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BuPROPion


Special Alerts

Antidepressant Use in Pediatric Patients - October 15, 2004

In March 2004, the Food and Drug Administration (FDA) issued a Public Health Advisory concerning the use of antidepressant medications in which they called attention to reports of both suicidal ideation and suicide attempts in children taking antidepressant drugs for the treatment of major depressive disorder (MDD). In September 2004, a review of the existing data was completed by two FDA Advisory Committees. The FDA has now instructed the manufacturers of ALL antidepressants to revise the labeling for their products to include a boxed warning and expanded warning statements that alert healthcare providers to an increased risk of suicidality (suicidal thinking and behavior) in children and adolescents being treated with these agents, and to include additional information about the results of pediatric studies. The FDA also informed manufacturers that a Patient Medication Guide (MedGuide), which will be given to patients receiving the drugs advising them of the risk and precautions, is appropriate for these drug products.

The risk of suicidality for these drugs was identified in a combined analysis of short-term (up to 4 months) placebo-controlled trials of nine antidepressant drugs, including the selective serotonin reuptake inhibitors (SSRIs) and others, in children and adolescents with major depressive disorder (MDD), obsessive compulsive disorder (OCD), or other psychiatric disorders. A total of 24 trials involving over 4400 patients were included. The analysis showed a greater risk of suicidality during the first few months of treatment in those receiving antidepressants. The average risk of such events on drug was 4%, compared to a rate of 2% in groups receiving placebo. No suicides occurred in these trials. Based on this data, the FDA has determined that the following points are appropriate for inclusion in the boxed warning:

Antidepressants increase the risk of suicidal thinking and behavior (suicidality) in children and adolescents with MDD and other psychiatric disorders.

Anyone considering the use of an antidepressant in a child or adolescent for any clinical use must balance the risk of increased suicidality with the clinical need.

Patients who are started on therapy should be observed closely for clinical worsening, suicidality, or unusual changes in behavior.

Families and caregivers should be advised to closely observe the patient and to communicate with the prescriber.

A statement regarding whether the particular drug is approved for any pediatric indication(s) and, if so, which one(s).

Among the antidepressants, only fluoxetine is approved for use in treating MDD in pediatric patients. Clomipramine, fluoxetine, fluvoxamine, and sertraline are approved for OCD in pediatric patients. None of the drugs is FDA approved for other psychiatric indications in children.

Pediatric patients being treated with antidepressants for any indication should be closely observed for clinical worsening, as well as agitation, irritability, 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). This monitoring should include daily observation by families and caregivers and frequent contact with the physician. It is also recommended that prescriptions for antidepressants be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose.

In addition to the boxed warning and other information in professional labeling on antidepressants, MedGuides are being prepared for all of the antidepressants to provide information about the risk of suicidality in children and adolescents for patients and their families and caregivers. MedGuides are intended to be distributed by the pharmacist with each prescription or refill of a medication.

The FDA plans to work closely with the manufacturers of all approved antidepressant products to optimize the safe use of these drugs and implement the proposed labeling changes and other safety communications in a timely manner.

Additional information can be found on the FDA website at: http://www.fda.gov/medwatch/SAFETY/2004/safety04.htm#ssri, last accessed October 21, 2004.


Pronunciation

 (byoo PROE pee on)


U.S. Brand Names

 Wellbutrin®; Wellbutrin SR®; Wellbutrin XL™; Zyban®


Generic Available

 Yes: Excludes Wellbutrin XL™


Canadian Brand Names

 Wellbutrin®; Zyban®


Use

 Treatment of depression; adjunct in smoking cessation


Use - Unlabeled/Investigational

 Attention-deficit/hyperactivity disorder (ADHD)


Pregnancy Risk Factor

 B


Lactation

 Enters breast milk/not recommended (AAP rates "of concern")


Contraindications

 Hypersensitivity to bupropion or any component of the formulation; seizure disorder; anorexia/bulimia; use of MAO inhibitors within 14 days; patients undergoing abrupt discontinuation of ethanol or sedatives (including benzodiazepines); patients receiving other dosage forms of bupropion


