Bupropion

Pronunciation

Pronunciation: bue-PROE-pee-on
Class: Antidepressant, Smoking deterrent Bupropion hydrobromide

Trade Names

Aplenzin
- Tablets, ER, oral 174 mg
- Tablets, ER, oral 348 mg
- Tablets, ER, oral 522 mg

Bupropion hydrochloride

Wellbutrin
- Tablets, oral 75 mg as hydrochloride
- Tablets, oral 100 mg as hydrochloride

Wellbutrin SR (12 h)
- Tablets, sustained-release, oral 100 mg as hydrochloride
- Tablets, sustained-release, oral 150 mg as hydrochloride
- Tablets, sustained-release, oral 200 mg as hydrochloride

Wellbutrin XL (24 h)
- Tablets, ER, oral 150 mg as hydrochloride
- Tablets, ER, oral 300 mg as hydrochloride

Zyban
- Tablets, ER, oral 150 mg as hydrochloride

ratio-Bupropion SR (Canada)
Sandoz Bupropion SR (Canada)

Pharmacology

Exact mechanism of antidepressant or smoking deterrent activity is unknown, but it is presumed to be mediated by noradrenergic and/or dopaminergic mechanisms.

Slideshow: Depression, the Risk of Suicide, and Treatment Options

Pharmacokinetics

Absorption

Steady state achieved in approximately 8 days.

Immediate release

T max within 2 h.

Sustained release (SR)

T max approximately 3 h. Food increases AUC by 11% to 35%.

ER (XL, Aplenzin )

T max approximately 5 h. Food increases AUC by 19% ( Aplenzin ).

Distribution

Bupropion is 84% protein bound. Vd is 1,950 L ( Zyban ).

Metabolism

Extensively metabolized by hydroxylation or oxidation in the liver. CYP2B6 is involved in formation of hydroxybupropion (50% as potent as bupropion). The other 2 main metabolites are threohydrobupropion and erythrohydrobupropion, which are 20% as potent as bupropion.

Elimination

87% excreted in urine, 10% in feces, and 0.5% as unchanged drug; elimination half-life is approximately 21 h (bupropion), approximately 20 h (hydroxybupropion), approximately 37 h (threohydrobupropion), and approximately 33 h (erythrohydrobupropion).

Special Populations

Renal Function Impairment

Elimination of bupropion and/or major metabolites may be reduced.

Hepatic Function Impairment

Elimination of hydroxybupropion is reduced in patients with alcoholic liver disease. Bupropion C max increased 70%, AUC increased 3-fold, and mean half-life increased to 29 h in patients with severe hepatic impairment. Mean half-life for active metabolites increased 2- to 5-fold in patients with severe hepatic impairment.

Elderly

May be at risk of accumulation of bupropion and its metabolites.

Gender

AUC was approximately 13% higher in men ( Aplenzin ).

Indications and Usage

Treatment of major depressive disorder (MDD) ( Wellbutrin , Wellbutrin SR , Wellbutrin XL only).

Smoking cessation ( Zyban only).

Prevention of seasonal major depressive episodes in patients with seasonal affective disorder ( Wellbutrin XL only).

Unlabeled Uses

Treatment of neuropathic pain and enhancement of weight loss; treatment of attention deficit hyperactivity disorder; treatment of aphthous ulcers; treatment of premenstrual dysphoric disorder; prevention of migraine.

Contraindications

Seizure disorder; current or prior diagnosis of bulimia or anorexia nervosa; concurrent treatment with or within 14 days of discontinuation of an MAOI; concurrent treatment with other bupropion products; patients undergoing abrupt discontinuation of alcohol or sedatives; hypersensitivity to bupropion or any other component of the product(s).

Dosage and Administration

Major Depressive Disorder
Adults Immediate release

PO 100 mg twice daily initially; may increase to 100 mg 3 times daily after 3 days. Increases in dose should not exceed 100 mg per day in a 3-day period (max daily dose, 450 mg; max single dose, 150 mg).

