Bupropion

Brand Name: Wellbutrin

Description

WELLBUTRIN (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 has a bitter taste and produces the sensation of local anesthesia on the oral mucosa.

Pharmacology

The neurochemical mechanism of the antidepressant effect of bupropion is not known. Bupropion does not inhibit monoamine oxidase. Compared to classical tricyclic antidepressants, it is a weak blocker of the neuronal uptake of serotonin and norepinephrine; it also inhibits the neuronal re-uptake of dopamine to some extent.

In humans, following oral administration of bupropion, peak plasma bupropion concentrations are usually achieved within 2 hours.

Indications and Usage

Bupropion is indicated for the treatment of depression. A physician considering bupropion for the management of a patient's first episodes of depression should be aware that the drug may cause generalized seizures with an approximate incidence of 0.4% (4/1000). This incidence of seizures may exceed that of other marketed antidepressants by as much as fourfold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted.

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.

Contraindications

Bupropion is contraindicated in patients with a seizure disorder. Bupropion is also 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. The concurrent administration of bupropion 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. Bupropion is contraindicated in patients who have shown an allergic response to it.

Warnings

Seizures: Bupropion is associated with seizures in approximately 0.4% (4/1000) 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 fourfold. This relative risk is only an approximate estimate because no direct comparative studies have been conducted. The estimate seizure incidence for bupropion 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.

In trial studies: 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.

Precautions

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 treatmen

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.

Drug Interactions

No systematic data have been collected on the consequences of the concomitant administration of bupropion and other drugs.

Studies in animals demonstrate that the acute toxicity of buproprion is enhanced by the MAO inhibitor phenelzine.

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.

BEFORE USING THIS MEDICINE: INFORM YOUR DOCTOR OR PHARMACIST of all prescription and over-the-counter medicine that you are taking. This includes monoamine oxide (MAO) inhibitors, HIV protease inhibitors, and Zyban. Inform your doctor of any other medical conditions including seizures, allergies, pregnancy, or breast-feeding.

Pregnancy & Nursing:

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. 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.

Use in the Elderly: Bupropion has not been systematically evaluated in older patients.

Adverse Reactions

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 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.

Cardiovascular: Frequent was edema; infrequent were chest pain, EKG abnormalities, 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.

Musculoskeletal: Rare was musculoskeletal chest pain.

Physical/Psychological Dependence:
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.

Overdose

Signs and Symptoms

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.

Treatment

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.

Dosage

Several weeks (1-4) may pass before your condition improves.

HOW TO USE THIS MEDICINE:
Follow the directions for using this medicine provided by your doctor. Space your doses evenly throughout the day.

Store this medicine at room temperature in a tightly-closed container, away from heat and light.
Continue to take this medicine even if you feel better.
Do not miss any doses. If you miss a dose of this medicine, take it as soon as you remember. Take the remaining doses for the day at evenly spaced intervals at least 4 hours apart. Do not take 2 doses at once.

Additional Information: Do not share this medicine with others for whom it was not prescribed. Do not use this medicine for other health conditions. Keep this medicine out of the reach of children.

It is particularly important to administer bupropion in a manner most likely to minimize the risk of seizure (see WARNINGS). 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 hyponotic 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 should exceed 150 mg. Bupropion should be administered t.i.d., preferably with at least 6 hours between successive doses.

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

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.

IF YOU WILL BE USING THIS MEDICINE FOR AN EXTENDED PERIOD OF TIME, be sure to obtain necessary refills before your supply runs out.

How Supplied

Tablets are supplied for oral administration as 100-mg and 150-mg.