Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3519
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Bupropion Hydrochloride (Tablet, Film Coated)
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General Dosing Considerations: It is particularly important to administer bupropion hydrochloride tablets in a manner most likely to minimize the risk of seizure . Increases in dose should not exceed 100 mg/day in a 3-day period. Gradual escalation in dosage is also important if agitation, motor restlessness, and insomnia, often seen during the initial days of treatment, are to be minimized. If necessary, these effects may be managed by temporary reduction of dose or the short-term administration of an intermediate to long-acting sedative hypnotic. A sedative hypnotic usually is not required beyond the first week of treatment. Insomnia may also be minimized by avoiding bedtime doses. If distressing, untoward effects supervene, dose escalation should be stopped. No single dose of bupropion hydrochloride tablets should exceed 150 mg. Bupropion hydrochloride tablets should be administered 3 times daily, preferably with at least 6 hours between successive doses.<br/>Usual Dosage for Adults: The usual adult dose is 300 mg/day, given 3 times daily. Dosing should begin at 200 mg/day, given as 100 mg twice daily. Based on clinical response, this dose may be increased to 300 mg/day, given as 100 mg 3 times daily, no sooner than 3 days after beginning therapy (see Table 3).<br/>Increasing the Dosage Above 300 mg/Day: As with other antidepressants, the full antidepressant effect of bupropion hydrochloride tablets may not be evident until 4 weeks of treatment or longer. An increase in dosage, up to a maximum of 450 mg/day, given in divided doses of not more than 150 mg each, may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day. Dosing above 300 mg/day may be accomplished using the 75 or 100 mg tablets. The 100 mg tablet must be administered 4 times daily with at least 4 hours between successive doses, in order not to exceed the limit of 150 mg in a single dose. Bupropion hydrochloride tablets should be discontinued in patients who do not demonstrate an adequate response after an appropriate period of treatment at 450 mg/day.<br/>Maintenance Treatment: The lowest dose that maintains remission is recommended. Although it is not known how long the patient should remain on bupropion hydrochloride tablets, it is generally recognized that acute episodes of depression require several months or longer of antidepressant drug treatment.<br/>Dosage Adjustment for Patients with Impaired Hepatic Function: Bupropion hydrochloride tablets should be used with extreme caution in patients with severe hepatic cirrhosis. The dose should not exceed 75 mg once a day in these patients. Bupropion hydrochloride tablets should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a reduced frequency and/or dose should be considered in patients with mild to moderate hepatic cirrhosis .<br/>Dosage Adjustment for Patients with Impaired Renal Function: Bupropion hydrochloride tablets should be used with caution in patients with renal impairment and a reduced frequency and/or dose should be considered .
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Bupropion hydrochloride, an antidepressant of the aminoketone class, is 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 CHCINO���HCI. 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. It has the following structural formula: Each bupropion hydrochloride tablet intended for oral administration contains 75 mg or 100 mg bupropion hydrochloride. In addition, each bupropion hydrochloride tablet contains the following inactive ingredients: FD&C Blue No. 2 aluminum lake, FD&C Red No. 40 aluminum lake, hydroxypropyl methylcellulose, microcrystalline cellulose, potassium chloride, pregelatinized starch, stearic acid, titanium dioxide, and triethyl citrate.
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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) stimulant effects in animals, as evidenced by increased locomotor activity, 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.<br/>Pharmacokinetics: Bupropion is a racemic mixture. The pharmacological activity and pharmacokinetics of the individual enantiomers have not been studied. In humans, following oral administration of bupropion hydrochloride tablets, 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 are maintained in chronic use.<br/>Absorption: The absolute bioavailability of bupropion hydrochloride tablets 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.<br/>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, whereas the extent of protein binding of the threohydrobupropion metabolite is about half that seen with bupropion.<br/>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 metachlorobenzoic 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 their plasma concentrations are as high or higher than those of bupropion. Because bupropion is extensively metabolized, there is the potential for drug-drug interactions, particularly with those agents that are metabolized by the cytochrome P450IIB6 (CYP2B6) isoenzyme. Although bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there is the potential for drug-drug interactions when bupropion is co-administered with drugs metabolized by this isoenzyme . Following a single dose in humans, peak plasma concentrations of hydroxybupropion occur approximately 3 hours after administration of bupropion hydrochloride tablets. 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 to 450 mg/day.<br/>Elimination: Following oral administration of 200 mg ofC-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 hydrochloride tablets excreted unchanged was only 0.5%, a finding consistent with the extensive metabolism of bupropion.<br/>Populations 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 metabolitesof 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.<br/>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 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, C, and T) and its active metabolites (t) in patients with mild to moderate hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis, the bupropion Cand 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 Cwas approximately 69% lower. For the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion, the mean Cwas approximately 31% lower. The mean AUC increased by about 1/-fold for hydroxybupropion and about 2/-fold for threo/erythrohydrobupropion. The median Twas 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 .<br/>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 Cand AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. The elimination of the major metabolites of bupropion may be reduced by impaired renal function .<br/>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.<br/>Age: The effects of age on the pharmacokinetics of bupropion and its metabolites have not been fully characterized, but an exploration of steady-state bupropion concentrations from several depression efficacy studies involving patients dosed in a range of 300 to 750 mg/day, on a 3 times 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 .<br/>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.<br/>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, half-life, T, AUC or clearance of bupropion or its active metabolites between smokers and nonsmokers.