Warnings/Precautions

 When using immediate release tablets, seizure risk is increased at total daily dosage >450 mg, individual dosages >150 mg, or by sudden, large increments in dose. Data for the immediate-release formulation of bupropion revealed a seizure incidence of 0.4% in patients treated at doses in the 300-450 mg/day range. The estimated seizure incidence increases almost 10-fold between 450 mg and 600 mg per day. Data for the sustained release dosage form revealed a seizure incidence of 0.1% in patients treated at a dosage range of 100-300 mg/day, and increases to ~0.4% at the maximum recommended dose of 400 mg/day. The risk of seizures is increased in patients with a history of seizures, anorexia/bulimia, head trauma, CNS tumor, severe hepatic cirrhosis, abrupt discontinuation of sedative-hypnotics or ethanol, medications which lower seizure threshold (antipsychotics, antidepressants, theophyllines, systemic steroids), stimulants, or hypoglycemic agents. Discontinue and do not restart in patients experiencing a seizure. May cause CNS stimulation (restlessness, anxiety, insomnia) or anorexia. May cause weight loss; use caution in patients where weight loss is not desirable. The incidence of sexual dysfunction with bupropion is generally lower than with SSRIs.

May worsen psychosis in some patients or precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Monitor for worsening of depression or suicidality, especially during initiation of therapy or with dose increases or decreases. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy. Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their healthcare provider if any of these symptoms or worsening depression occur.

Antidepressants increase the risk of suicidal thinking and behavior in children and adolescents with MDD and other depressive disorders; consider risk prior to prescribing. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; the child's family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. A medication guide should be dispensed with each prescription. Bupropion is not FDA approved for use in children.

Use caution in patients with cardiovascular disease, history of hypertension, or coronary artery disease; treatment-emergent hypertension (including some severe cases) has been reported, both with bupropion alone and in combination with nicotine transdermal systems. Use with caution in patients with hepatic or renal dysfunction and in elderly patients. Elderly patients may be at greater risk of accumulation during chronic dosing. May cause motor or cognitive impairment in some patients, use with caution if tasks requiring alertness such as operating machinery or driving are undertaken. Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity resembling serum sickness reported.


Adverse Reactions

 Frequencies, when reported, reflect highest incidence reported with sustained release product.

>10%:

Central nervous system: Dizziness (11%), headache (25%), insomnia (16%)

Gastrointestinal: Nausea (18%), xerostomia (24%)

Respiratory: Pharyngitis (11%)

1% to 10%:

Cardiovascular: Arrhythmias, chest pain (4%), flushing, hypertension (may be severe), hypotension, palpitation (5%), syncope, tachycardia

Central nervous system: Agitation (9%), anxiety (6%), confusion, depression, euphoria, hostility, irritability (2%), memory decreased (3%), migraine, nervousness (3%), sleep disturbance, somnolence (3%)

Dermatologic: Pruritus (4%), rash (4%), sweating increased (5%), urticaria (1%)

Endocrine & metabolic: Hot flashes, libido decreased, menstrual complaints

Gastrointestinal: Abdominal pain, anorexia (3%), appetite increased, constipation (5%), diarrhea (7%), dyspepsia, dysphagia (2%), taste perversion (4%), vomiting (2%)

Genitourinary: Urinary frequency (5%)

Neuromuscular & skeletal: Arthralgia (4%), arthritis (2%), myalgia (6%), neck pain, paresthesia (2%), tremor (3%), twitching (2%)

Ocular: Amblyopia (2%), blurred vision

Otic: Auditory disturbance, tinnitus (6%)

Respiratory: Cough increased (2%), sinusitis (1%)

Miscellaneous: Allergic reaction (including anaphylaxis, pruritus, urticaria), infection

