Bupropion Hydrochloride

BUPROPION HYDROCHLORIDE

·  Class

·  antidepressant

·  Dosage, Adult (usual)

·  depression initial 100mg BID, maintenance 100mg TID, MAX 450mg/day

·  depression SR formulation: initial dose 150mg QD, maintenance 150mg BID MAX 400mg/day

·  smoking cessation 150mg QD x 3days then 150mg BID x 7-12 weeks

·  Dose Adjustments:

·  renal impairment

·  liver disease

·  Administration

·  smoking cessation patients should set a quit date within first 2 weeks of treatment

·  How Supplied

·  150 MG SUSTAINED-RELEASE TABLET

·  100 MG, 75 MG TABLET

·  Indications

·  depression

·  smoking cessation

·  Contraindications

·  seizure disorders

·  prior or current diagnosis of bulimia or anorexia

·  concomitant MAO inhibitor

·  hypersensitivity to bupropion products

·  concomitant use of other bupropion products

·  Adverse Effects

·  N/V

·  seizures/tremors

·  agitation

·  insomnia

·  hypersensitivity reaction (arthralgia, myalgia, fever, rash)

·  hypertension

·  Drug Interactions

·  clorgyline

·  desipramine

·  flecainide

·  fluoxetine

·  guanfacine

·  haloperidol

·  imipramine

·  iproniazid

·  isocarboxazid

·  metoprolol

·  moclobemide

·  nialamide

·  nortriptyline

·  pargyline

·  paroxetine

·  phenelzine

·  procarbazine

·  propafenone

·  risperidone

·  selegiline

·  sertraline

·  thioridazine

·  toloxatone

·  tranylcypromine

·  zolpidem

·  Pregnancy Category

·  B

·  Breast Feeding

controversial

DRUGDEX DRUG EVALUATIONS

BUPROPION

·  0.0 OVERVIEW

·  A. Bupropion is an antidepressant agent which is structurally different from tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), and monoamine oxidase inhibitors (MAOI).

·  B. DOSING INFORMATION: Dosing should begin at 200 mg/day, (100 mg BID) or 150 mg of the sustained-release (SR) and may be increased to 300 mg/day (100 mg TID or 150 mg BID of the SR), based on clinical response. Doses should not exceed 450 mg/day.

·  C. PHARMACOKINETICS: Rapidly absorbed from the gastrointestinal tract with peak plasma concentrations in approximately 2 hours. The volume of distribution is 19 to 21 L/kg with 80% plasma protein binding. The drug is extensively metabolized in the liver to at least 4 metabolites. Elimination half-life is 14 hours.

·  D. CAUTIONS: Adverse effects of bupropion include nausea, vomiting, constipation, dry mouth, agitation, insomnia, headache/migraine and tremor. Seizures have been reported with bupropion; when taken in recommended doses, the incidence is similar to that with imipramine.

·  E. CLINICAL APPLICATIONS: Bupropion is useful as an alternative to tricyclic, SSRI, and MAO inhibitor antidepressants for the treatment of depression. It also may be helpful as an augmentation agent to existing monotherapy for depression. It is indicated as an aid to smoking cessation treatment.

·  1.0 DOSING INFORMATION

·  1.1 DOSAGE FORMS

·  A. Information on specific products and dosage forms can be obtained by referring to the Product Index.

·  1.2 STORAGE AND STABILITY

·  A. ORAL

·  1. Protect from light and moisture and store at room temperature 15 to 25 degrees Centigrade (59 to 77 degrees Fahrenheit) (Prod Info Wellbutrin(R), 1999). Store bupropion sustained release at room temperature, 20 to 25 degrees Celsius (68 to 77 degrees Fahrenheit), in a tight, light-resistant container (USP) (Prod Info Wellbutrin(R) SR, 1999).