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Bupropion hydrochloride tablets are contraindicated in patients with a seizure disorder. Bupropion hydrochloride tablets are contraindicated in patients treated with ZYBAN' (bupropion hydrochloride) Sustained-Release Tablets; Wellbutrin SR' (bupropion hydrochloride), the sustained-release formulation; Wellbutrin XL' (bupropion hydrochloride), the extended-release formulation; or any other medications that contain bupropion because the incidence of seizure is dose dependent. Bupropion hydrochloride tablets are contraindicated in patients with a current or prior diagnosis of bulimia or anorexia nervosa because of a higher incidence of seizures noted in such patients treated with bupropion hydrochloride tablets. Bupropion hydrochloride tablets are contraindicated in patients undergoing abrupt discontinuation of alcohol or sedatives (including benzodiazepines). The concurrent administration of bupropion hydrochloride tablets 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 tablets. Bupropion hydrochloride tablets are contraindicated in patients who have shown an allergic response to bupropion or the other ingredients that make up bupropion hydrochloride tablets.
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Bupropion hydrochloride tablets, USP are supplied as: 75 mg: Lavender, round, film-coated tablets, debossed GG 929 on one side and plain on the reverse side. NDC 0781-1053-31 in bottles of 30 tablets NDC 0781-1053-01 in bottles of 100 tablets NDC 0781-1053-10 in bottles of 1000 tablets 100 mg: Lavender, round, film-coated tablets, debossed GG 930 on one side and plain on the reverse side. NDC 0781-1064-31 in bottles of 30 tablets NDC 0781-1064-01 in bottles of 100 tablets NDC 0781-1064-10 in bottles of 1000 tablets Store at 20��-25��C (68��-77��F) (see USP Controlled Room Temperature). Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP.
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Suicidality and Antidepressant Drugs: 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 tablets 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 or older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started onantidepressant 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 is not approved for use in pediatric patients.
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dailymed-ingredient:FD&C_blue_no._2_aluminum_lake,
dailymed-ingredient:FD&C_red_no._40_aluminum_lake,
dailymed-ingredient:hydroxypropyl_methylcellulose,
dailymed-ingredient:microcrystaline_cellulose,
dailymed-ingredient:potassium_chloride,
dailymed-ingredient:pregelatinized_starch,
dailymed-ingredient:stearic_acid,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:triethyl_citrate
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General:<br/>Agitation and Insomnia: A substantial proportion of patients treated with bupropion hydrochloride tablets experience some degree of increased restlessness, agitation, anxiety, and insomnia, especially shortly after initiation of treatment. In clinical studies, these symptoms were sometimes of sufficient magnitude to require treatment with sedative/hypnotic drugs. In approximately 2% of patients, symptoms were sufficiently severe to require discontinuation of treatment with bupropion hydrochloride tablets.<br/>Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Depressed patients treated with bupropion hydrochloride tablets have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychosis, concentration disturbance, paranoia, and confusion. Because of the uncontrolled nature of many studies, it is impossible to provide a precise estimate of the extent of risk imposed by treatment with bupropion hydrochloride tablets. In several cases, neuropsychiatric phenomena abated upon dose reduction and/or withdrawal of treatment.<br/>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 tablets are expected to pose similar risks.<br/>Altered Appetite and Weight: A weight loss of greater than 5 lbs occurred in 28% of patients receiving bupropion hydrochloride tablets. This incidence is approximately double that seen in comparable patients treated with tricyclics or placebo. Furthermore, while 35% of patients receiving tricyclic antidepressants gained weight, only 9.4% of patients treated with bupropion did. Consequently, if weight loss is a major presenting sign of a patient's depressive illness, the anorectic and/or weight reducing potential of bupropion hydrochloride tablets should be considered.<br/>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 tablets 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.<br/>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 sustained-release formulation of bupropion (ZYBAN Sustained-Release Tablets), nicotine transdermal system (NTS), the combination of sustained-release bupropion plus NTS, and placebo as an aid to smoking cessation suggest a higher incidence of treatment-emergent hypertension in patients treated with the combination of sustained-release bupropion and NTS. In this study, 6.1% of patients treated with the combination of sustained-release bupropion and NTS had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1% of patients treated with sustained-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 tablets 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.<br/>Hepatic Impairment: Bupropion hydrochloride tablets should be used with extreme caution in patients with severe hepatic cirrhosis. In these patients, a reduced dose and frequency is required. Bupropion hydrochloride tablets should be used with caution in patients with hepatic impairment (including mild to moderate hepatic cirrhosis) and a 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 .