Postmarketing and/or case reports: Accommodation abnormality, akinesia, alopecia, amnesia, anemia, angioedema, aphasia, ataxia, atrioventricular block, bronchospasm, bruxism, chills, colitis, coma, coordination abnormal, cystitis, deafness, delirium, depersonalization, derealization, diplopia, dry eye, dry skin, dysarthria, dyskinesia, dyspareunia, dysphoria, dyspnea, dystonia, dysuria, ecchymosis, edema, EEG abnormality, ejaculation abnormality, emotional lability, enuresis, epistaxis, esophagitis, exfoliative dermatitis, extrapyramidal syndrome, extrasystoles, facial edema, fever with rash (and other symptoms suggestive of delayed hypersensitivity resembling serum sickness), flushing, frigidity, gastric reflux, gastrointestinal hemorrhage, gingivitis, glossitis, glycosuria, gum hemorrhage, gynecomastia, hallucinations, hepatic damage, hepatitis, hirsutism, hostility, hyperglycemia, hyperkinesia, hypertonia, hypesthesia, hypoglycemia, hypokinesia, hypomania, impotence, intestinal perforation, jaundice, leg cramps, leukocytosis, leukopenia, libido increased, lymphadenopathy, maculopapular rash, malaise, manic reaction, mouth ulcers, muscle rigidity, muscle weakness, musculoskeletal chest pain, mydriasis, MI, myoclonus, neuralgia, neuropathy, nocturia, painful erection, pallor, pancreatitis, pancytopenia, paranoia, paranoid reaction, paresthesia, peripheral edema, phlebitis, photosensitivity, polyuria, postural hypotension, prostate disorder, pulmonary embolism, rhabdomyolysis, salivation increased, salpingitis, sciatica, seizure, SIADH, stomach ulcer, stomatitis, stroke, suicidal ideation, tardive dyskinesia, testicular swelling, thirst, thrombocytopenia, tongue edema, urinary incontinence, urinary retention, vaginal irritation, vaginitis, vasodilation, vertigo


Overdosage/Toxicology

 Symptoms of overdose include labored breathing, salivation, ataxia, and convulsions. Dialysis may be of limited value after drug absorption because of slow tissue-to-plasma diffusion. Treatment is symptomatic and supportive.


Drug Interactions

 Substrate of CYP1A2 (minor), 2A6 (minor), 2B6 (major), 2C8/9 (minor), 2D6 (minor), 2E1 (minor), 3A4 (minor); Inhibits CYP2D6 (weak)

Note: Seizure threshold-lowering agents: Use with caution in individuals receiving other agents that may lower seizure threshold (antipsychotics, antidepressants, fluoroquinolones, theophylline, abrupt discontinuation of benzodiazepines, systemic steroids)

Amantadine: Concurrent use appears to result in a higher incidence of adverse effects; use caution.

Cimetidine: May increase effect of bupropion (due to effect on bupropion metabolites)

CYP2B6 inducers: May decrease the levels/effects of bupropion. Example inducers include carbamazepine, nevirapine, phenobarbital, phenytoin, and rifampin.

CYP2B6 inhibitors: May increase the levels/effects of bupropion. Example inhibitors include desipramine, paroxetine, and sertraline.

Levodopa: Toxicity of bupropion is enhanced by levodopa

MAO inhibitors: Toxicity of bupropion is enhanced by MAO inhibitors (phenelzine); concurrent use is contraindicated

Nicotine: Treatment-emergent hypertension may occur; monitor BP in patients treated with bupropion and nicotine patch

Selegiline: When used in low doses (<10 mg/day), risk of interaction is theoretically lower than with nonselective MAO inhibitors

Tricyclic antidepressants: Serum levels may be increased by bupropion; in addition, these agents lower seizure threshold (see "Note")

Warfarin: Coadministration has resulted in altered PT/INR and thrombotic or hemorrhagic events. Monitor INR.


Ethanol/Nutrition/Herb Interactions

Ethanol: Ethanol (may increase CNS depression).

Herb/Nutraceutical: Avoid valerian, St John's wort, SAMe, gotu kola, kava kava (may increase CNS depression).


Stability

 Store at controlled of 20°C to 25°C (68°F to 77°F).


Mechanism of Action

 Aminoketone antidepressant structurally different from all other marketed antidepressants; like other antidepressants the mechanism of bupropion's activity is not fully understood. Bupropion is a relatively weak inhibitor of the neuronal uptake of serotonin, norepinephrine, and dopamine, and does not inhibit monoamine oxidase. Metabolite inhibits the reuptake of norepinephrine. The primary mechanism of action is thought to be dopaminergic and/or noradrenergic.


