Bupropion

Pronunciation: (bue-PROE-pee-on)
Class: Antidepressant, Smoking deterrent

Trade Names

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

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

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

Pharmacokinetics

Absorption

Steady state achieved in approximately 8 days.

Immediate release

T _max within 2 h.

Sustained release (SR)

T _max approximately 3 h.

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.

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 to 24 h (hydroxybupropion), approximately 37 to 51 h (threohydrobupropion), and approximately 31 to 33 h (erythrohydrobupropion).

Special Populations

Renal Function Impairment

Elimination of major metabolites may be reduced. Dose adjustment may be necessary.

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.

Indications and Usage

Treatment of major depressive disorder (MDD); 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 (bupropion SR); treatment of attention deficit hyperactivity disorder.

Contraindications

Seizure disorder; current or prior diagnosis of bulimia or anorexia nervosa; concurrent treatment with or within 14 days of discontinuation of MAOIs; concurrent treatment with multiple bupropion products (eg, coadministration of Zyban for smoking cessation and Wellbutrin for depression); patients undergoing abrupt discontinuation of alcohol or sedatives; hypersensitivity to bupropion or any other component of the product(s).

Dosage and Administration

MDD
Adults Immediate release

PO 100 mg twice daily initially; may increase to 100 mg 3 times daily after 3 days (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.

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.

Maintenance dose

PO Clinical data are not available regarding long-term treatment for smoking cessation. Whether to continue treatment beyond 12 wk must be determined for individual patients.

Combination treatment

PO Bupropion may be used in combination with a nicotine transdermal system for smoking cessation.

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 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 3î“¸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; do not 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; do not 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, Budeprion XL 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, efavirenz, phenobarbital, phenytoin, rifampin

May decrease bupropion serum concentrations. Observe the clinical response. If an interaction is suspected, adjust bupropion dose as needed or discontinue the other drug. Do not exceed the maximum recommended bupropion dose.

Cyclosporine

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

Drugs metabolized by CYP2D6 (eg, desipramine, flecainide, haloperidol, imipramine, metoprolol, nortriptyline, propafenone, risperidone, 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. If an interaction is suspected, adjust therapy as needed.

Inhibitors of CYP2B6 (cimetidine, clopidogrel, cyclophosphamide, orphenadrine, thiotepa, ticlopidine)

May increase bupropion plasma levels and the risk of adverse reactions. The bupropion dosage may need to be adjusted when the CYP2B inhibitor is started or stopped.

Linezolid, MAOIs, selegiline

May increase risk of acute bupropion toxicity. Discontinue MAOIs at least 14 days before starting bupropion.

Nelfinavir, 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. Do not exceed the maximum recommended bupropion dose.

Nicotine patch

Coadministration may cause hypertension. Monitor BP.

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.

Theophylline, warfarin, and other drugs extensively metabolized

Plasma concentrations of these agents may increase following smoking cessation because of deinduction of hepatic enzymes.

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%); edema (at least 1%); syncope (1%); AV block, extrasystoles, MI, orthostatic hypotension, phlebitis, pulmonary embolism, third-degree heart block (postmarketing).

CNS

Headache (34%); agitation (32%); insomnia (31%); dizziness (22%); tremor (21%); sedation (20%); disturbed concentration (9%); akinesia/bradykinesia, anxiety, confusion (8%); hostility (6%); fatigue, nervousness (5%); asthenia, decreased appetite, impaired sleep quality, migraine, sensory disturbances (4%); abnormal dreams, decreased libido, decreased memory, feeling jittery, irritability, somnolence (3%); CNS stimulation, paresthesia (2%); ataxia/incoordination, decreased sexual function, depression, dyskinesia, dystonia, hallucinations, increased libido, mania/hypomania, myoclonus, seizure (at least 1%); delusions (1%); abnormal EEG, aggression, aphasia, coma, delirium, dysarthria, euphoria, extrapyramidal syndrome, hypokinesia, manic reaction, neuralgia, neuropathy, paranoid ideation, paresthesia, restlessness, unmasking tardive dyskinesia (postmarketing).

Dermatologic

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

EENT

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

GI

Dry mouth (28%); constipation (26%); anorexia, nausea (18%); abdominal pain (9%); diarrhea (7%); flatulence (6%); increased appetite, taste perversion, vomiting (4%); dyspepsia, gustatory disturbance (3%); dysphagia (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 (4%); arthritis, pain in extremity (3%); akathisia, muscle spasm, twitch (2%); arthralgia, muscle rigidity, muscle weakness, myalgia, rhabdomyolysis (postmarketing).

Respiratory

Upper respiratory tract infection (9%); sinusitis (5%); cough (4%); pneumonia (postmarketing).

Miscellaneous

Infection (9%); upper respiratory tract complaints (5%); chest pain (4%); pain (3%); bronchitis, fever (2%); 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. Closely observe all patients who are started on 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 children.

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. Depressed mood may be a symptom of nicotine withdrawal. Depression, rarely including suicidal ideation, has been reported in smokers undergoing a smoking cessation attempt without medication. However, some of these symptoms have occurred in patients taking bupropion who continued to smoke. 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. Advise patients and caregivers that the patient should stop taking bupropion and contact a health care provider immediately if agitation, hostility, depressed mood, or changes in thinking or behavior that are not typical for the patient are observed, or if the patient develops suicidal ideation or suicidal behavior. In many postmarketing cases, resolution of symptoms after discontinuation of Zyban was reported, although in some cases the symptoms persisted. Provide ongoing monitoring and supportive care until symptoms resolve.

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 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.

Hazardous Tasks

May impair judgment, thinking, or motor skills.

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 with 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 , Budeprion SR , Budeprion XL , 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. 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 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. 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.

Suicide

Suicidal ideation is inherent in depression and may persist until significant remission occurs. Closely supervise high-risk patients during initial drug therapy. Prescribe smallest quantity of medication consistent with good patient management in order to reduce risk of overdose.

Overdosage

Symptoms

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

Patient Information

Advise patient or caregiver to read the Medication Guide before starting therapy and to read and check for new information each time the medication is refilled.
If patient is a child or adolescent being treated for depression, advise patient, family, or caregiver 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 patient that bupropion contains the same active ingredients as the smoking cessation aid Zyban . Caution patient not to use these in combination or with any other medication containing bupropion.
Review dosing schedule with patient. Advise patient to avoid taking at bedtime to minimize problems with sleeping.
Advise patient that dose will be started low and then increased, if necessary, until max benefit is obtained.
Advise patient to take each dose without regard to meals, but to take with food if stomach upset occurs.
Advise patient 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 patient 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 patient 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 patient taking XL tablets to take prescribed dose once daily with at least 24 h between doses to minimize the risk of seizures. Explain to patient 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 patient taking SR tablets, XL tablets, or Aplenzin to swallow tablets whole and not to chew, divide, or crush.
Caution patient that if dose is missed, not to take an extra dose to catch up because of the increased risk of seizure. Advise patient 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 patient to contact 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 patient to take frequent sips of water, suck on ice chips or sugarless hard candy, or chew sugarless gum if dry mouth occurs.
Advise patient, family, or caregiver to be alert for abnormal changes in mood or thinking and to immediately report any of the following to 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 patient to stop taking the medication and immediately notify 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 patient to minimize, or completely avoid, consumption of alcoholic beverages while taking bupropion. Caution patient that excessive use or abrupt discontinuation of alcohol or sedatives (eg, benzodiazepines) may increase the risk of having a seizure.
Advise patient 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.