Brand name: Wellbutrin
Bupropion
Brand name: Wellbutrin |
|
Antidepressant
Bupropion hydrochloride, an antidepressant of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic, 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 emperical formula is C13H18CINO*HCl. Bupropion 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.
Bupropion is supplied for oral administration as 75 mg (yellow-gold) and 100 mg (red) film-coated tablets. Each tablet contains the labeled amount of bupropion hydrochloride and the inactive ingredients: 75 mg tablet - D&C Yellow No. 10 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hydroxypropyl methylcelluose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide; 100 mg tablet - FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl cellulose, hydroxypropyl methylcellulose, microcrystalline cellulose, polyethylene glycol, talc, and titanium dioxide.
Bupropion produces dose-related 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.
Absorption, Distribution, Pharmacokinetics, Metabolism, and Elimination:
Oral bioavailability and single-dose pharmacokinetics:
In humans,
following oral administration of bupropion, peak plasma bupropion concentrations
are usually achieved within 2 hours, followed by a biphasic decline. The average
half-life of the second (post-distributional) phase is approximately 14 hours,
with a range of 8 to 24 hours. Six hours after a single dose, plasma bupropion
concentrations are approximately 30% of peak concentrations. Plasma bupropion
concentrations are dose-proportional following single doses of 100 to 250 mg;
however, it is not known if the proportionality between dose and plasma level is
maintained in chronic use.
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. For example, the absolute bioavailability of bupropion in animals (rats and dogs) ranges from 5% to 20%.
Metabolism:
Following oral administration of 200 mg of
14C-bupropion, 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 documenting the extensive
metabolism of bupropion.
Several of the known metabolites of bupropion are pharmacologically active, but their potency and toxicity relative to bupropion have not been fully characterized. However, because of their longer elimination half-lives, the plasma concentrations of at least two of the known metabolites can be expected, especially in chronic use, to be very much higher than the plasma concentration of bupropion. This is of potential clinical importance because factors or conditions altering metabolic capacity (e.g., liver disease, congestive heart failure, age, concomitant medications, etc.) or elimination may be expected to influence the degree and extend of accumulation of these active metabolites.
Furthermore, bupropion has been shown to induce its own metabolism in three animal species (mice, rats, and dogs) following subchronic administration. If induction also occurs in humans, the relative contribution of bupropion and its metabolites to the clinical effects of bupropion may be changed in chronic use.
Plasma and urinary metabolites so far identified include biotransformation products formed via reduction of the carbonyl group and/or hydroxylation of the tert-butyl group of bupropion. Four basic metabolites have been identified.
They are the erythro- and threo-amino alcohols of bupropion, the erythro-amino diol of bupropion, and a morpholinol, metabolite (formed from hydroxylation of the tert-butyl group of bupropion).
The morpholinol metabolite appears in the systemic circulation almost as rapidly as the parent drug following a single oral dose. Its peak level is three times the peak level of the parent drug; it has a half life on the order of 24 hours; and its AUC 0 to 60 hours is about 15 times that of bupropion.
The threo-amino alcohol metabolite has a plasma concentration time profile similar to that of the morpholinol metabolite. The erythro-amino alcohol and the erythro-amino diol metabolites generally cannot be detected in the systemic circulation following a single oral dose of the parent drug. The morpholinol and the threo-amino alcohol metabolites have been found to be half as potent as bupropion in animal screening tests for antidepressant drugs.
During a chronic dosing study in 14 depressed patients with left ventricular dysfunction, it was found that there was substantial interpatient variability (two- to five-fold) in the trough steady-state concentrations of bupropion and the morpholinol and threo-amino alcohol metabolites. In addition, the steady-state plasma concentrations of these metabolites were 10 to 100 times the steady-state concentrations of the parent drug.
The effect of other disease states and altered organ function on the metabolism and/or elimination of bupropion has not been studied in detail. However, 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 conjugation in the liver prior to urinary excretion. The preliminary results of a comparative single-dose pharmacokinetic study in normal versus cirrhotic patients indicated that half-lives of the metabolites were prolonged by cirrhosis and that the metabolites accumulated to levels two to three times those in normals.