SR

PO 150 mg once daily initially; may increase to 150 mg twice daily as early as day 4 of therapy (max daily dose, 400 mg; max single dose, 200 mg).

XL

PO 150 mg once daily initially; may increase to 300 mg once daily as early as day 4 of therapy (max daily dose, 450 mg).

Aplenzin

PO 174 mg once daily in the morning initially; may increase to 348 mg once daily as early as day 4 of therapy (max, 522 mg/day).

Seasonal Affective Disorder
Adults

PO 150 mg initially as a single dose in the morning. The dose may be increased to 300 mg after 1 wk. Continue treatment through the winter season and taper/discontinue in early spring.

Smoking Deterrent
Adults Initial dose

PO 150 mg once daily for first 3 days, increasing to 150 mg twice daily. Do not exceed 300 mg/day. Initiate treatment while patient is still smoking. Patient should set target date to quit smoking within the first 2 wk of treatment; continue treatment for 7 to 12 wk.

Hepatic Function Impairment (Severe Hepatic Cirrhosis)
Adults Immediate release

PO Do not exceed 75 mg once daily.

SR

PO Do not exceed 100 mg once daily or 150 mg every other day.

XL

PO Do not exceed 150 mg every other day.

Aplenzin

PO Do not exceed 174 mg every other day.

Zyban

PO Do not exceed 150 mg every other day.

Hepatic Function Impairment (Mild to Moderate)
Adults

PO Consider reduced frequency and/or dose.

Renal Function Impairment
Adults

PO Consider reduced frequency and/or dose.

General Advice

  • Immediate-release, SR, and XL tablets can be interchanged on a total mg-to-mg daily dose.
  • When switching from bupropion hydrochloride ( Wellbutrin immediate release, SR, and XL) to bupropion hydrobromide ( Aplenzin ), give the equivalent total daily dose when possible (bupropion hydrobromide 174, 348, and 522 mg = bupropion hydrochloride 150, 300, and 450 mg, respectively).
  • Administer prescribed dose without regard to meals. Administer with food if GI upset occurs.
  • Avoid bedtime doses to minimize insomnia.
  • Periodically reassess patients to determine the need for treatment.
  • For prevention of seasonal major depressive episodes, initiate treatment in the autumn prior to the onset of depressive symptoms and continue through the winter; taper and discontinue in early spring.
  • Patients whose seasonal major depressive episodes are infrequent or not associated with impairment generally should not be treated prophylactically.
  • Immediate release
  • To reduce risk of seizures, do not exceed a dosage increase of 100 mg/day in a 3-day period, 150 mg as a single dose, or total daily dose of 450 mg.
  • Separate doses by at least 6 h.
  • SR
  • To reduce risk of seizures, do not exceed a total daily dose of 400 mg (300 mg for smoking deterrent) or 200 mg (150 mg for smoking deterrent) as a single dose. Administer dose twice daily with at least 8 h between doses.
  • Instruct patients to swallow tablets whole, and not to crush, chew, or divide.
  • XL
  • To reduce risk of seizures, do not exceed total daily dose of 450 mg.
  • Administer prescribed dose once daily in the morning.
  • Instruct patients to swallow tablets whole, and not to crush, chew, or divide.
  • Separate doses by at least 24 h.
  • Aplenzin
  • To reduce risk of seizures, do not exceed 522 mg daily.
  • Swallow whole and do not crush, divide, or chew tablets.
  • Separate doses by at least 24 h.
  • Full antidepressant effect may not be evident until 4 wk of treatment or longer.

Storage/Stability

Store immediate-release tablets between 59° and 77°F. Protect from light and moisture. Store SR tablets and Zyban between 68° and 77°F. Store Wellbutrin XL and Aplenzin between 59° and 86°F.

Drug Interactions

Alcohol

Adverse neuropsychiatric reactions or reduced alcohol tolerance may occur. Advise patients to minimize or avoid alcohol consumption while taking bupropion.