Pharmacodynamics/Kinetics

Absorption: Rapid

Distribution: Vd: 19-21 L/kg

Protein binding: 82% to 88%

Metabolism: Extensively hepatic to 3 active metabolites: Hydroxybupropion, erythrohydrobupropion, threohydrobupropion (metabolite activity ranges from 1 /5 to 1 /2 potency of bupropion)

Bioavailability: 5% to 20% in animals

Half-life:

Distribution: 3-4 hours

Elimination: 21 ± 9 hours; Metabolites: Hydroxybupropion: 20 ± 5 hours; Erythrohydrobupropion: 33 ± 10 hours; Threohydrobupropion: 37 ± 13 hours

Time to peak, serum: Bupropion: ~3 hours; bupropion extended release: ~5 hours

Metabolites: Hydroxybupropion, erythrohydrobupropion, threohydrobupropion: 6 hours

Excretion: Urine (87%); feces (10%)


Dosage

 Oral:

Children and Adolescents: ADHD (unlabeled use): 1.4-6 mg/kg/day

Adults:

Depression:

Immediate release: 100 mg 3 times/day; begin at 100 mg twice daily; may increase to a maximum dose of 450 mg/day

Sustained release: Initial: 150 mg/day in the morning; may increase to 150 mg twice daily by day 4 if tolerated; target dose: 300 mg/day given as 150 mg twice daily; maximum dose: 400 mg/day given as 200 mg twice daily

Extended release: Initial: 150 mg/day in the morning; may increase as early as day 4 of dosing to 300 mg/day; maximum dose: 450 mg/day

Smoking cessation (Zyban®): Initiate with 150 mg once daily for 3 days; increase to 150 mg twice daily; treatment should continue for 7-12 weeks

Elderly: Depression: 50-100 mg/day, increase by 50-100 mg every 3-4 days as tolerated; there is evidence that the elderly respond at 150 mg/day in divided doses, but some may require a higher dose

Dosing adjustment/comments in renal impairment: Effect of renal disease on bupropion's pharmacokinetics has not been studied; elimination of the major metabolites of bupropion may be affected by reduced renal function. Patients with renal failure should receive a reduced dosage initially and be closely monitored.

Dosing adjustment in hepatic impairment:

Note: The mean AUC increased by ~1.5-fold for hydroxybupropion and ~2.5-fold for erythro/threohydrobupropion; median Tmax was observed 19 hours later for hydroxybupropion, 31 hours later for erythro/threohydrobupropion; mean half-life for hydroxybupropion increased fivefold, and increased twofold for erythro/threohydrobupropion in patients with severe hepatic cirrhosis compared to healthy volunteers.

Mild to moderate hepatic impairment: Use with caution and/or reduced dose/frequency

Severe hepatic cirrhosis: Use with extreme caution; maximum dose:

Wellbutrin®: 75 mg/day

Wellbutrin SR®: 100 mg/day or 150 mg every other day

Wellbutrin XL™: 150 mg every other day

Zyban®: 150 mg every other day


Administration

 May be taken without regard to meals. Zyban® and extended release tablets should be swallowed whole; do not crush, chew, or divide. The insoluble shell of the extended-release tablet may remain intact during GI transit and is eliminated in the feces. Wellbutrin® SR may be divided, but not crushed or chewed.


Monitoring Parameters

 Body weight; mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, panic attacks


Reference Range

 Therapeutic levels (trough, 12 hours after last dose): 50-100 ng/mL


Patient Education

 Be aware that bupropion is marketed under different names and should not be taken together; Zyban® is for smoking cessation and Wellbutrin® is for treatment of depression. Note: Excessive use or abrupt discontinuation of alcohol or sedatives may alter seizure threshold.

