Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1785
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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 managedby 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 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 below).<br/>Increasing the Dosage Above 300 mg/day: As with other antidepressants, the full antidepressant effect of bupropion 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 mg 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 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, 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 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 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 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, USP, 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 CHClNO���HCl. Bupropion hydrochloride powder is white or almost 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: Bupropion Hydrochloride Tablets, USP for oral administration, are available containing 75 mg or 100 mg of bupropion hydrochloride. Each tablet also contains the following inactive ingredients: anhydrous lactose, colloidal silicon dioxide, crospovidone, hydrochloric acid, hypromellose, microcrystalline cellulose, polydextrose, polyethylene glycol, stearic acid and titanium dioxide. In addition, the 75 mg tablets contain synthetic red iron oxide, synthetic yellow iron oxide and triacetin and the 100 mg tablets contain FD&C Blue No. 2 aluminum lake, FD&C Yellow No. 6 aluminum lake and triacetin.
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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 10-fold 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, 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 of3 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 mg to 250 mg; however, it is not known if the proportionality between dose and plasma level is maintained in chronic use.<br/>Absorption: The absolute bioavailability of bupropion 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 coadministered 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 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 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 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.<br/>Hepatic: The effect of hepatic impairment on the pharmacokinetics of bupropion was
characterized in two 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 eight patients with alcoholic liver disease than in eight healthy volunteers (32��14 hours vs. 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 two 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 nine patients with mild to moderate hepatic cirrhosis compared to eight 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-fold 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 interstudy comparison between normal subjects and patients with end stage renal failure demonstrated that the parent drug Cand AUC values were comparable in the two groups, whereas the hydroxybupropion and threohydrobupropion metabolites had a 2.3-fold 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, USP are available containing 75 mg or 100 mg of bupropion hydrochloride, USP. The 75 mg tablets are peach film-coated, round, unscored tablets debossed with M on one side of the tablet and 433 on the other side. They are available as follows: NDC 0378-0433-01bottles of 100 tablets The 100 mg tablets are light blue film-coated, round, unscored tablets debossed withM on one side of the tablet and 435 on the other side. They are available as follows: NDC 0378-0435-01bottles of 100 tablets Store at 20��to 25��C (68��to 77��F). [See USP for Controlled Room Temperature.] Protect from light and moisture. Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure. PHARMACIST: Dispense a Medication Guide (combined with patient information) with each prescription.
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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 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 ofthe need for close observation and communication with the prescriber. Bupropion is not approved for use in pediatric patients.
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dailymed-ingredient:anhydrous_lactose,
dailymed-ingredient:colloidal_silicon_dioxide,
dailymed-ingredient:crospovidone,
dailymed-ingredient:hydrochloric_acid,
dailymed-ingredient:hypromellose,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polydextrose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:stearic_acid,
dailymed-ingredient:synthetic_red_iron_oxide,
dailymed-ingredient:synthetic_yellow_iron_oxide,
dailymed-ingredient:titanium_dioxide,
dailymed-ingredient:triacetin
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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, 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 are agitation, dry mouth, insomnia, headache/migraine, nausea/vomiting, constipation, and tremor. Adverse events were sufficiently troublesome to cause discontinuation of treatment with bupropion in approximately 10% of the 2,400 patients and volunteers who participated in clinical trials during the product's initial development. The more common events causing discontinuation include neuropsychiatric disturbances (3%), 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 under relatively similar conditions of daily dosage (300 mg 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 is provided in WARNINGS and PRECAUTIONS.<br/>Other Events Observed During the Development of Bupropion: The conditions and duration of exposure to bupropion 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. The following enumeration is organized by organ system and describes events in terms of their relative frequency of reporting in the database. 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. 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. Dermatologic: Frequent were nonspecific rashes; infrequent were alopecia and dry skin; rare were change in hair color, hirsutism, and acne. Endocrine: Infrequent was gynecomastia; rare were glycosuria and hormone level change. Gastrointestinal: Infrequent were dysphagia, thirst disturbance, and liver damage/jaundice; rare were rectal complaints, colitis, gastrointestinal bleeding, intestinal perforation, and stomach ulcer. 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. Hematologic/Oncologic: Rare were lymphadenopathy, anemia, and pancytopenia. Musculoskeletal: Rare was musculoskeletal chest pain. 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. 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. Oral Complaints: Frequent was stomatitis; infrequent were toothache, bruxism, gum irritation, and oral edema; rare was glossitis. Respiratory: Infrequent were bronchitis and shortness of breath/dyspnea; rare were epistaxis, rate or rhythm disorder, pneumonia, and pulmonary embolism. Special Senses: Infrequent was visual disturbance; rare was diplopia. 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: Body (General): arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity. These symptoms may resemble serum sickness . Cardiovascular: hypertension , orthostatic hypotension, third degree heart block Endocrine: syndrome of inappropriate antidiuretic hormone secretion, hyperglycemia, hypoglycemia Gastrointestinal: esophagitis, hepatitis, liver damage 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 Musculoskeletal: arthralgia, myalgia, muscle rigidity/fever/rhabdomyolysis, muscle weakness Nervous: aggression, coma, delirium, dream abnormalities, paranoid ideation, paresthesia, restlessness, unmasking of tardive dyskinesia Skin and Appendages: Stevens-Johnson Syndrome, angioedema, exfoliative dermatitis, urticaria Special Senses: tinnitus, increased intraocular pressure
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Bupropion hydrochloride tablets are indicated for the treatment of major depressive disorder. A physician considering bupropion 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 studieshave been conducted . The efficacy of bupropion has been established in three placebo-controlled trials, including two 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 four of the following eight 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 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 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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