Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1464
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WELLBUTRIN (Tablet)
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General Dosing Considerations: It is particularly important to administer WELLBUTRIN
in a manner most likely to minimize the risk of seizure (see WARNINGS).
Increases in dose should not exceed 100 mg/day in a 3-day period.
Gradual escalation in dosage is also important if agitation, motor
restlessness, and insomnia, often seen during the initial days of
treatment, are to be minimized. If necessary, these effects may be
managed by temporary reduction of dose or the short-term administration
of an intermediate to long-acting sedative hypnotic. A sedative hypnotic
usually is not required beyond the first week of treatment. Insomnia
may also be minimized by avoiding bedtime doses. If distressing, untoward
effects supervene, dose escalation should be stopped. No single dose of WELLBUTRIN should exceed 150 mg. WELLBUTRIN
should be administered 3 times daily, preferably with at least 6 hours
between successive doses.<br/>Usual Dosage for Adults: The usual adult dose is 300 mg/day, given 3
times daily. Dosing should begin at 200 mg/day, given as 100 mg
twice daily. Based on clinical response, this dose may be increased
to 300 mg/day, given as 100 mg 3 times daily, no sooner
than 3 days after beginning therapy (see Table 3).<br/>Increasing the Dosage Above
300 mg/Day: As with other antidepressants, the full antidepressant
effect of WELLBUTRIN may not be evident until 4 weeks of treatment
or longer. An increase in dosage, up to a maximum of 450 mg/day,
given in divided doses of not more than 150 mg each, may be considered
for patients in whom no clinical improvement is noted after several
weeks of treatment at 300 mg/day. Dosing above 300 mg/day
may be accomplished using the 75- or 100-mg tablets. The 100-mg tablet
must be administered 4 times daily with at least 4 hours between
successive doses, in order not to exceed the limit of 150 mg
in a single dose. WELLBUTRIN should be discontinued in patients who
do not demonstrate an adequate response after an appropriate period
of treatment at 450 mg/day.<br/>Maintenance Treatment: The lowest dose that maintains remission is recommended.
Although it is not known how long the patient should remain on WELLBUTRIN,
it is generally recognized that acute episodes of depression require
several months or longer of antidepressant drug treatment.<br/>Dosage Adjustment for Patients
with Impaired Hepatic Function: WELLBUTRIN should be used with extreme caution in
patients with severe hepatic cirrhosis. The dose should not exceed
75 mg once a day in these patients. WELLBUTRIN should be used
with caution in patients with hepatic impairment (including mild to
moderate hepatic cirrhosis) and a reduced frequency and/or dose should
be considered in patients with mild to moderate hepatic cirrhosis
(see CLINICAL PHARMACOLOGY, WARNINGS, and PRECAUTIONS).<br/>Dosage Adjustment for Patients
with Impaired Renal Function: WELLBUTRIN should
be used with caution in patients with renal impairment and a reduced
frequency and/or dose should be considered (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
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| dailymed-instance:descripti... |
WELLBUTRIN (bupropion hydrochloride), an antidepressant
of the aminoketone class, is chemically unrelated to tricyclic, tetracyclic,
selective serotonin re-uptake inhibitor, or other known antidepressant
agents. Its structure closely resembles that of diethylpropion; it
is related to phenylethylamines. It is designated as (��)-1-(3-chlorophenyl)-2-[(1,1-dimethylethyl)amino]-1-propanone
hydrochloride. The molecular weight is 276.2. The empirical formula
is CHClNO���HCl. Bupropion hydrochloride
powder is white, crystalline, and highly soluble in water. It has
a bitter taste and produces the sensation of local anesthesia on the
oral mucosa. The structural formula is: WELLBUTRIN is supplied for oral administration as 75-mg (yellow-gold)
and 100-mg (red) film-coated tablets. Each tablet contains the labeled
amount of bupropion hydrochloride and the inactive ingredients: 75-mg
tablet���D&C Yellow No. 10 Lake, FD&C Yellow No. 6
Lake, hydroxypropyl cellulose, hypromellose, microcrystalline cellulose,
polyethylene glycol, talc, and titanium dioxide; 100-mg tablet���FD&C Red No. 40 Lake, FD&C Yellow No. 6 Lake, hydroxypropyl
cellulose, hypromellose, microcrystalline cellulose, polyethylene
glycol, talc, and titanium dioxide.
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Pharmacodynamics: The neurochemical mechanism of the antidepressant
effect of bupropion is not known. Bupropion is a relatively weak inhibitor
of the neuronal uptake of norepinephrine and dopamine, and does not
inhibit monoamine oxidase or the re-uptake of serotonin. Bupropion produces dose-related central nervous system
(CNS) stimulant effects in animals, as evidenced by increased locomotor
activity, increased rates of responding in various schedule-controlled
operant behavior tasks, and, at high doses, induction of mild stereotyped
behavior. Bupropion causes convulsions in rodents
and dogs at doses approximately tenfold the dose recommended as the
human antidepressant dose.<br/>Pharmacokinetics: Bupropion is a racemic mixture. The pharmacological
activity and pharmacokinetics of the individual enantiomers have not
been studied. In humans, following oral administration of WELLBUTRIN,
peak plasma bupropion concentrations are usually achieved within 2 hours,
followed by a biphasic decline. The terminal phase has a mean half-life
of 14 hours, with a range of 8 to 24 hours. The distribution
phase has a mean half-life of 3 to 4 hours. The mean elimination
half-life (��SD) of bupropion after chronic dosing is 21 (��9)
hours, and steady-state plasma concentrations of bupropion are reached
within 8 days. Plasma bupropion concentrations are dose-proportional
following single doses of 100 to 250 mg; however, it is not known
if the proportionality between dose and plasma level is maintained
in chronic use.<br/>Absorption: The absolute
bioavailability of WELLBUTRIN Tablets in humans has not been determined
because an intravenous formulation for human use is not available.
However, it appears likely that only a small proportion of any orally
administered dose reaches the systemic circulation intact.<br/>Distribution: In vitro tests show that bupropion is 84% bound
to human plasma protein at concentrations up to 200 mcg/mL. The
extent of protein binding of the hydroxybupropion metabolite is similar
to that for bupropion, whereas the extent of protein binding of the
threohydrobupropion metabolite is about half that seen with bupropion.<br/>Metabolism: Bupropion
is extensively metabolized in humans. Three metabolites have been
shown to be active: hydroxybupropion, which is formed via hydroxylation
of the tert-butyl group of
bupropion, and the amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
which are formed via reduction of the carbonyl group. In vitro findings
suggest that cytochrome P450IIB6 (CYP2B6) is the principal isoenzyme
involved in the formation of hydroxybupropion, while cytochrome P450
isoenzymes are not involved in the formation of threohydrobupropion.
Oxidation of the bupropion side chain results in the formation of
a glycine conjugate of meta-chlorobenzoic acid, which is then excreted
as the major urinary metabolite. The potency and toxicity of the metabolites
relative to bupropion have not been fully characterized. However,
it has been demonstrated in an antidepressant screening test in mice
that hydroxybupropion is one half as potent as bupropion, while threohydrobupropion
and erythrohydrobupropion are 5-fold less potent than bupropion. This
may be of clinical importance because their plasma concentrations
are as high or higher than those of bupropion. Because bupropion is extensively metabolized, there is the potential
for drug-drug interactions, particularly with those agents that are
metabolized by the cytochrome P450IIB6 (CYP2B6) isoenzyme. Although
bupropion is not metabolized by cytochrome P450IID6 (CYP2D6), there
is the potential for drug-drug interactions when bupropion is coadministered
with drugs metabolized by this isoenzyme (see PRECAUTIONS: Drug Interactions). Following a single dose in humans, peak plasma concentrations
of hydroxybupropion occur approximately 3 hours after administration
of WELLBUTRIN Tablets. Peak plasma concentrations of hydroxybupropion
are approximately 10 times the peak level of the parent drug
at steady state. The elimination half-life of hydroxybupropion is
approximately 20 (��5) hours, and its AUC at steady state
is about 17 times that of bupropion. The times to peak concentrations
for the erythrohydrobupropion and threohydrobupropion metabolites
are similar to that of the hydroxybupropion metabolite. However, their
elimination half-lives are longer, 33 (��10) and 37 (��13)
hours, respectively, and steady-state AUCs are 1.5 and 7 times
that of bupropion, respectively. Bupropion and
its metabolites exhibit linear kinetics following chronic administration
of 300 to 450 mg/day.<br/>Elimination: Following
oral administration of 200 mg ofC-bupropion in
humans, 87% and 10% of the radioactive dose were recovered in the
urine and feces, respectively. However, the fraction of the oral dose
of WELLBUTRIN excreted unchanged was only 0.5%, a finding consistent
with the extensive metabolism of bupropion.<br/>Populations Subgroups: Factors or conditions altering metabolic capacity
(e.g., liver disease, congestive heart failure [CHF], age, concomitant
medications, etc.) or elimination may be expected to influence the
degree and extent of accumulation of the active metabolites of bupropion.
The elimination of the major metabolites of bupropion may be affected
by reduced renal or hepatic function because they are moderately polar
compounds and are likely to undergo further metabolism or conjugation
in the liver prior tourinary excretion.<br/>Hepatic: The effect of hepatic impairment on the pharmacokinetics
of bupropion was characterized in 2 single-dose studies, one in patients
with alcoholic liver disease and one in patients with mild to severe
cirrhosis. The first study showed that the half-life of hydroxybupropion
was significantly longer in 8 patients with alcoholic liver disease
than in 8 healthy volunteers (32��14 hours versus 21��5 hours,
respectively). Although not statistically significant, the AUCs for
bupropion and hydroxybupropion were more variable and tended to be
greater (by 53% to 57%) in volunteers with alcoholic liver disease.
The differences in half-life for bupropion and the other metabolites
in the 2 patient groups were minimal. The second
study showed that there were no statistically significant differences
in the pharmacokinetics of bupropion and its active metabolites in
9 patients with mild to moderate hepatic cirrhosis compared to
8 healthy volunteers. However, more variability was observed in some
of the pharmacokinetic parameters for bupropion (AUC, C, and T) and its active metabolites (t) in patients with mild to moderate hepatic cirrhosis. In addition,
in patients with severe hepatic cirrhosis, the bupropion Cand AUC were substantially increased (mean difference: by approximately
70% and 3-fold, respectively) and more variable when compared to values
in healthy volunteers; the mean bupropion half-life was also longer
(29 hours in patients with severe hepatic cirrhosis vs. 19 hours in
healthy subjects). For the metabolite hydroxybupropion, the mean Cwas approximately 69% lower. For the combined amino-alcohol
isomers threohydrobupropion and erythrohydrobupropion, the mean Cwas approximately 31% lower. The mean AUC increased by
about 1��-fold for hydroxybupropion and about 2��-fold for
threo/erythrohydrobupropion. The median Twas observed
19 hours later for hydroxybupropion and 31 hours later for threo/erythrohydrobupropion.
The mean half-lives for hydroxybupropion and threo/erythrohydrobupropion
were increased 5- and 2-fold, respectively, in patients with severe
hepatic cirrhosis compared to healthy volunteers (see WARNINGS, PRECAUTIONS,
and DOSAGE AND ADMINISTRATION).<br/>Renal: There is limited information on the pharmacokinetics
of bupropion in patients with renal impairment. An inter-study comparison
between normal subjects and patients with end-stage renal failure
demonstrated that the parent drug Cand AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
metabolites had a 2.3���and 2.8���fold increase, respectively,
in AUC for patients with end-stage renal failure. The elimination
of the major metabolites of bupropion may be reduced by impaired renal
function (see PRECAUTIONS: Renal Impairment).<br/>Left Ventricular Dysfunction: During a chronic dosing study in 14 depressed patients
with left ventricular dysfunction (history of CHF or an enlarged heart
on x-ray), no apparent effect on the pharmacokinetics of bupropion
or its metabolites was revealed, compared to healthy volunteers.<br/>Age: The effects of age on the pharmacokinetics of bupropion
and its metabolites have not been fully characterized, but an exploration
of steady-state bupropion concentrations from several depression efficacy
studies involving patients dosed in a range of 300 to 750 mg/day,
on a 3 times daily schedule, revealed no relationship between age
(18 to 83 years) and plasma concentration of bupropion. A single-dose
pharmacokinetic study demonstrated that the disposition of bupropion
and its metabolites in elderly subjects was similar to that of younger
subjects. These data suggest there is no prominent effect of age on
bupropion concentration; however, another pharmacokinetic study, single
and multiple dose, has suggested that the elderly are at increased
risk for accumulation of bupropion and its metabolites (see PRECAUTIONS:
Geriatric Use).<br/>Gender: A single-dose
study involving 12 healthy male and 12 healthy female volunteers
revealed no sex-related differences in the pharmacokinetic parameters
of bupropion.<br/>Smokers: The effects of cigarette smoking on the pharmacokinetics
of bupropion were studied in 34 healthy male and female volunteers;
17 were chronic cigarette smokers and 17 were nonsmokers. Following
oral administration of a single 150-mg dose of bupropion, there were
no statistically significant differences in C, half-life,
T, AUC or clearance of bupropion or its active metabolites
between smokers and nonsmokers.
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WELLBUTRIN is contraindicated in patients with a
seizure disorder. WELLBUTRIN is contraindicated
in patients treated with ZYBAN (bupropion hydrochloride)
Sustained-Release Tablets; WELLBUTRIN SR (bupropion
hydrochloride), the sustained-release formulation; WELLBUTRIN XL (bupropion hydrochloride), the extended-release formulation;
or any other medications that contain bupropion because the incidence
of seizure is dose dependent. WELLBUTRIN is
contraindicated in patients with a current or prior diagnosis of bulimia
or anorexia nervosa because of a higher incidence of seizures noted
in such patients treated with WELLBUTRIN. WELLBUTRIN
is contraindicated in patients undergoing abrupt discontinuation of
alcohol or sedatives (including benzodiazepines). The concurrent administration of WELLBUTRIN and a monoamine oxidase
(MAO) inhibitor is contraindicated. At least 14 days should elapse
between discontinuation of an MAO inhibitor and initiation of treatment
with WELLBUTRIN. WELLBUTRIN is contraindicated
in patients who have shown an allergic response to bupropion or the
other ingredients that make up WELLBUTRIN Tablets.
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WELLBUTRIN Tablets, 75 mg of bupropion hydrochloride,
are yellow-gold, round, biconvex tablets printed with���WELLBUTRIN 75���in bottles of 100 (NDC 0173-0177-55). WELLBUTRIN
Tablets, 100 mg of bupropion hydrochloride, are red, round, biconvex
tablets printed with���WELLBUTRIN 100���in bottles of
100 (NDC 0173-0178-55). Store at 15��to 25��C (59��to 77��F). Protect from
light and moisture.
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Suicidality and Antidepressant
Drugs: Antidepressants increased the risk compared
to placebo of suicidal thinking and behavior (suicidality) in children,
adolescents, and young adults in short-term studies of major depressive
disorder (MDD) and other psychiatric disorders. Anyone considering
the use of WELLBUTRIN or any other antidepressant in a child, adolescent,
or young adult must balance this risk with the clinical need. Short-term
studies did not show an increase inthe risk of suicidality with antidepressants
compared to placebo in adults beyond age 24; there was a reduction
in risk with antidepressants compared to placebo in adults aged 65
and older. Depression and certain other psychiatric disorders are
themselves associated with increases in the risk of suicide. Patients
of all ages who are started on antidepressant therapy should be monitored
appropriately and observed closely for clinical worsening, suicidality,
or unusual changes in behavior. Families and caregivers should be
advised of the need for close observation and communication with the
prescriber. WELLBUTRIN is not approved for use in pediatric patients.
(See WARNINGS: Clinical Worsening and Suicide Risk, PRECAUTIONS: Information
for Patients, and PRECAUTIONS: Pediatric Use.)
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dailymed-ingredient:D&C_Yellow_No._10_Lake,
dailymed-ingredient:FD&C_Yellow_No._6_lake,
dailymed-ingredient:hydroxypropyl_cellulose,
dailymed-ingredient:hypromellose,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:talc,
dailymed-ingredient:titanium_dioxide
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| dailymed-instance:precautio... |
General:<br/>Agitation and Insomnia: A substantial
proportion of patients treated with WELLBUTRIN experience some degree
of increased restlessness, agitation, anxiety, and insomnia, especially
shortly after initiation of treatment. In clinical studies, these
symptoms were sometimes of sufficient magnitude to require treatment
with sedative/hypnotic drugs. In approximately 2% of patients, symptoms
were sufficiently severe to require discontinuation of treatment with
WELLBUTRIN.<br/>Psychosis, Confusion, and
Other Neuropsychiatric Phenomena: Depressed patients treated with WELLBUTRIN have
been reported to show a variety of neuropsychiatric signs and symptoms
including delusions, hallucinations, psychosis, concentration disturbance,
paranoia, and confusion. Because of the uncontrolled nature of many
studies, it is impossible to provide a precise estimate of the extent
of risk imposed by treatment with WELLBUTRIN. In several cases, neuropsychiatric
phenomena abated upon dose reduction and/or withdrawal of treatment.<br/>Activation of Psychosis and/or
Mania: Antidepressants
can precipitate manic episodes in bipolar disorder patients during
the depressed phase of their illness and may activate latent psychosis
in other susceptible patients. WELLBUTRIN is expected to pose similar
risks.<br/>Altered Appetite and Weight: A weight loss
of greater than 5 lbs occurred in 28% of patients receiving WELLBUTRIN.
This incidence is approximately double that seen in comparable patients
treated with tricyclics or placebo. Furthermore, while 35% of patients
receiving tricyclic antidepressants gained weight, only 9.4% of patients
treated with WELLBUTRIN did. Consequently, if weight loss is a major
presenting sign of a patient's depressive illness, the anorectic
and/or weight reducing potential of WELLBUTRIN should be considered.<br/>Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized
by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring
medical treatment have been reported in clinical trials with bupropion.
In addition, there have been rare spontaneous postmarketing reports
of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic
shock associated with bupropion. A patient should stop taking WELLBUTRIN
and consult a doctor if experiencing allergic or anaphylactoid/anaphylactic
reactions (e.g., skin rash, pruritus, hives, chest pain, edema, and
shortness of breath) during treatment. Arthralgia,
myalgia, and fever with rash and other symptoms suggestive of delayed
hypersensitivity have been reported in association with bupropion.
These symptoms may resemble serum sickness.<br/>Cardiovascular Effects: In clinical practice, hypertension, in some cases
severe, requiring acute treatment, has been reported in patients receiving
bupropion alone and in combination with nicotine replacement therapy.
These events have been observed in both patients with and without
evidence of preexisting hypertension. Data from
a comparative study of the sustained-release formulation of bupropion
(ZYBAN Sustained-Release Tablets), nicotine transdermal
system (NTS), the combination of sustained-release bupropion plus
NTS, and placebo as an aid to smoking cessation suggest a higher incidence
of treatment-emergent hypertension in patients treated with the combination
ofsustained-release bupropion and NTS. In this study, 6.1% of patients
treated with the combination of sustained-release bupropion and NTS
had treatment-emergent hypertension compared to 2.5%, 1.6%, and 3.1%
of patients treated with sustained-release bupropion, NTS, and placebo,
respectively. The majority of these patients had evidence of preexisting
hypertension.Three patients (1.2%) treated with the combination of
ZYBAN and NTS and 1 patient (0.4%) treated with NTS had study medication
discontinued due tohypertension compared to none of the patients
treated with ZYBAN or placebo. Monitoring of blood pressure is recommended
in patients who receive the combination of bupropion and nicotine
replacement. There is no clinical experience
establishing the safety of WELLBUTRIN in patients with a recent history
of myocardial infarction or unstable heart disease. Therefore, care
should be exercised if it is used in these groups. Bupropion was well
tolerated in depressed patients who had previously developed orthostatic
hypotension while receiving tricyclic antidepressants and was also
generally well tolerated in a group of 36 depressed inpatients with
stable congestive heart failure (CHF). However, bupropion was associated
with a rise in supine blood pressure in the study of patients with
CHF, resulting in discontinuation of treatment in 2 patients for exacerbation
of baseline hypertension.<br/>Hepatic Impairment: WELLBUTRIN should be used with extreme caution in
patients with severe hepatic cirrhosis. In these patients, a reduced
dose and frequency is required. WELLBUTRIN should be used with caution
in patients with hepatic impairment (including mild to moderate hepatic
cirrhosis) and a reduced frequency and/or dose should be considered
in patients with mildto moderate hepatic cirrhosis. All patients with hepatic impairment should be closely monitored
for possible adverse effects that could indicate high drug and metabolite
levels (see CLINICAL PHARMACOLOGY, WARNINGS, and DOSAGE AND ADMINISTRATION).<br/>Renal Impairment: There is limited information on the pharmacokinetics
of bupropion in patients with renal impairment. An inter-study comparison
between normal subjects and patients with end-stage renal failure
demonstrated that the parent drug Cand AUC values were
comparable in the 2 groups, whereas the hydroxybupropion and threohydrobupropion
metabolites had a 2.3���and 2.8���fold increase, respectively,
in AUC for patients with end-stage renal failure. Bupropion is extensively
metabolized in the liver to active metabolites, which are further
metabolized and subsequently excreted by the kidneys. WELLBUTRIN should
be used with caution in patients with renal impairment and a reduced
frequency and/or dose should be considered as bupropion and the metabolites
of bupropion may accumulate in such patients to a greater extent than
usual. The patient should be closely monitored for possible adverse
effects that could indicate high drug or metabolite levels.<br/>Information for Patients: Prescribers or other health professionals should
inform patients, their families, and their caregivers about the benefits
and risks associated with treatment with WELLBUTRIN and should counsel
them in its appropriate use. A patient Medication Guide about���Antidepressant
Medicines, Depression and Other Serious Mental Illnesses, and Suicidal
Thoughts or Actions���and other important information about
using WELLBUTRIN is available for WELLBUTRIN. The prescriber or health
professional should instruct patients, their families, and their caregivers
to read the Medication Guide and should assist them in understanding
its contents. Patients should be given the opportunity to discuss
the contents of the Medication Guide and to obtain answers to any
questions they may have. The complete text of the Medication Guide
is reprinted at the end of this document. Patients
should be advised of the following issues and asked to alert their
prescriber if these occur while taking WELLBUTRIN.<br/>Clinical Worsening and Suicide
Risk: Patients, their families, and their caregivers should
be encouraged to be alert to the emergence of anxiety, agitation,
panic attacks, insomnia, irritability, hostility, aggressiveness,
impulsivity, akathisia (psychomotor restlessness), hypomania, mania,
other unusual changes in behavior, worsening of depression, and suicidal
ideation, especially early during antidepressant treatment and when
the dose is adjusted up or down. Families and caregivers of patients
shouldbe advised to look for the emergence of such symptoms on a
day-to-day basis, since changes may be abrupt. Such symptoms should
be reported to the patient's prescriber or health professional,
especially if they are severe, abrupt in onset, or were not part of
the patient's presenting symptoms. Symptoms such as these may
be associated with an increased risk for suicidal thinking and behavior
and indicate a need for very close monitoring and possibly changes
in the medication. Patients should be made aware
that WELLBUTRIN contains the same active ingredient found in ZYBAN,
used as an aid to smoking cessation, and that WELLBUTRIN should not
be used in combination with ZYBAN or any other medications that contain
bupropion hydrochloride (such as WELLBUTRIN SR, the sustained-release
formulation and WELLBUTRIN XL, the extended-release formulation). Patients should be instructed to take WELLBUTRIN in equally
divided doses 3 or 4 times a day to minimize the risk of seizure. Patients should be told that WELLBUTRIN should be discontinued
and not restarted if they experience a seizure while on treatment. Patients should be told that any CNS-active drug like
WELLBUTRIN may impair their ability to perform tasks requiring judgment
or motor and cognitive skills. Consequently, until they are reasonably
certain that WELLBUTRIN does not adversely affect their performance,
they should refrain from driving an automobile or operating complex,
hazardous machinery. Patients should be told
that the excessive use or abrupt discontinuation of alcohol or sedatives
(including benzodiazepines) may alter the seizure threshold. Some
patients have reported lower alcohol tolerance during treatment with
WELLBUTRIN. Patients should be advised that the consumption of alcohol
should be minimized or avoided. Patients should
be advised to inform their physicians if they are taking or plan to
take any prescription or over-the-counter drugs. Concern is warranted
because WELLBUTRIN and other drugs may affect each other's
metabolism. Patients should be advised to notify
their physicians if they become pregnant or intend to become pregnant
during therapy.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions: Few systemic
data have been collected on the metabolism of bupropion following
concomitant administration with other drugs or, alternatively, the
effect of concomitant administration of bupropion on the metabolism
of other drugs. Because bupropion is extensively
metabolized, the coadministration of other drugs may affect its clinical
activity. In vitro studies indicate that bupropion is primarily
metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore,
the potential exists for a drug interaction between WELLBUTRIN and
drugs that are the substrates or inhibitors of the CYP2B6 isoenzyme
(e.g., orphenadrine, thiotepa, and cyclophosphamide). In addition,
in vitro studies suggest that paroxetine, sertraline, norfluoxetine,
and fluvoxamine as well as nelfinavir, ritonavir, and efavirenz inhibit
the hydroxylation of bupropion. No clinical studies have been performed
to evaluate this finding. The threohydrobupropion metabolite of bupropion
does not appear to be produced by the cytochrome P450 isoenzymes.
The effects of concomitant administration of cimetidine on the pharmacokinetics
of bupropion and its active metabolites were studied in 24 healthy
young male volunteers. Following oral administration of two 150-mg
sustained-release tablets with and without 800 mg of cimetidine,
the pharmacokinetics of bupropion and hydroxybupropion were unaffected.
However, there were 16% and 32% increases in the AUC and C, respectively, of the combined moieties of threohydrobupropion and
erythrohydrobupropion. While not systematically
studied, certain drugs may induce the metabolism of bupropion (e.g.,
carbamazepine, phenobarbital, phenytoin). Multiple
oral doses of bupropion had no statistically significant effects on
the single dose pharmacokinetics of lamotrigine in 12 healthy volunteers. Animal data indicated that bupropion may be an inducer
of drug-metabolizing enzymes in humans. In one study, following chronic
administration of bupropion, 100 mg 3 times daily to 8 healthy
male volunteers for 14 days, there was no evidence of induction
of its own metabolism. Nevertheless, there may be the potential for
clinically important alterations of blood levels of coadministered
drugs.<br/>Drugs Metabolized by Cytochrome
P450IID6 (CYP2D6): Many drugs, including most antidepressants (SSRIs,
many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics
are metabolized by the CYP2D6 isoenzyme. Although bupropion is not
metabolized by this isoenzyme, bupropion and hydroxybupropion are
inhibitors of the CYP2D6 isoenzyme in vitro. In a study of 15 male
subjects (ages 19 to 35 years) who were extensive metabolizers
of the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg
twice daily followed by a single dose of 50 mg desipramine increased
the C, AUC, and tof desipramine by an
average of approximately 2-, 5- and 2-fold, respectively. The effect
was present for at least 7 days after the last dose of bupropion.
Concomitant use of bupropion with other drugs metabolized by CYP2D6
has not been formally studied. Therefore, coadministration
of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including
certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol,
risperidone, thioridazine), beta-blockers (e.g., metoprolol), and
Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be
approached with caution and should be initiated at the lower end of
the dose range of the concomitant medication. If bupropion is added
to the treatment regimen of a patient already receiving a drug metabolized
by CYP2D6, the need to decrease the dose of the original medication
should be considered, particularly for those concomitant medications
with a narrow therapeutic index.<br/>MAO Inhibitors: Studies in animals demonstrate that the acute toxicity
of bupropion is enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).<br/>Levodopa and Amantadine: Limited clinical data suggest a higher incidence
of adverse experiences in patients receiving bupropion concurrently
with either levodopa or amantadine. Administration of WELLBUTRIN Tablets
to patients receiving either levodopa or amantadine concurrently should
be undertaken with caution, using small initial doses and small gradual
dose increases.<br/>Drugs that Lower Seizure Threshold: Concurrent administration of WELLBUTRIN and agents
(e.g., antipsychotics, other antidepressants, theophylline, systemic
steroids, etc.) that lower seizure threshold should be undertaken
only with extreme caution (see WARNINGS). Low initial dosing and small
gradual dose increases should be employed.<br/>Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).<br/>Alcohol: In postmarketing
experience, there have been rare reports of adverse neuropsychiatric
events or reduced alcohol tolerance in patients who were drinking
alcohol during treatment with WELLBUTRIN. The consumption of alcohol
during treatment with WELLBUTRIN should be minimized or avoided (also
see CONTRAINDICATIONS).<br/>Carcinogenesis, Mutagenesis,
Impairment of Fertility: Lifetime carcinogenicity studies were performed
in rats and mice at doses up to 300 and 150 mg/kg/day, respectively.
In the rat study there was an increase in nodular proliferative lesions
of the liver at doses of 100 to 300 mg/kg/day; lower doses were
not tested. The question of whether or not such lesions may be precursors
of neoplasms of the liver is currently unresolved. Similar liver lesions
were not seen in the mouse study, and no increase in malignant tumors
of the liver and other organs was seen in either study. Bupropion produced a borderline positive response (2 to
3 times control mutation rate) in some strains in the Ames bacterial
mutagenicity test, and a high oral dose (300 mg/kg, but not 100
or 200 mg/kg) produced a low incidence of chromosomal aberrations
in rats. The relevance of these results in estimating the risk of
human exposure to therapeutic doses is unknown. A fertility study was performed in rats; no evidence of impairment
of fertility was encountered at oral doses up to 300 mg/kg/day.<br/>Pregnancy:<br/>Teratogenic Effects: Pregnancy Category C. In studies conducted in rats
and rabbits, bupropion was administered orally at doses up to 450
and 150 mg/kg/day, respectively (approximately 11 and 7 times the
maximum recommended human dose [MRHD], respectively, on a mg/mbasis), during the period of organogenesis. No clear evidence
of teratogenic activity was found in either species; however, in rabbits,
slightly increased incidences of fetal malformations and skeletal
variations were observed at the lowest dose tested (25 mg/kg/day,
approximately equal to the MRHD on a mg/mbasis) and greater.
Decreased fetal weights were seen at 50 mg/kg and greater. When rats were administered bupropion at oral doses of
up to 300 mg/kg/day (approximately 7 times the MRHD on a mg/mbasis) prior to mating and throughout pregnancy and lactation,
there were no apparent adverse effects on offspring development. One study has been conducted in pregnant women. This retrospective,
managed-care database study assessed the risk of congenital malformations
overall, and cardiovascular malformations specifically, following
exposure to bupropion in the first trimester compared to the risk
of these malformations following exposure to other antidepressants
in the first trimester and bupropion outside of the first trimester.
This study included 7,005 infants with antidepressant exposure during
pregnancy, 1,213 of whom were exposed to bupropion in the first trimester.
The study showed no greater risk for congenital malformations overall,
or cardiovascular malformations specifically, following first trimester
bupropion exposure compared to exposure to all other antidepressants
in the first trimester, or bupropion outside of the first trimester.
The results of this study have not been corroborated. WELLBUTRIN should
be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus. To monitor fetal
outcomes of pregnant women exposed to WELLBUTRIN, GlaxoSmithKline
maintains a Bupropion Pregnancy Registry. Healthcare providers are
encouraged to register patients by calling (800) 336-2176.<br/>Labor and Delivery: The effect of WELLBUTRIN on labor and delivery in
humans is unknown.<br/>Nursing Mothers: Like many other drugs, bupropion and its metabolites
are secreted in human milk. Because of the potential for serious adverse
reactions in nursing infants from WELLBUTRIN, a decision should be
made whether to discontinue nursing or to discontinue the drug, taking
into account the importance of the drug to the mother.<br/>Pediatric Use: Safety and effectiveness in the pediatric population
have not been established (see BOX WARNING and WARNINGS: Clinical
Worsening and Suicide Risk). Anyone considering the use of WELLBUTRIN
in a child or adolescent must balance the potential risks with the
clinical need.<br/>Geriatric Use: Of the approximately 6,000 patients who participated
in clinical trials with bupropion sustained-release tablets (depression
and smoking cessation studies), 275 were 65 and over and 47 were 75
and over. In addition, several hundred patients 65 and over participated
in clinical trials using the immediate-release formulation of bupropion
(depression studies). Nooverall differences in safety or effectiveness
were observed between these subjects and younger subjects, and other
reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity
of some older individuals cannot be ruled out. A single-dose pharmacokinetic study demonstrated that the disposition
of bupropion and its metabolites in elderly subjects was similar to
that of younger subjects; however, another pharmacokinetic study,
single and multiple dose, has suggested that the elderly are at increased
risk for accumulation of bupropion and its metabolites (see CLINICAL
PHARMACOLOGY). Bupropion is extensively metabolized
in the liver to active metabolites, which are further metabolized
and excreted by the kidneys. The risk of toxic reaction to this drug
may be greater in patients with impaired renal function. Because elderly
patients are more likely to have decreased renal function, care should
be taken in dose selection, and it may be useful to monitor renal
function (see PRECAUTIONS: Renal Impairment and DOSAGE AND ADMINISTRATION).
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| dailymed-instance:overdosag... |
Human Overdose Experience: Overdoses of up to 30 g or more of bupropion
have been reported. Seizure was reported in approximately one third
of all cases. Other serious reactions reported with overdoses of bupropion
alone included hallucinations, loss of consciousness, sinus tachycardia,
and ECG changes such as conduction disturbances or arrhythmias. Fever,
muscle rigidity, rhabdomyolysis, hypotension, stupor, coma, and respiratory
failure have been reported mainly when bupropion was part of multiple
drug overdoses. Although most patients recovered
without sequelae, deaths associated with overdoses of bupropion alone
have been reported in patients ingesting large doses of the drug.
Multiple uncontrolled seizures, bradycardia, cardiac failure, and
cardiac arrest prior to death were reported in these patients.<br/>Overdosage Management: Ensure an adequate
airway, oxygenation, and ventilation. Monitor cardiac rhythm and vital
signs. EEG monitoring is also recommended for the first 48 hours
post-ingestion. General supportive and symptomatic measures are also
recommended. Induction of emesis is not recommended. Gastric lavage
with a large-bore orogastric tube with appropriate airway protection,
if needed, may be indicated if performed soon after ingestion or in
symptomatic patients. Activated charcoal should
be administered. There is no experience with the use of forced diuresis,
dialysis, hemoperfusion, or exchange transfusion in the management
of bupropion overdoses. No specific antidotes for bupropion are known. Due to the dose-related risk of seizures with WELLBUTRIN,
hospitalization following suspected overdose should be considered.
Based on studies in animals, it is recommended that seizures be treated
with intravenous benzodiazepine administration and other supportive
measures, as appropriate. In managing overdosage,
consider the possibility of multiple drug involvement. The physician
should consider contacting a poison control center for additional
information on the treatment of any overdose. Telephone numbers for
certified poison control centers are listed in the Physicians' Desk Reference (PDR).
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| dailymed-instance:genericMe... |
bupropion hydrochloride
|
| dailymed-instance:fullName |
WELLBUTRIN (Tablet)
|
| dailymed-instance:warning |
Clinical Worsening and Suicide
Risk: Patients with major depressive disorder (MDD), both
adult and pediatric, may experience worsening of their depression
and/or the emergence of suicidal ideation and behavior (suicidality)
or unusual changes in behavior, whether or not they are taking antidepressant
medications, and this risk may persist until significant remission
occurs. Suicide is a known risk of depression and certain other psychiatric
disorders, and these disorders themselves are the strongest predictors
of suicide. There has been a long-standing concern, however, that
antidepressants may have a role in inducing worsening of depression
and the emergence of suicidality in certain patients during the early
phases of treatment. Pooled analyses of short-term placebo-controlled
trials of antidepressant drugs (SSRIs and others) showed that these
drugs increase the risk of suicidal thinking and behavior (suicidality)
in children, adolescents, and young adults (ages 18-24) with major
depressive disorder (MDD) and other psychiatric disorders. Short-term
studies did not show an increase in the risk of suicidality with antidepressants
compared to placebo in adults beyond age 24; there was a reduction
with antidepressants compared to placebo in adults aged 65 and older. The pooled analyses of placebo-controlled trials in children
and adolescents with MDD, obsessive compulsive disorder (OCD), or
other psychiatric disorders included a total of 24 short-term trials
of 9 antidepresssant drugs in over 4,400 patients. The pooled analyses
of placebo-controlled trials in adults with MDD or other psychiatric
disorders included a total of 295 short-term trials (median duration
of 2 months) of 11 antidepressant drugs in over 77,000 patients. There
was considerable variation in risk of suicidality among drugs, but
a tendency toward an increase in the younger patients for almost all
drugs studied. There were differences in absolute risk of suicidality
across the different indications, with the highest incidence in MDD.
The risk differences (drug vs placebo), however, were relatively stable
within age strata and across indications. These risk differences (drug-placebo
difference in the number of cases of suicidality per 1,000 patients
treated) are provided in Table 1. No suicides occurred in any of the pediatric trials.
There were suicides in the adult trials, but the number was not sufficient
to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term
use, i.e., beyond several months. However, there is substantial evidence
from placebo-controlled maintenance trials in adults with depression
that the use of antidepressants can delay the recurrence of depression. All patients being treated with
antidepressants for any indication should be monitored appropriately
and observed closely for clinical worsening, 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. The following symptoms,
anxiety, agitation, panic attacks, insomnia, irritability, hostility,
aggressiveness, impulsivity, akathisia (psychomotor restlessness),
hypomania, and mania, have been reported in adult and pediatric patients
being treated with antidepressants for major depressive disorder as
well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and
either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms
may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen,
including possibly discontinuing the medication, in patients whose
depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients
being treated with antidepressants for major depressive disorder or
other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation,
irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report
such symptoms immediately to healthcare providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for WELLBUTRIN should be written for the smallest
quantity of tablets consistent with good patient management, in order
to reduce the risk of overdose.<br/>Screening Patients for Bipolar
Disorder: A major depressive
episode may be the initial presentation of bipolar disorder. It is
generally believed (though not established in controlled trials) that
treating such an episode with an antidepressant alone may increase
the likelihood of precipitation of a mixed/manic episode in patients
at risk for bipolar disorder. