the immediate-release formulation of Bupropion, with regard to both rate and extent of absorption, for parent drug and metabolites.
In a longer-term study, outpatients meeting DSM-IV criteria for major depressive disorder, recurrent type, who had responded during an 8-week open trial on Bupropion hydrochloride extended-release tablets (SR) (150 mg twice daily) were randomized to continuation of their same Bupropion hydrochloride extended-release tablets (SR) dose or placebo, for up to 44 weeks of observation for relapse. Response during the open phase was defined as CGI Improvement score of 1 (very much improved) or 2 (much improved) for each of the final 3 weeks. Relapse during the double-blind phase was defined as the investigator’s judgment that drug treatment was needed for worsening depressive symptoms. Patients receiving continued treatment with Bupropion hydrochloride extended-release tablets (SR) experienced significantly lower relapse rates over the subsequent 44 weeks compared to those receiving placebo.
Indications and Usage for Bupropion
Bupropion hydrochloride extended-release tablets USP (SR) are indicated for the treatment of major depressive disorder. The efficacy of Bupropion in the treatment of a major depressive episode was established in two 4-week controlled trials of depressed inpatients and in one 6-week controlled trial of depressed outpatients whose diagnoses corresponded most closely to the Major Depression category of the APA Diagnostic and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY).
A major depressive episode (DSM-IV) implies the presence of 1) depressed mood or 2) loss of interest or pleasure; in addition, at least 5 of the following symptoms have been present during the same 2-week period and represent a change from previous functioning: depressed mood, markedly diminished interest or pleasure in usual activities, significant change in weight and/or appetite, insomnia or hypersomnia, psychomotor agitation or retardation, increased fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, a suicide attempt or suicidal ideation.
The efficacy of Bupropion hydrochloride extended-release tablets USP (SR) in maintaining an antidepressant response for up to 44 weeks following 8 weeks of acute treatment was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY). Nevertheless, the physician who elects to use Bupropion hydrochloride extended-release tablets USP (SR) for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
Contraindications
Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients with a seizure disorder.
Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients treated with ZYBAN (Bupropion hydrochloride) sustained-release tablets, Bupropion hydrochloride tablets (immediate-release formulation), Bupropion hydrochloride extended-release tablets (XL) (the extended-release formulation) or any other medications that contain Bupropion because the incidence of seizure is dose dependent.
Bupropion hydrochloride extended-release tablets (SR) are 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.
Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines).
The concurrent administration of Bupropion hydrochloride extended-release tablets (SR) 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 Bupropion hydrochloride extended-release tablets (SR).
Bupropion hydrochloride extended-release tablets (SR) are contraindicated in patients who have shown an allergic response to Bupropion or the other ingredients that make up Bupropion hydrochloride extended-release tablets (SR).
Warnings
Clinical Worsening and Suicide Risk in Treating Psychiatric Disorders
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 to 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. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in 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 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 Bupropion hydrochloride extended-release tablets (SR) should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.
Neuropsychiatric Symptoms and Suicide Risk in Smoking Cessation Treatment
WELLBUTRIN, Bupropion hydrochloride extended-release tablets (SR), and WELLBUTRIN XL are not approved for smoking cessation treatment, but Bupropion under the name ZYBAN is approved for this use. Serious neuropsychiatric symptoms have been reported in patients taking Bupropion for smoking cessation (see BOXED WARNING, ADVERSE REACTIONS). These have included changes in mood (including depression and mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt, and completed suicide. Some reported cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking Bupropion who continued to smoke. When symptoms 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 psychiatric 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 thinking that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many post-marketing cases, resolution of symptoms 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 cessation should be weighed against the benefits of its use. ZYBAN has been demonstrated to increase the likelihood of abstinence from smoking for as long as six months compared to treatment 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 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 Bupropion hydrochloride extended-release tablets (SR) is not approved for use in treating bipolar depression.
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, such as WELLBUTRIN (Bupropion hydrochloride), the immediate-release formulation or WELLBUTRIN XL (Bupropion hydrochloride), the extended-release formulation.
Seizures
Bupropion is associated with a dose-related risk of seizures. The risk of seizures is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with Bupropion hydrochloride extended-release tablets (SR). Bupropion hydrochloride extended-release tablets (SR) should be discontinued and not restarted in patients who experience a seizure while on treatment.
- Dose: At doses of Bupropion hydrochloride extended-release tablets (SR) up to a dose of 300 mg/day, the incidence of seizure is approximately 0.1% (1/1,000) and increases to approximately 0.4% (4/1,000) at the maximum recommended dose of 400 mg/day.
Data for the immediate-release formulation of Bupropion revealed a seizure incidence of approximately 0.4% (i.e., 13 of 3,200 patients followed prospectively) in patients treated at doses in a range of 300 mg/day to 450 mg/day. The 450-mg/day upper limit of this dose range is close to the currently recommended maximum dose of 400 mg/day for Bupropion hydrochloride extended-release tablets (SR). This seizure incidence (0.4%) may exceed that of other marketed antidepressants and Bupropion hydrochloride extended-release tablets (SR) up to 300 mg/day by as much as 4-fold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted.
Additional data accumulated for the immediate-release formulation of Bupropion suggested that the estimated seizure incidence increases almost tenfold between 450 mg/day and 600 mg/day, which is twice the usual adult dose and one and one-half the maximum recommended daily dose (400 mg) of Bupropion hydrochloride extended-release tablets (SR). This disproportionate increase in seizure incidence with dose incrementation calls for caution in dosing.
Data for Bupropion hydrochloride extended-release tablets (SR) revealed a seizure incidence of approximately 0.1% (i.e., 3 of 3,100 patients followed prospectively) in patients treated at doses in a range of 100 mg/day to 300 mg/day. It is not possible to know if the lower seizure incidence observed in this study involving the extended-release formulation of Bupropion resulted from the different formulation or the lower dose used. However, as noted above, the immediate-release and extended-release formulations are bioequivalent with regard to both rate and extent of absorption during steady state (the most pertinent condition to estimating seizure incidence), since most observed seizures occur under steady-state conditions.
- 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.
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 Bupropion hydrochloride extended-release tablets (SR) does not exceed 400 mg,
- the daily dose is administered twice daily, and
- the rate of incrementation of dose is gradual.
- No single dose should exceed 200 mg to avoid high peak concentrations of Bupropion and/or its metabolites.
Bupropion hydrochloride extended-release tablets (SR) 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, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold.
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, as peak Bupropion, as well as AUC, levels are substantially increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 100 mg every day or 150 mg every other 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.
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.
| 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.
| 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 Lost >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 Buprop
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