<br/>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 Cand AUC values were comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3- and 2.8-fold increase, respectively, in AUC for patients with end-stage renal failure. Bupropion is extensively metabolized in the liver to active metabolites, which are further metabolized and subsequently excreted by the kidneys. Bupropion hydrochloride tablets 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.<br/>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 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���and other important information about using bupropion hydrochloride tablets is available for bupropion hydrochloride tablets. 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.<br/>Clinical Worsening and Suicide Risk: 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. Patients should be made aware that bupropion hydrochloride tablets contain the same active ingredient found in ZYBAN, used as an aid to smoking cessation, and that bupropion hydrochloride tablets should not be used in combination with ZYBAN or any other medications that contain bupropion hydrochloride (such as Wellbutrin SR, the sustained-release formulation and Wellbutrin XL, the extended-release formulation). Patients should be instructed to take bupropion hydrochloride tablets in equally divided doses 3 or 4 times a day to minimize the risk of seizure. Patients should be told that bupropion hydrochloride tablets 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 tablets may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion hydrochloride tablets 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 tablets. 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 tablets 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.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>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 coadministration 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 tablets and drugs that are substrates or inhibitors of the CYP2B6 isoenzyme (e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition, in vitro studies suggest that paroxetine, sertraline, norfluoxetine, and fluvoxamine as well as nelfinavir, ritonavir, and efavirenz inhibit the hydroxylation of bupropion. No clinical studies have been performed to evaluate this finding. The threohydrobupropion metabolite of bupropiondoes 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 sustained-release tablets 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 C, respectively, of the combined moieties of threohydrobupropion and erythrohydrobupropion. 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 coadministered drugs.<br/>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 the 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 C, AUC, and tof 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 concomitantmedication. 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.<br/>MAO Inhibitors: Studies in animals demonstrate that the acute toxicity of bupropion is enhanced by the MAO inhibitor phenelzine .<br/>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 tablets to patients receiving either levodopa or amantadine concurrently should be undertaken with caution, using small initial doses and small gradual dose increases.<br/>Drugs that Lower Seizure Threshold: Concurrent administration of bupropion hydrochloride tablets and agents (e.g., antipsychotics, other antidepressants, theophylline, systemic steroids, etc.) that lower seizure threshold should be undertaken only with extreme caution . Low initial dosing and small gradual dose increases should be employed.<br/>Nicotine Transdermal System:<br/>Alcohol: In post-marketing 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 tablets. The consumption of alcohol during treatment with bupropion hydrochloride tablets should be minimized or avoided .<br/>Carcinogenesis, Mutagenesis, Impairment of Fertility: Lifetime carcinogenicity studies were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day; 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 borderline positive response (2 to 3 times control mutation rate) in some strains in the Ames bacterial mutagenicity test, and a high oral dose (300 mg/kg, but not 100 or 200 mg/kg) produced a low incidence of chromosomal aberrations in rats. The relevance of these results in estimating the risk of human exposure to therapeutic doses is unknown. A fertility study was performed in rats; no evidence of impairment of fertility was encountered at oral doses up to 300 mg/kg/day.<br/>Pregnancy:<br/>Teratogenic Effects:<br/>Labor and Delivery: The effect of bupropion hydrochloride tablets on labor and delivery in humans is unknown.<br/>Nursing Mothers: Like many other drugs, bupropion hydrochloride tablets and its metabolites are secreted in human milk. Because of the potential for serious adverse reactions in nursing infants from bupropion, 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.<br/>Pediatric Use: Safety and effectiveness in the pediatric population have not been established . Anyone considering the use of bupropion hydrochloride tablets in a child or adolescent must balance the potential risks with the clinical need.<br/>Geriatric Use: Of the approximately 6,000 patients who participated in clinical trials with bupropion sustained-release tablets (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 . 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 .