·  1.3 ADULT DOSAGE

·  1.3.1 NORMAL DOSE

·  A. ORAL

·  1. The recommended initial dose is 200 milligrams/day, administered as 100 milligram doses once in the morning and once in the evening (Prod Info Wellbutrin(R), 1999). Based on clinical response, this dose may be increased to 300 milligrams/day, administered as three 100-milligram doses. This increase should not occur sooner than 3 days after beginning therapy.

·  2. The recommended initial dose of bupropion sustained release is 150 milligrams (mg) given as a single daily dose in the morning. If the initial dose is tolerated, an increase to 150 mg twice daily is recommended as early as day 4. There should be an interval of at least 8 hours between doses. An increase in dosage to the maximum of 400 mg/day given as 200 mg twice daily may be considered for patients in whom no clinical improvement is noted after several weeks of treatment at 300 mg/day (Prod Info Wellbutrin(R) SR, 1999).

·  3. A maximum bupropion dose of 450 milligrams/day may be considered for patients who are unresponsive to several weeks of 300 milligrams/day (Prod Info Wellbutrin(R), 1999). Single doses of bupropion should not exceed 150 milligrams. The 100-milligram tablets must be administered 4 times daily with at least 4 hours between successive doses, in order not to exceed the limit of 150 milligrams in a single dose.

·  4. Bupropion should be discontinued in patients who have failed to demonstrate an adequate therapeutic response after an appropriate period of therapy of 450 milligrams/day. Escalating the dose higher than 450 milligrams/day is not recommended by the manufacturer due to the increased risk of seizures (Prod Info Wellbutrin(R), 1999).

·  5. In clinical trials, doses of bupropion have ranged from 300 to 750 milligrams/day in divided doses (Fann et al, 1981; Stern & Harto-Truax, 1980; Zung, 1983; Stern et al, 1983). These dosages were more effective than placebo in treating depression as measured by the Hamilton Scale for Depression and Clinical Global Impression Scores.

·  6. For smoking cessation, the recommended dose is 150 milligrams (mg) twice daily; an initial dose of 150 mg/day for the first 3 days is recommended. Dosing intervals should be at least 8 hours apart. Approximately 1 week is needed to achieve steady-state blood levels, therefore, treatment should be initiated while the patient is still smoking and a quit date should be set for the second week. Treatment may be continued for 7 to 12 weeks. If by the seventh week no progress has been made towards quitting, then it is unlikely that the patient will quit (Prod Info Zyban(R), 1999).

·  7. No clinical data is available regarding maintenance therapy with bupropion for smoking cessation. However, the manufacturer states that since the drug has been used for longer periods of time in the treatment of depression, continuing treatment for greater than 12 weeks is feasible and should be determined on an individual basis (Prod Info Zyban(R), 1999).

·  B. ADMINISTRATION TECHNIQUE

·  1. Splitting bupropion extended-release tablets may be a useful option for some patients (Chochren, 1999). A higher rate of release than that observed with whole tablets occurs during the first 15 minutes; thereafter the release characteristics in divided and whole tablets are similar. Tablets should be used soon after splitting due to their hygroscopic properties with degradation occurring rapidly if exposed to moisture. Crushing or chewing will nullify the extended release formulation.

·  1.3.2 DOSAGE IN RENAL FAILURE

·  A. The manufacturer indicates that bupropion HCl and its metabolites are almost completely excreted through the kidney, and patients with renal failure should receive a reduced frequency and/or dose initially and be closely monitored for toxic effects (Prod Info Wellbutrin(R) SR, 2000; Prod Info Wellbutrin(R), 2000; Prod Info Zyban(R), 2000).

·  1.3.3 DOSAGE IN HEPATIC INSUFFICIENCY

·  A. Bupropion is extensively metabolized and its metabolites are conjugated in the liver, therefore, patients with hepatic insufficiency should receive a reduced frequency and/or dose and be closely monitored for toxic effect (Prod Info Wellbutrin(R) SR, 2000; Prod Info Wellbutrin(R), 2000; Prod Info Zyban(R), 2000).

·  B. Preliminary results of a comparative pharmacokinetic study in normal versus cirrhotic patients indicated that the half-lives of the metabolites were prolonged in cirrhotic patients (Prod Info Wellbutrin(R), 1999).

