Professional Information

Bupropion

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

Trade Names:
Aplenzin
- Tablets, ER 174 mg as hydrobromide
- Tablets, ER 348 mg as hydrobromide
- Tablets, ER 522 mg as hydrobromide

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

Trade Names:
Budeprion XL (24 h)
- Tablets, ER 300 mg as hydrochloride

Trade Names:
Wellbutrin
- Tablets 75 mg as hydrochloride
- Tablets 100 mg as hydrochloride

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

Trade Names:
Wellbutrin XL (24 h)
- Tablets, ER 150 mg as hydrochloride
- Tablets, ER 300 mg as hydrochloride

Trade Names:
Zyban
- Tablets, ER 150 mg as hydrochloride

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

Pharmacology

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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 about 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.

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 about 21 h (bupropion), about 20 h (hydroxybupropion), about 37 h (threohydrobupropion), and about 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 males.

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); abrupt discontinuation of alcohol or sedatives; hypersensitivity to bupropion or any other component of the product.

Dosage and Administration

MDD
Adults

Immediate-release

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).

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).

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

174 mg once daily in the morning initially; may increase to 348 mg once daily as early as day 4 of therapy (max daily dose, 522 mg) (174 mg tablet not currently marketed; expected launch in mid-year 2009).

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.

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

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.

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.

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.
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.

Storage/Stability

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

Drug Interactions

Alcohol

Adverse neuropsychiatric reactions or reduced alcohol tolerance may occur.

Amantadine, levodopa

Incidence of bupropion adverse reactions may be increased.

Antidepressants, antipsychotics, systemic steroids, theophylline

May lower seizure threshold.

Carbamazepine, phenobarbital, phenytoin, rifampin

May decrease bupropion serum concentrations.

Cyclosporine

Cyclosporine concentrations may be reduced.

Drugs metabolized by CYP2D6 (eg, desipramine, flecainide, fluoxetine, haloperidol, imipramine, metoprolol, nortriptyline, paroxetine, propafenone, risperidone, sertraline, thioridazine)

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

Efavirenz, nelfinavir, ritonavir

Plasma levels of bupropion may be decreased, increasing the risk of adverse reactions.

Guanfacine

Risk of bupropion toxicity may be increased.

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

May increase bupropion plasma levels and risk of adverse reactions.

Linezolid, MAOIs, selegiline

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

Nicotine patch

Coadministration may cause hypertension.

Theophylline, warfarin, and other drugs extensively metabolized

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

Laboratory Test Interactions

None well documented.

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, hirsutis, 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

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. When considering the use of any antidepressant, 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.

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. The following symptoms may represent precursors to suicidality and should be reported to the health care provider immediately if noted or suspected: aggressiveness, agitation, anxiety, hostility, hypomania, impulsivity, insomnia, irritability, mania, panic attacks, and psychomotor restlessness. 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.

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.

Renal Function

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

Hepatic Function

Use with caution in patients with hepatic impairment. Consider reduced frequency and/or dose (reduced frequency of dosing for Zyban ). 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.

Allergic reaction

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

Altered appetite and weight

Has been associated with decreased appetite and weight loss; consider anorectic and/or weight-reducing potential of bupropion when determining treatment for depressed patient 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

Inform patients that the same active ingredient (bupropion) is found in Aplenzin , Budeprion SR , Budeprion XL , Wellbutrin , Wellbutrin SR , Wellbutrin XL, and Zyban .

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 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.

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 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 more than 150 mg/day to take in 2 divided doses with at least 8 h between doses to minimize risk of seizures.
Advise patient taking XL tablets to take prescribed dose once daily with at least 24 h between doses to minimize 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.