The effect of age on plasma concentrations of bupropion and its metabolites has not been characterized.
In vitro tests show that bupropion is 80% or more bound to human albumin at plasma concentrations up to 800 micromolar (200 mcg/mL).
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 re-evaluate the long-term usefulness of the drug for the individual patient.
During the initial development, 25 among approximately 2400 patients treated with bupropion experienced seizures. At the time of seizure, seven patients were receiving daily doses of 450 mg or below for an incidence of 0.33% (3/1000) within the recommended dose range. Twelve patients experienced seizures at 600 mg per day (2.3% incidence); six additional patients has 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 3200 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 five 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 and the presence of predisposing factors. A significant seizure, CNS tumor, concomitant medications that lower seizure threshold, etc.) was present in approximately one-half of the patients experiencing a seizure. 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.
Recommendations for reducing the risk of seizure:
Retrospective
analysis of clinical experience gained during the development of bupropion
suggests that the risk of seizure may be minimized if (1) the total daily dose
of bupropion does not exceed 450 mg, (2) the daily dose is administered t.i.d.,
with each single dose not to exceed 150 mg to avoid high peak concentrations of
bupropion and/or its metabolites, and (3) the rate of incrementation of dose is
very gradual. Extreme caution should be used when bupropion is (1) administered
to patients with a history of seizure, cranial trauma, or other
predisposition(s) toward seizure, or (2) prescribed with other agents (e.g.,
antipsychotics, other antidepressants, etc.) or treatment regimens (e.g., abrupt
discontinuation of a benzodiazepine) that lower seizure threshold.
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.
Although scattered abnormalities in liver function tests were detected in
patients participating in clinical trials, there is no clinical evidence that
bupropion acts as a hepatotoxin in humans.
General:
Agitation and Insomnia: A substantial proportion of patients treated with bupropion 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.
Psychosis, Confusion, and Other Neuropsychiatric Phenomena: Patients treated with bupropion have been reported to show a variety of neuropsychiatric signs and symptoms including delusions, hallucinations, psychotic episodes, confusion, and paranoia. 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. In several cases, neuropsychitric phenomena abated upon dose reduction and/or withdrawal of treatment.
Activation of Psychosis and/or Mania: Antidepressants can precipitate manic episodes in Bipolar Manic Depressive patients during the depressed phase of their illness and may activate latent psychosis in other susceptible patients. Bupropion is expected to pose similar risks.
Altered Appetite and Weight: A weight loss of greater than 5 pounds occurred in 28% of patients receiving bupropion. This incidence is approximately double that seen in comparable patients treated with tricyclics or placebo. Furthermore, while 34.5% 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 should be considered.
Suicide: The possibility of a suicide attempt is inherent in depression and may persist until significant remission occurs. Accordingly, prescriptions for bupropion should be written for the smallest number of tablets consistent with good patient management.
Use in Patients with Systemic Illness:
There is no clinical
experience establishing the safety of bupropion 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 patients who has previously developed orthostatic hypotension while receiving
tricyclic antidepressants.
Because bupropion HCl and its metabolites are almost completely excreted through the kidney and metabolites are likely to undergo conjugation in the liver prior to urinary excretion, treatment of patients with renal or hepatic, impairment should be initiated at reduced dosage as bupropion and its metabolites may accumulate in such patients beyond concentrations expected in patients without renal or hepatic impairment. The patient should be closely monitored for possible toxic effects of elevated blood and tissue levels of drug and metabolites.
Information for Patients:
Physicians are advised to discuss the
following issues with patients:
Patients should be instructed to take bupropion in equally divided doses three or four times a day to minimize the risk of seizure.
Patients should be told that any CNS-active drug like bupropion may impair their ability to perform tasks requiring judgment or motor and cognitive skills. Consequently, until they are reasonably certain that bupropion does not adversely affect their performance, they should refrain from driving an automobile or operating complex, hazardous machinery.