·  C. Bupropion's disposition was monitored following a single oral 200 milligrams dose in 8 healthy volunteers and 8 age-matched and weight-matched volunteers with alcoholic liver disease. The mean elimination half-life of the morpholinol metabolite was significantly prolonged in subjects with liver disease while half-lives for bupropion, erythroamino alcohol and threoamino alcohol were minimally changed. Although these results were encouraging, alcoholic liver disease-patients should be initially dosed cautiously with bupropion (DeVane et al, 1990).

·  1.3.4 DOSAGE IN GERIATRIC PATIENTS

·  A. SUMMARY: No overall difference in safety or effectiveness has been seen in older patients versus younger patients, and disposition of bupropion and its metabolites appears to be similar (Prod Info Wellbutrin (R), 1999). One study, however, did demonstrate that the elderly are at increased risk for accumulation of bupropion and its metabolites.

·  B. Bupropion was effective in the treatment of depression in geriatric outpatients (55 years or older) at daily doses of up to 450 milligrams/day (Kirksey & Stern, 1984; Kane et al, 1983).

·  C. The clinical safety and efficacy of bupropion 150 milligrams/day and 300 milligrams/day was studied in depressed patients 55 years of age or older. Both doses of bupropion were equal to imipramine in antidepressant activity. Patients on imipramine experienced more anticholinergic side effects while patients on bupropion experienced more insomnia and headaches (Branconnier et al, 1983).

·  1.3.5 DOSAGE ADJUSTMENT DURING DIALYSIS

·  A. It is anticipated that dialysis clearance would be highly inefficient due to bupropion's large assumed Vd beta of 1.4 to 3.2 L/kg and slow diffusion from tissue binding sites and plasma. In a single patient on hemodialysis, bupropion AUC's did not significantly differ on days when the patient was dialyzed. AUCs for 3 of the active metabolites were 10 to 20% lower on dialysis days. These data indicate that dosage adjustment during hemodialysis is not necessary (Pers Comm, 1985).

·  1.3.6 DOSAGE IN OTHER DISEASE STATES

·  A. DIABETES

·  1. Studies in mice have shown that bupropion stimulates insulin secretion in the presence of low, threshold, and high glucose concentration levels and therefore should be administered with caution to type II diabetic patients treated with hypoglycemic medications (El-Dakhakhny et al, 1996).

·  B. DOSING TO REDUCE SEIZURE RISK

·  1. Retrospective analysis of clinical experiences suggests that the risk of seizure with bupropion may be minimized by not exceeding 450 milligrams (mg) daily of bupropion immediate-release and 400 mg of the sustained-release. Administration should be 3 times daily with the immediate release and twice daily with the sustained-release. No single dose of the sustained-release should exceed 200 mg. All doses should be increased gradually (Prod Info Wellbutrin(R) SR, 1999; Prod Info Wellbutrin(R), 1999).

·  C. SMOKERS

·  1. Dosage adjustments are not necessary in cigarette smokers, no significant pharmacokinetic differences (Hsyu et al, 1997).

·  1.4 PEDIATRIC DOSAGE

·  1.4.1 NORMAL DOSE

·  A. ORAL:

·  1. Safety and effectiveness in pediatric patients has not been established (Prod Info Wellbutrin (R), 1999).

·  2.0 PHARMACOKINETICS

·  2.1 ONSET AND DURATION

·  2.1.1 ONSET

·  A. INITIAL RESPONSE:

·  1. Depression: 4 weeks (Prod Info Wellbutrin (R), 1999; Stern & Harto-Truax, 1980).

·  a. With high doses (above 300 mg): 8 days (Stern & Harto-Truax, 1980).

·  2.1.2 DURATION

·  A. MULTIPLE DOSE:

·  1. Depression: Improvement continued after 52 weeks (Gardner, 1983).