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Human Overdose Experience: Overdoses of up to 30 g or more of bupropion have been reported. Seizure was reported in approximately one third of all cases. Other serious reactions reported with overdoses of bupropion alone included hallucinations, loss of consciousness, sinus tachycardia, and ECG changes such as conduction disturbances or arrhythmias. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported mainly when bupropion was part of multiple drug overdoses. Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported in patients ingesting large doses of the drug. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.<br/>Overdosage Management: Ensure an adequate airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital signs. EEG monitoring is also recommended for the first 48 hours post-ingestion. General supportive and symptomatic measures are also recommended. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Activated charcoal should be administered. There is no experience with the use of forced diuresis, dialysis, hemoperfusion, or exchange transfusion in the management of bupropion overdoses. No specific antidotes for bupropion are known. Due to the dose-related risk of seizures with bupropion hydrochloride tablets, hospitalization following suspected overdose should be considered. Based on studies in animals, it is recommended that seizures be treated with intravenous benzodiazepine administration and other supportive measures, as appropriate. In managing overdosage, consider the possibility of multiple drug involvement. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians' Desk Reference (PDR).
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Bupropion Hydrochloride
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Bupropion Hydrochloride (Tablet, Film Coated)
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Adverse events commonly encountered in patients treated with bupropion hydrochloride tablets are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor. Adverse events were sufficiently troublesome to cause discontinuation of treatment with bupropion hydrochloride tablets in approximately 10% of the 2400 patients and volunteers who participated in clinical trials during the product's initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3.0%), primarily agitation and abnormalities in mental status; gastrointestinal disturbances (2.1%), primarily nausea and vomiting; neurological disturbances (1.7%), primarily seizures, headaches, and sleep disturbances; and dermatologic problems (1.4%), primarily rashes. It is important to note, however, that many of these events occurred at doses that exceed the recommended daily dose. Accurate estimates of the incidence of adverse events associated with the use of any drug are difficult to obtain. Estimates are influenced by drug dose, detection technique, setting, physician judgments, etc. Consequently, Table 2 is presented solely to indicate the relative frequency of adverse events reported in representative controlled clinical studies conducted to evaluate the safety and efficacy of bupropion hydrochloride tablets under relatively similar conditions of daily dosage (300 to 600 mg), setting, and duration (3 to 4 weeks). The figures cited cannot be used to predict precisely the incidence of untoward events in the course of usual medical practice where patient characteristics and other factors must differ from those which prevailed in the clinical trials. These incidence figures also cannot be compared with those obtained from other clinical studies involving related drug products as each group of drug trials is conducted under a different set of conditions. Finally, it is important to emphasize that the tabulation does not reflect the relative severity and/or clinical importance of the events. A better perspective on the serious adverse events associated with the use of bupropion hydrochloride tablets is provided in WARNINGS and PRECAUTIONS.<br/>Other Events Observed During the Development of Bupropion Hydrochloride Tablets: The conditions and duration of exposure to bupropion hydrochloride tablets varied greatly, and a substantial proportion of the experience was gained in open and uncontrolled clinical settings. During this experience, numerous adverse events were reported; however, without appropriate controls, it is impossible to determine with certainty which events were or were not caused by bupropion hydrochloride tablets. The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the data base. Events of major clinical importance are also described in WARNINGS and PRECAUTIONS. The following definitions of frequency are used: Frequent adverse events are defined as those occurring in at least 1/100 patients. Infrequent adverse events are those occurring in 1/100 to 1/1,000 patients, while rare events are those occurring in less than 1/1,000 patients.<br/>Cardiovascular: Frequent was edema; infrequent were chest pain, electrocardiogram (ECG) abnormalities (premature beats and nonspecific ST-T changes), and shortness of breath/dyspnea; rare were flushing, pallor, phlebitis, and myocardial infarction.<br/>Dermatologic: Frequent were nonspecific rashes; infrequent were alopecia and dry skin; rare were change in hair color, hirsutism, and acne.<br/>Endocrine: Infrequent was gynecomastia; rare were glycosuria and hormone level change.<br/>Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice; rare were rectal complaints, colitis, gastrointestinal bleeding, intestinal perforation, and stomach ulcer.<br/>Genitourinary: Frequent was nocturia; infrequent were vaginal irritation, testicular swelling, urinary tract infection, painful erection, and retarded ejaculation; rare were dysuria, enuresis, urinary incontinence, menopause, ovarian disorder, pelvic infection, cystitis, dyspareunia, and painful ejaculation.<br/>Hematologic/Oncologic: Rare were lymphadenopathy, anemia, and pancytopenia.<br/>Musculoskeletal: Rare was musculoskeletal chest pain.<br/>Neurological: Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were electroencephalogram (EEG) abnormality, abnormal neurological exam, impaired attention, sciatica, and aphasia.