Patients should be told that the use and cessation of use of alcohol may alter the seizure threshold, and, therefore, that the consumption of alcohol should be minimized, and, if possible, avoided completely.
Patients should be advised to inform their physician if they are taking or plan to take any prescription or over-the-counter drugs. Concern is warranted because bupropion and other drugs may affect each others metabolism.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy.
Drug Interactions:
No systematic data have been collected on the
consequences of the concomitant administration of bupropion and other drugs.
However, animal data suggest that bupropion may be an inducer of drug metabolizing enzymes. This may be of potential clinical importance because the blood levels of co-administered drugs may be altered.
Alternatively, because bupropion is extensively metabolized, the co-administration of other drugs may affect its clinical activity. In particular, care should be exercised when administering drugs known to affect hepatic drug-metabolizing enzyme systems (e.g., carbamazepine, cimetidine, phenobarbital, phenytoin).
Studies in animals demonstrate that the acute toxicity of buproprion is enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).
Limited clinical data suggest a higher incidence of adverse experiences in patients receiving concurrent administration of bupropion and L-dopa. Administration of bupropion to patients receiving L-dopa concurrently should be undertaken with caution, using small initial doses and small gradual dose increases.
Concurrent administration of bupropion and agents which lower seizure threshold should be undertaken only with extreme caution (see WARNINGS). Low initial dosing and small gradual dose increases should be employed.
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, 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.
Pregnancy: Teratogenic Effects:
Pregnancy Category B: Reproduction
studies have been performed in rabbits and rats at doses up to 15 to 45 times
the human daily dose and have revealed no definitive evidence of impaired
fertility or harm to the fetus due to bupropion. (In rabbits, a slightly
increased incidence of fetal abnormalities was seen in two studies, but there
was no increase in any specific abnormality.) There are no adequate and
well-controlled studies in pregnant women. Because animal reproduction studies
are not always predictive of human response, this drug should be used during
pregnancy only if clearly needed.
Labor and Delivery:
The effect of bupropion on labor and delivery
in humans is unknown.
Nursing Mothers:
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.
Pediatric Use:
The safety and effectiveness of bupropion in
individuals under 18 years old have not been established.
Use in the Elderly:
Bupropion has not been systematically evaluated
in older patients.
Adverse events were sufficiently troublesome to cause discontinuation of treatment with bupropion in approximately ten percent 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, the table below 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 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.
| TREATMENT EMERGENT ADVERSE EXPERIENCE
INCIDENCE IN PLACEBO-CONTROLLED CLINICAL TRIALS * (Percent of Patients Reporting) | ||
|---|---|---|
| Adverse Experience | Bupropion Patients (n=323) | Placebo Patients (n=185) |
| CARDIOVASCULAR | ||
| Cardiac Arrhythmias | 5.3 | 4.3 |
| Dizziness | 22.3 | 16.2 |
| Hypertension | 4.3 | 1.6 |
| Hypotension | 2.5 | 2.2 |
| Palpitations | 3.7 | 2.2 |
| Syncope | 1.2 | 0.5 |
| Tachycardia | 10.8 | 8.6 |
| DERMATOLOGIC | ||