Amantadine, levodopa

Incidence of bupropion adverse reactions may be increased. Use small initial dosages and small, gradual dosage increases of bupropion.

Carbamazepine, CYP2B6 inducers (eg, efavirenz, phenobarbital, phenytoin, rifampin)

May decrease bupropion serum concentrations. Observe the clinical response. If an interaction is suspected, adjust the bupropion dose as needed or discontinue the other drug.

Cyclosporine

Cyclosporine concentrations may be reduced. Close clinical and laboratory monitoring of cyclosporine is warranted when bupropion is started or stopped.

Drugs metabolized by CYP2D6 (eg, desipramine, flecainide, haloperidol, iloperidone, imipramine, metoprolol, nortriptyline, propafenone, risperidone, tamoxifen, thioridazine)

Plasma levels of these agents may be elevated by bupropion. Use with caution and adjust the dose of the CYP2D6 substrate as needed.

Drugs that lower the seizure threshold (eg, antidepressants, antipsychotics, systemic steroids, theophylline, tramadol)

Bupropion is associated with a dose-dependent risk of seizures. Undertake the coadministration of bupropion and agents that lower the seizure threshold with extreme caution, starting with low doses and gradual dose increases.

Drugs used in clinical situations that may increase the risk of seizures (addictions [eg, cocaine, opiates, stimulants], diabetes treated with oral hypoglycemic agents or insulin, excessive use of alcohol or sedatives [including benzodiazepines], nonprescription anorectics and stimulants)

The risk of seizures may be increased in patients receiving bupropion. Use with caution and closely monitor patients.

Guanfacine

Risk of bupropion toxicity may be increased. Closely monitor patients.

Inhibitors of CYP2B6 (eg, cimetidine, clopidogrel, ticlopidine)

May increase bupropion plasma levels and the risk of adverse reactions. The bupropion dosage may need to be adjusted when the CYP2B6 inhibitor is started or stopped.

Linezolid, MAOIs

May increase risk of acute bupropion toxicity. Coadministration with MAOIs is contraindicated. Discontinue MAOIs at least 14 days before starting bupropion. Avoid concurrent use of bupropion and linezolid.

Nicotine replacement therapy

Coadministration may cause hypertension. Monitor BP.

Ritonavir

Plasma levels of bupropion may be reduced, decreasing the pharmacologic effect. Monitor the clinical response and be prepared to adjust the bupropion dose if needed.

SSRIs (eg, fluoxetine, paroxetine, sertraline)

Bupropion may inhibit the metabolism of certain SSRIs, increasing their plasma concentration. If bupropion is added to the treatment regimen of SSRIs metabolized by CYP2D6, consider a dosage reduction in the medication. In addition, the risk of serotonin syndrome may be increased. Closely monitor the clinical response and adjust treatment as needed.

Tiagabine

The risk of seizures may be increased. Coadminister with caution. Consider alternative therapy for one of the agents.

Warfarin

Altered PT and/or INR infrequently associated with hemorrhagic or thrombotic complications were observed when bupropion was administered with warfarin. Monitor anticoagulant activity and adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Tachycardia (11%); palpitation (6%); cardiac arrhythmia (5%); flushing, hypertension (4%); hot flashes, hypotension (3%); syncope (1%); AV block, extrasystoles, MI, orthostatic hypotension, phlebitis, pulmonary embolism, third-degree heart block (postmarketing).