Depression: Take as directed, in equally divided doses; do not take in larger dose or more often than recommended. Do not discontinue without consulting prescriber. Do not use alcohol or OTC medications not approved by prescriber. May cause drowsiness, clouded sensorium, headache, restlessness, or agitation (use caution when driving or engaging in tasks requiring alertness until response to drug is known); nausea, vomiting, or dry mouth (small, frequent meals, frequent mouth care, chewing gum, or sucking lozenges may help); constipation (increased exercise, fluids, fruit, or fiber may help); or impotence (reversible). Report persistent CNS effects (eg, agitation, confusion, anxiety, restlessness, insomnia, psychosis, hallucinations, seizures); suicidal ideation; muscle weakness or tremor; skin rash or irritation; chest pain or palpitations, abdominal pain or blood in stools; yellowing of skin or eyes; or respiratory difficulty, bronchitis, or unusual cough.

Smoking cessation: Use as directed; do not take extra doses. Do not combine nicotine patches with use of Zyban® unless approved by prescriber. May cause dry mouth and insomnia (these may resolve with continued use). Report any respiratory difficulty, unusual cough, dizziness, or muscle tremors.

Breast-feeding precaution: Breast-feeding is not recommended.


Nursing Implications

 Be aware that drug may cause seizures


Anesthesia and Critical Care Concerns/Other Considerations

 There are relatively few cardiovascular side effects compared to tricyclic antidepressants. However, several case reports include cardiovascular complications, including hypotension and MI. Use with caution in patients with recent MI or unstable angina. Recent information suggests that hypertension, in some cases severe and requiring acute treatment, has been reported in patients receiving bupropion alone, and especially when bupropion is used in conjunction with nicotine replacement therapy. Monitoring of blood pressure is recommended in patients receiving the combination of bupropion and nicotine replacement, particularly in those with hypertension and/or significant coronary artery disease.


Cardiovascular Considerations

 There are relatively few cardiovascular side effects compared to tricyclic antidepressants. However, several case reports include cardiovascular complications, including hypotension, hypertension, and MI. Use with caution in patients with recent MI or unstable angina. Recent information suggests that hypertension, in some cases severe and requiring acute treatment, has been reported in patients receiving bupropion alone, and especially when bupropion is used in conjunction with nicotine replacement therapy. These events have been observed in both patients with and without evidence of pre-existing hypertension. Data from a comparative study of sustained-release bupropion, nicotine transdermal system (NTS), the combination of sustained-release bupropion and NTS, and placebo suggest a higher incidence of treatment-emergent hypertension (>6%) in patients treated with the combination of sustained-release bupropion and NTS. The majority of these patients had evidence of pre-existing hypertension. Monitoring of blood pressure is recommended in patients receiving the combination of bupropion and nicotine replacement, particularly in those with hypertension and/or significant coronary artery disease. Possible potential problems need to be balanced against the very substantial benefits of smoking cessation.


Dental Health: Effects on Dental Treatment

 Key adverse event(s) related to dental treatment: Abnormal taste, significant xerostomia (normal salivary flow resumes with discontinuation).


Dental Health: Vasoconstrictor/Local Anesthetic Precautions

 Although this is not a tricyclic antidepressant, it can cause hypertensive episodes and should be used with caution in the presence of a vasoconstrictor.


Mental Health: Child/Adolescent Considerations

 Attention-deficit/hyperactivity disorder (ADHD): 1.4-5.7 mg/kg/day (mean: 3.3 mg/kg/day) was utilized in 15 ADHD subjects 7-17 years of age (Barrickman, 1995); 72 children with ADHD (6-12 years of age) received 3-6 mg/kg/day (Conners, 1996); adolescents with conduct disorder and substance use disorder were titrated to a maximum fixed daily dose of 300 mg (Riggs, 1998). The immediate-release dosage form was studied in clinical trials for indications other than depression in 104 pediatric patients. This limited exposure does not allow for assessment of the safety of bupropion in pediatric patients.

Barrickman LL, Petty PJ, Allen AJ, et al, "Bupropion Versus Methylphenidate in the Treatment of Attention-Deficit Hyperactivity Disorder," J Am Acad Child Adolesc Psychiatry , 1995, 34(5):649-57.

Conners CK, Casat CD, Gualtieri CT, et al, "Bupropion Hydrochloride in Attention Deficit Disorder With Hyperactivity," J Am Acad Child Adolesc Psychiatry , 1996, 35(10):1314-21.