| Pruritus | 2.2 | 0.0 |
| Rash | 8.0 | 6.5 |
| GASTROINTESTINAL | ||
| Anorexia | 18.3 | 18.4 |
| Appetite increase | 3.7 | 2.2 |
| Constipation | 26.0 | 17.3 |
| Diarrhea | 6.8 | 8.6 |
| Dyspepsia | 3.1 | 2.2 |
| Nausea/Vomiting | 22.9 | 18.9 |
| Weight Gain | 13.6 | 22.7 |
| Weight Loss | 23.2 | 23.2 |
| GENITOURINARY | ||
| Impotence | 3.4 | 3.1 |
| Menstrual Complaints | 4.7 | 1.1 |
| Urinary Frequency | 2.5 | 2.2 |
| Urinary Retention | 1.9 | 2.2 |
| MUSCULOSKELETAL | ||
| Arthritis | 3.1 | 2.7 |
| NEUROLOGICAL | ||
| Akathisia | 1.5 | 1.1 |
| Akinesia/Bradykinesia | 8.0 | 8.6 |
| Cutaneous Temperature Disturbance | 1.9 | 1.6 |
| Dry Mouth | 27.6 | 18.4 |
| Excessive Sweating | 22.3 | 14.6 |
| Headache/Migraine | 25.7 | 22.2 |
| Impaired Sleep Quality | 4.0 | 1.6 |
| Increased Salivary Flow | 3.4 | 3.8 |
| Insomnia | 18.6 | 15.7 |
| Muscle Spasms | 1.9 | 3.2 |
| Pseudoparkinsonism | 1.5 | 1.6 |
| Sedation | 19.8 | 19.5 |
| Sensory Disturbance | 4.0 | 3.2 |
| Tremor | 21.1 | 7.6 |
| NEUROPSYCHIATRIC | ||
| Agitation | 31.9 | 22.2 |
| Anxiety | 3.1 | 1.1 |
| Confusion | 8.4 | 4.9 |
| Decreased Libido | 3.1 | 1.6 |
| Delusions | 1.2 | 1.1 |
| Disturbed concentration | 3.1 | 3.8 |
| Euphoria | 1.2 | 0.5 |
| Hostility | 5.6 | 3.8 |
| NONSPECIFIC | ||
| Fatigue | 5.0 | 8.6 |
| Fever/Chills | 1.2 | 0.5 |
| RESPIRATORY | ||
| Upper Respiratory Complaints | 5.0 | 11.4 |
| SPECIAL SENSES | ||
| Auditory Disturbance | 5.3 | 3.2 |
| Blurred Vission | 14.6 | 10.3 |
| Gustatory Disturbance | 3.1 | 1.1 |
* Events reported by at least 1% of patients receiving bupropion are included.
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 described 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 1/1000 patients, while rare events are those occurring in less than 1/1000 patients.
Cardiovascular: Frequent was edema; infrequent were chest pain, EKG
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, G.I. 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, dysparenuia, and painful ejaculation.
Hematologic/Oncologic: Rare were lymphadenopathy, anemia, and
pancytopenia.
Musculoskeletal: Rare was musculoskeletal chest pain.
Neurological: (see WARNINGS) Frequent were ataxia/incoordination, seizure, myoclonus, dyskinesia, and dystonia; infrequent were mydriasis, vertigo, and dysarthria; rare were EEG abnormality, abnormal neurological exam, impaired attention, sciatica, and aphasia.
Neuropsychiatric: (see PRECAUTIONS) 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.
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:
Cardiovascular: orthostatic hypotension, third degree heart block
Endocrine: syndrome of inappropriate antidiuretic hormone
secretion
Gastrointestinal: esophagitis, hepatitis
Hemic and Lymphatic: ecchymosis, leukocytosis, leukopenia
Musculoskeletal: arthralgia, myalgia, muscle
rigidity/fever/rhabdomyolysis
Nervous: coma, delirium, dream abnormalities, paresthesia, unmasking
of tardive dyskinesia
Skin and Appendages: Stevens-Johnson syndrome, angioedema, exfoliative
dermatitis, urticaria
Special Senses: tinnitus
Humans:
Controlled clinical studies conducted in normal volunteers,
in subjects with a history of multiple drug abuse, and in depressed patients
showed some increase in motor activity and agitation/excitement.
In a population of individuals experienced with drugs of abuse, a single dose of 400 mg bupropion produced mild amphetamine-like activity as compared to placebo on the morphine-benzedrine subscale of the Addiction Research Center Index (ARCI) and a score intermediate between placebo and amphetamine on the Liking Scale of the ARCI. These scales measure general feelings of euphoria and drug desirability.