CNS

Insomnia (40%); headache (34%); agitation (32%); migraine (26%); dizziness (22%); tremor (21%); sedation (20%); disturbed concentration (9%); akinesia/bradykinesia, anxiety, confusion (8%); hostility (6%); dream abnormality, fatigue, nervousness (5%); asthenia, impaired sleep quality, sensory disturbances (4%); decreased libido, decreased memory, feeling jittery, irritability, somnolence (3%); akathisia, CNS stimulation, paresthesia, pseudoparkinsonism (2%); ataxia/incoordination, decreased sexual function, depression, dyskinesia, dystonia, hallucinations, increased libido, mania/hypomania, myoclonus, seizure (at least 1%); abnormal thinking, delusions, euphoria (1%); abnormal EEG, aggression, aphasia, coma, completed suicide, delirium, dysarthria, extrapyramidal syndrome, hypokinesia, manic reaction, neuralgia, neuropathy, paranoid ideation, paresthesia, restlessness, suicide attempt, unmasking tardive dyskinesia (postmarketing).

Dermatologic

Sweating (22%); rash (8%); pruritus (4%); dry skin, urticaria (2%); nonspecific rashes (at least 1%); alopecia, angioedema, erythema multiforme, exfoliative dermatitis, hirsutism, Stevens-Johnson syndrome (postmarketing).

EENT

Blurred vision (15%); nasopharyngitis (13%); rhinitis (12%); pharyngitis (11%); tinnitus (6%); auditory disturbance (5%); amblyopia, diplopia (3%); deafness, increased IOP, mydriasis (postmarketing).

GI

Dry mouth (28%); constipation (26%); nausea/vomiting (23%); anorexia, nausea (18%); abdominal pain (9%); diarrhea (7%); flatulence (6%); decreased appetite, increased appetite, taste perversion, vomiting (4%); dyspepsia, gustatory disturbance (3%); dysphagia, mouth ulcer (2%); stomatitis (at least 1%); colitis, esophagitis, GI hemorrhage, gum hemorrhage, intestinal perforation, pancreatitis, stomach ulcer (postmarketing).

Genitourinary

Menstrual complaints, urinary frequency (5%); impotence (3%); dysmenorrhea, urinary retention, urinary urgency, vaginal hemorrhage (2%); nocturia (at least 1%); UTI (1%); abnormal ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful erection, salpingitis, urinary incontinence, vaginitis (postmarketing).

Hematologic-Lymphatic

Altered PT or INR, anemia, ecchymosis, leukocytosis, leukopenia, lymphadenopathy, pancytopenia, thrombocytopenia (postmarketing).

Hepatic

Hepatitis, liver damage (postmarketing).

Metabolic-Nutritional

Weight loss (23%); weight gain (14%); glycosuria (postmarketing).

Musculoskeletal

Myalgia (6%); arthralgia (5%); arthritis, pain in extremity (3%); muscle spasm, neck pain, twitch (2%); muscle rigidity, muscle weakness, rhabdomyolysis (postmarketing).

Respiratory

Upper respiratory tract infection (9%); sinusitis, upper respiratory tract complaints (5%); cough (4%); increased cough (3%); bronchitis, epistaxis (2%); dyspnea (1%); pneumonia (postmarketing).

Miscellaneous

Infection (9%); chest pain (4%); pain (3%); cutaneous temperature disturbance, fever (2%); edema, flu-like symptoms (at least 1%); allergic reactions, fever/chills (1%); anaphylactic shock, delayed hypersensitivity, fever with rash, hyperglycemia, hypoglycemia, serum sickness–like reactions, SIADH, symptoms of delayed hypersensitivity (postmarketing).

Precautions

Warnings

Psychiatric disorders

Antidepressants increased the risk of suicidal thinking and behavior in short-term studies in children, adolescents, and young adults with MDD and other psychiatric disorders compared with placebo. When considering the use of any antidepressant in a child, adolescent, or young adult, balance this risk with clinical need. Appropriately monitor patients of all ages who are started on antidepressant therapy and closely observe all patients who are started on bupropion therapy for clinical worsening, suicidality, or unusual changes in behavior during the initial few months of therapy or at times of increases or decreases in dose. Advise families and caregivers of the need for close observation and communication with the health care provider. Bupropion is not approved for use in pediatric patients.