Riggs PD, Leon SL, Mikulich SK, et al, "An Open Trial of Bupropion for ADHD in Adolescents With Substance Use Disorders and Conduct Disorder," J Am Acad Child Adolesc Psychiatry , 1998, 37(12):1271-8.


Dosage Forms

Tablet, as hydrochloride (Wellbutrin®): 75 mg, 100 mg

Tablet, extended release, as hydrochloride (Wellbutrin XL™): 150 mg, 300 mg

Tablet, sustained release, as hydrochloride: 100 mg, 150 mg [equivalent to Wellbutrin® SR], 150 mg [equivalent to Zyban®]

Wellbutrin® SR: 100 mg, 150 mg, 200 mg

Zyban®: 150 mg


References

"American Academy of Pediatrics Committee on Drugs. The Transfer of Drugs and Other Chemicals Into Human Milk," Pediatrics , 2001, 108(3):776-89.

"American Academy of Pediatrics Subcommittee on Attention-Deficit/Hyperactivity Disorder and Committee on Quality Improvement. Clinical Practice Guidelines: Treatment of the School-Aged Child With Attention-Deficit/Hyperactivity Disorder," Pediatrics , 2001, 108(4):1033-44.

Barrickman LL, Petty PJ, Allen AJ, et al, "Bupropion Versus Methylphenidate in the Treatment of Attention-Deficit Hyperactivity Disorder," J Am Acad Child Adolesc Psychiatry , 1995, 34(5):649-57.

Branconnier RJ, Cole JO, Ghazvinian S, et al, "Clinical Pharmacology of Bupropion and Imipramine in Elderly Depressives," J Clin Psychiatry , 1983, 44(5 Pt 2):130-3.

Conners CK, Casat CD, Gualtieri CT, et al, "Bupropion Hydrochloride in Attention Deficit Disorder With Hyperactivity," J Am Acad Child Adolesc Psychiatry , 1996, 35(10):1314-21.

Davidson J, "Seizures and Bupropion: A Review," J Clin Psychiatry , 1989, 50(7):256-61.

GlaxoSmithKline [data on file], "Wellbutrin® SR, GAZZ/96/0006/00, Study Report Synopsis, 1996, 1-8.

Hayes PE and Kristoff CA, "Adverse Reactions to Five New Antidepressants," Clin Pharm , 1986, 5:471-80.

Jennison TA, Brown P, Crossett J, et al, "A High-Performance Liquid Chromatographic Method for Quantitating Bupropion in Human Plasma or Serum," J Anal Toxicol , 1995, 19(2):69-72.

Kane JM, Cole K, Sarantakos S, et al, "Safety and Efficacy of Bupropion in Elderly Patients: Preliminary Observations," J Clin Psychiatry , 1983, 44(5 Pt 2):134-6.

Kavoussi RJ, Segraves RT, Hughes AR, et al, "Double-Blind Comparison of Bupropion Sustained Release and Sertraline in Depressed Outpatients," J Clin Psychiatry , 1997, 58(12):532-7.

Riggs PD, Leon SL, Mikulich SK, et al, "An Open Trial of Bupropion for ADHD in Adolescents With Substance Use Disorders and Conduct Disorder," J Am Acad Child Adolesc Psychiatry , 1998, 37(12):1271-8.

Spencer T, Biederman J, Kerman K, et al, "Desipramine Treatment of Children With Attention-Deficit Hyperactivity Disorder and Tic Disorder or Tourette's Syndrome," J Am Acad Child Adolesc Psychiatry , 1993, 32(2):354-60.

Van Wyck FJ, Manberg PJ, Miller LL, et al, "Overview of Clinically Significant Adverse Reactions to Bupropion," J Clin Psychiatry , 1983, 44(5 Pt 2):191-6.


International Brand Names

 Odranal® (AR); Quomem® (ES, TH); Wellbutrin® (AR, CA, CO, CR, CZ, DO, EC, GT, HN, HU, MX, PA, RO, SV); Zyban® (AT, AU, BE, BR, CA, CH, DE, DK, FR, GB, HU, IE, IL, IN, IT, NL, NO, PL, PT, RO, SE, SG, SI, YU); Zyntabac® (ES)


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