Findings in clinical trials, however, are not known to predict the abuse potential of drugs reliably. Nonetheless, evidence from single-dose studies does suggest that the recommended daily dosage of bupropion when administered in divided doses is not likely to be especially reinforcing to amphetamine or stimulant abusers. However, higher doses, which could not be tested because of the risk of seizure, might be modestly attractive to those who abuse stimulant drugs.
Animals:
Studies in rodents have shown that bupropion exhibits some
pharmacologic actions common to psychostimulants, including increases in
locomotor activity and the production of a mild stereotyped behavior and
increases in rates of responding in several schedule-controlled behavior
paradigms. Drug discrimination studies in rats showed stimulus generalization
between bupropion and amphetamine and other psychostimulants. Rhesus monkeys
have been shown to self-administer bupropion intravenously.
Human Overdose Experience:
There has been limited clinical
experience with overdosage of bupropion. Thirteen overdoses occurred during
clinical trials. Twelve patients ingested 850 to 4200 mg and recovered without
significant sequelae. Another patient who ingested 9000 mg of bupropion and 300
mg of tranylcypromine experienced a grand mal seizure and recovered without
further sequelae.
Since introduction, overdoses of bupropion up to 17,500 mg 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, and tachycardia. Fever, muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory failure have been reported when bupropion was part of multiple drug overdoses.
Although most patients recovered without sequelae, deaths associated with overdoses of bupropion alone have been reported rarely in patients ingesting massive doses of bupropion. Multiple uncontrolled seizures, bradycardia, cardiac failure, and cardiac arrest prior to death were reported in these patients.
Management of Overdose:
Following suspected overdose,
hospitalization is advised. If the patient is conscious, vomiting should be
induced by syrup of ipecac. Activated charcoal also may be administered every 6
hours during the first 12 hours after ingestion. Baseline laboratory values
should be obtained. Electrocardiogram and EEG monitoring also are recommended
for the next 48 hours. Adequate fluid intake should be provided.
If the patient is stuporous, comatose, or convulsing, airway intubation is recommended prior to undertaking gastric lavage. Although there is little clinical experience with lavage following an overdose of bupropion, it is likely to be of benefit within the first 12 hours after ingestion since absorption of the drug may not yet be complete.
While diuresis, dialysis, or hemoperfusion are sometimes used to treat drug overdosage, there is no experience with their use in the management of overdoses of bupropion. Because diffusion of bupropion from tissue to plasma may be slow, dialysis may be of minimal benefit several hours after overdose.
Based on studies in animals, it is recommended that seizures be treated with an intravenous benzodiazepine preparation and other supportive measures, as appropriate.
Further information about the treatment of overdoses may be available from a poison control center.
No single dose of bupropion should exceed 150 mg. Bupropion should be administered t.i.d., preferably with at least 6 hours between successive doses.
Usual Dosage for Adults:
The usual adult dose is 300 mg/day, given
t.i.d. Dosing should begin at 200 mg/day, given as 100 mg b.i.d. Based on
clinical response, this dose may be increased to 300 mg/day, given as 100 mg
t.i.d., no sooner than 3 days after beginning therapy (see table below).
| Dosing Regimen | |||||
|---|---|---|---|---|---|
| Treatment Day | Total Daily Dose | Tablet Strength | Number of Tablets | ||
| Morning | Midday | Evening | |||
| 1 | 200 mg | 100 mg | 1 | 0 | 1 |
| 4 | 300 mg | 100 mg | 1 | 1 | 1 |
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 or 100 mg tablets. The 100 mg tablet must be administered q.i.d.,
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.
Elderly Patients:
In general, older patients are known to
metabolize drugs more slowly and to be more sensitive to the anticholinergic,
sedative, and cardiovascular side effects of antidepressant drugs. Clinical
trials enrolled several hundred patients 60 years of age and older. The
experience with these patients and younger ones was similar.
Maintenance:
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.
Store at 15° to 25°C (59° to 77°F). Protect from light and moisture.
The research information is available separately on Internet Mental Health.