Smoking cessation

Bupropion under the name Zyban is approved for smoking cessation. Serious neuropsychiatric events, including but not limited to depression, suicidal ideation, suicide attempt, and completed suicide, have been reported in patients taking bupropion for smoking cessation. Some cases may have been complicated by the symptoms of nicotine withdrawal in patients who stopped smoking. Observe all patients being treated with bupropion for smoking cessation treatment for neuropsychiatric symptoms, including changes in behavior, hostility, agitation, depressed mood, and suicide-related events, including ideation, behavior, and attempted suicide. These symptoms, as well as worsening of preexisting psychiatric illness and completed suicide, have been reported in some patients attempting to quit smoking while taking Zyban in the postmarketing experience. Most reported symptoms were during treatment with Zyban , but some were following discontinuation of Zyban . These events have occurred in patients with and without preexisting psychiatric disease; some have experienced worsening of psychiatric illness.


Monitor

Monitor all patients for clinical worsening, suicidality, and unusual changes in behavior, especially during the first few months of therapy or at times of increases or decreases in dose. Monitor all patients with hepatic or renal impairment for possible adverse reactions that could indicate high drug and/or metabolite levels. Monitor BP in patients receiving a combination of bupropion and nicotine replacement. Frequently assess patient for response to treatment. Periodically review therapy to determine if therapy needs to be continued without change or if a dose change (eg, increase, decrease, discontinuation) is indicated.


Pregnancy

Category C .

Lactation

Excreted in breast milk. The American Academy of Pediatrics classifies bupropion's effect on the breast-feeding infant as unknown but may be of concern.

Children

Safety and efficacy not established.

Elderly

Use with caution. Because elderly patients are more likely to have decreased renal function, use care in dose selection and consider monitoring renal function.

Hypersensitivity

Anaphylactoid reactions characterized by pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported.

Renal Function

Use with caution; reduce frequency and/or dose as needed.

Hepatic Function

Use with caution; reduce frequency and/or dose (reduced frequency of dosing for Zyban ) as needed. Use with extreme caution in patients with severe hepatic cirrhosis; a reduced dose and/or frequency is required.

Special Risk Patients

To reduce the risk of seizure, use with extreme caution in patients with history of head trauma, seizure, CNS tumors, or severe hepatic cirrhosis; in patients taking other drugs known to increase the risk of seizures; in cases of excessive use of alcohol, or addiction to opiates, cocaine, or other stimulants; patients taking anorectics; and diabetic patients treated with oral hypoglycemics or insulin.

Hazardous Tasks

May impair judgment, thinking, or motor skills.

Tartrazine Sensitivity

Some products may contain tartrazine, which may cause allergic-type reactions (including bronchial asthma) in susceptible individuals.

Agitation/Insomnia

A substantial proportion of patients will experience restlessness, agitation, anxiety, and/or insomnia; treatment with a sedative/hypnotic agent or discontinuation of therapy may be required. Gradual escalation of dose may minimize symptoms.

Altered appetite and weight

Has been associated with weight gain or loss; consider anorectic and/or weight-reducing potential of bupropion when determining treatment for depressed patients who have weight loss as a major presenting symptom of the depression.

CV effects

Hypertension requiring treatment may occur in patients receiving bupropion alone and in combination with nicotine replacement therapy. Use bupropion with caution in patients with unstable heart disease or recent history of MI.

Neuropsychiatric signs/symptoms

Neuropsychiatric signs and symptoms, including delusions, hallucinations, psychosis, concentration disturbances, paranoia, and confusion, have been reported; may abate with dose reduction or withdrawal of drug.

Other bupropion medications

Bupropion is the same active ingredient found in Aplenzin , Wellbutrin , Wellbutrin SR , Wellbutrin XL, and Zyban . Do not use these drugs in combination.

Psychosis or mania

May precipitate mania in bipolar patients or activate latent psychosis in other patients.

Seizures

May occur. Dose-related risk; sudden and large increases in dose may contribute to increased risk. Discontinue use and do not restart bupropion in patients who experienced a seizure while on treatment.