·  2.2 DRUG CONCENTRATION LEVELS

·  2.2.1 THERAPEUTIC

·  A. THERAPEUTIC DRUG CONCENTRATION:

·  1. Depression, 10 to 20 ng/mL (not well-established) (Goodnick, 1992).

·  B. TIME TO PEAK CONCENTRATION:

·  1. Oral, regular release: 2 hours (Prod Info Wellbutrin, 1999; Findlay et al, 1981).

·  2. Oral, sustained release: 3 hours (Prod Info Wellbutrin(R) SR, 1999).

·  C. AREA UNDER THE CURVE: 1161/ng x hr/mL (Hsyu et al, 1997).

·  1. Area under the curve values were equivalent for the immediate release and sustained release formulations (Davidson & Connor, 1998).

·  2. No significant difference between smokers and nonsmokers (Hsyu et al, 1997).

·  2.3 ADME

·  2.3.1 ABSORPTION

·  A. BIOAVAILABILITY (F):

·  1. Route, dosage form: rapidly absorbed (Lai & Schroeder, 1983).

·  a. Absolute bioavailability has not been determined (Prod Info Wellbutrin(R), 1999). However, it appears that only a small proportion of the oral drug reaches the systemic circulation intact.

·  b. Bupropion immediate-release and sustained-release products are bioequivalent (Prod Info Wellbutrin(R) SR, 1999).

·  B. EFFECTS OF FOOD: None (Prod Info Wellbutrin(R) SR, 1999).

·  2.3.2 DISTRIBUTION

·  2.3.2.1 DISTRIBUTION SITES

·  A. TOTAL PROTEIN BINDING: 80% (Prod Info Wellbutrin(R), 1999; Findlay et al, 1981).

·  B. CEREBROSPINAL FLUID:

·  1. Concentrations of the parent drug in the brain are 10- to 25-fold higher than in plasma (Preskorn & Othmer, 1984; Ferris et al, 1983).

·  2.3.2.2 DISTRIBUTION KINETICS

·  A. DISTRIBUTION HALF LIFE: 1.2 to 1.4 hours (Findlay et al, 1981).

·  B. VOLUME OF DISTRIBUTION (Vd): 19 to 21 L/kg (Findlay et al, 1981).

·  2.3.3 METABOLISM

·  2.3.3.1 METABOLISM SITES AND KINETICS

·  A. Liver, major site (Schroeder, 1983).

·  1. Primarily by the CYP2B6 isoenzyme (Prod Info Wellbutrin(R) SR, 1999; Prod Info Zyban (R), 1999).

·  2. Considerable first pass metabolism occurs (Schroeder, 1983).

·  2.3.3.2 METABOLITES

·  A. Morpholinol, active (Prod Info Wellbutrin(R), 1999).

·  1. The morpholinol appears in the systemic curculation almost as rapidly as the parent drug. The morpholinol and the threo-amino have been found to be half as potent as bupropion in animal screening tests for antidepressant drugs (Smith et al, 1981; Prod Info Wellbutrin(R), 1999). The metabolites are 10 to 25 times less potent as inhibitors of dopamine uptake (Butz et al, 1982).

·  B. Erythro- and threo-amino alcohols, active (Prod Info Wellbutrin(R), 1999).

·  C. Erythro-amino diol bupropion, active (Prod Info Wellbutrin(R), 1999).

·  2.3.4 EXCRETION

·  2.3.4.1 BREAST MILK

·  A. BREASTFEEDING: Controversial

·  1. Bupropion accumulates in human breast milk in concentrations much higher than in maternal plasma. Two metabolites were also found. Neither bupropion nor its metabolites were detected in the infants' plasma, indicating that accumulation did not occur in the infants (Briggs et al, 1993).

·  2.3.4.2 KIDNEY

·  A. RENAL EXCRETION: 87% (Prod Info Wellbutrin(R), 1999).

·  2.3.4.3 OTHER

·  A. Feces, 10% (Prod Info Wellbutrin(R), 1999; Preskorn & Othmer, 1984).

·  2.3.5 HALF-LIFE