<br/>Neuropsychiatric: Frequent were mania/hypomania, increased libido, hallucinations, decrease in sexual function, and depression; infrequent were memory impairment, depersonalization, psychosis, dysphoria, mood instability, paranoia, formal thought disorder, and frigidity; rare was suicidal ideation.<br/>Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum irritation, and oral edema; rare was glossitis.<br/>Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare were epistaxis, rate or rhythm disorder, pneumonia, and pulmonary embolism.<br/>Special Senses: Infrequent was visual disturbance; rare was diplopia.<br/>Nonspecific: Frequent were flu-like symptoms; infrequent was nonspecific pain; rare were body odor, surgically related pain, infection, medication reaction, and overdose.<br/>Postintroduction Reports: Voluntary reports of adverse events temporally associated with bupropion that have been received since market introduction and which may have no causal relationship with the drug include the following:<br/>Body (General): Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness .<br/>Cardiovascular: Hypertension , orthostatic hypotension, third degree heart block<br/>Endocrine: Syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia, hypoglycemia<br/>Gastrointestinal: Esophagitis, hepatitis, liver damage<br/>Hemic and Lymphatic: Ecchymosis, leukocytosis, leukopenia, thrombocytopenia. Altered PT and/or INR, infrequently associated with hemorrhagic or thrombotic complications, were observed when bupropion was coadministered with warfarin.<br/>Musculoskeletal: Arthralgia, myalgia, muscle rigidity/fever/rhabdomyolysis, muscle weakness<br/>Nervous: Coma, delirium, dream abnormalities, paresthesia, unmasking of tardive dyskinesia<br/>Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative dermatitis, urticaria<br/>Special Senses: Tinnitus, increased intraocular pressure
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| dailymed-instance:warning |
Clinical Worsening and Suicide Risk: Patients with major depressive disorder (MDD), both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 antidepressant drugs in over 4400 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 11antidepressant 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 casesof suicidality per 1000 patients treated) are provided in Table 1. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. 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 health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for bupropion hydrochloride should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.<br/>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 treatmentwith 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 tablets is not approved for use in treating bipolar depression. Patients should be made aware that bupropion hydrochloride tablets contain the same active ingredient found in ZYBAN, used as an aid to smoking cessation treatment, and that bupropion hydrochloride tablets should not be used in combination with ZYBAN, or any other medications that contain bupropion, such as Wellbutrin SR (bupropion hydrochloride), the sustained-release formulation or Wellbutrin XL (bupropion hydrochloride), the extended-release formulation.<br/>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 bupropion hydrochloride tablets increases almost tenfold between 450 and 600 mg/day, which is twice the usually required 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 bupropion hydrochloride tablets 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 conducted to determine the incidence of seizure during an 8-week treatment exposure in approximately 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 seizures occurred during the initial 8-week treatment period and 5 seizures were reported in patients continuing treatment beyond 8 weeks, resulting in a total seizure incidence of 0.4%. The risk of seizure appears to be strongly associated with dose. Sudden and large increments in dose may contribute to increased risk. While many seizures occurred early in the course of treatment, some seizures did occur after several weeks at fixed dose. Bupropion hydrochloride tablets should be discontinued and not restarted in patients who experience a seizure while on treatment. The risk of seizure is also related to patient factors, clinical situations, and concomitant medications, which must be considered in selection of patients for therapy with bupropion hydrochloride tablets.<br/>Recommendations for Reducing the Risk of Seizure: Retrospective analysis of clinical experience gained during the development of bupropion hydrochloride tablets suggests that the risk of seizure may be minimized if Bupropion hydrochloride tablets 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.<br/>Hepatic Impairment: Bupropion hydrochloride tablets should be used with 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 increased and accumulation is likely to occur in such patients to a greater extent than usual. The dose should not exceed 75 mg once a day in these patients .<br/>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.
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| dailymed-instance:indicatio... |
Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder. A physician considering bupropion hydrochloride tablets for the management of a patient's first episode of depression should be aware that the drug may cause generalized seizures in a dose-dependent manner with an approximate incidence of 0.4% (4/1,000). 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 efficacy of bupropion hydrochloride tablets has been established in 3 placebo-controlled trials, including 2 of approximately 3 weeks' duration in depressed 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 relatively 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: change 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. Effectiveness of bupropion hydrochloride tablets in long-term use, that is, for more than 6 weeks, has not been systematically evaluated in controlled trials. Therefore, the physician who elects to use bupropion hydrochloride tablets for extended periods should periodically reevaluate the long-term usefulness of the drug for the individual patient.
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Bupropion Hydrochloride
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