Screening for bipolar disorder

A major depressive episode may be the initial presentation of bipolar disorder. Screen patients with depression for risk of bipolar disorder prior to initiating therapy with an antidepressant. Treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients with bipolar disorder.

Overdosage

Symptoms

Cardiac arrest; cardiac failure, death accompanied by bradycardia, and uncontrolled seizures prior to death; ECG changes, such as conduction disturbances or arrhythmias; hallucinations; loss of consciousness; QRS prolongation; seizures; sinus tachycardia.

Patient Information

  • If the patient is a child or adolescent being treated for depression, advise patients, families, or caregivers to read the Medication Guide before starting therapy and with each refill. Review face-to-face monitoring schedule required for use of drug in this situation.
  • Advise patients that bupropion contains the same active ingredients as the smoking cessation aid Zyban . Caution patients not to use these in combination or with any other medication containing bupropion.
  • Advise patients to take each dose without regard to meals, but to take with food if stomach upset occurs.
  • Advise patients using bupropion as a smoking deterrent that counseling and support during cessation and for a period of time afterwards are an important part of therapy and increase the chance of successfully quitting smoking.
  • Advise patients taking immediate-release tablets to take in equally divided doses 3 or 4 times daily with at least 6 h between doses to minimize risk of seizures.
  • Advise patients taking SR tablets in dosages of more than 150 mg/day to take in 2 divided doses with at least 8 h between doses to minimize the risk of seizures.
  • Advise patients taking XL tablets to take prescribed dose once daily with at least 24 h between doses to minimize the risk of seizures. Explain to patients that the medication in the XL tablet is contained in a plastic shell that slowly releases the medication over 24 h and the shell is then expelled in the stool.
  • Caution patients taking SR tablets, XL tablets, or Aplenzin to swallow tablets whole and not to chew, divide, or crush.
  • Caution patients that if dose is missed, not to take an extra dose to catch up because of the increased risk of seizure. Advise patients that if dose is missed, to skip that dose and take the next dose at the regularly scheduled time.
  • Advise patients that it may take 4 wk or more before improvement in depression symptoms is noted and not to stop taking the medication when they feel better.
  • Instruct patients to contact their health care provider if symptoms do not appear to be getting better, if they worsen, or if bothersome adverse reactions (eg, agitation, appetite loss, difficulty concentrating, dry mouth, excessive sedation, excessive sweating, headache, insomnia) occur.
  • Advise patients to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
  • Inform patients that quitting smoking with or without Zyban may be associated with nicotine withdrawal symptoms (including depression or agitation) or exacerbation of preexisting psychiatric illness.
  • Advise patients, families, or caregivers to be alert for abnormal changes in mood or thinking and to immediately report any of the following to their health care provider: agitation, akathisia (psychomotor restlessness), anxiety, change in mood, change in personality, hostility or aggressiveness, impulsivity, insomnia, irritability, panic attacks, or suicidal thoughts or behavior. Advise families and caregivers of patients to observe for emergence on a day-to-day basis because changes may be abrupt.
  • Instruct patients to stop taking the medication and immediately notify their health care provider if any of the following occur: confusion; delusions; difficulty breathing; hallucinations; paranoid thoughts; rash, hives, or itching; seizures; or swelling of the lips, face, or throat.
  • Instruct patients to minimize, or completely avoid, consumption of alcoholic beverages while taking bupropion. Caution patients that excessive use or abrupt discontinuation of alcohol or sedatives (eg, benzodiazepines) may increase the risk of having a seizure.
  • Advise patients that drug may impair judgment, thinking, or motor skills, or cause drowsiness or dizziness, and to use caution while driving or performing other tasks requiring mental alertness until tolerance is determined.
  • Advise female patients to notify their health care providers if they become pregnant or intend to become pregnant during therapy.
  • Advise patients that bupropion should be discontinued and not restarted if they experience a seizure while on treatment.

Copyright © 2009 Wolters Kluwer Health.

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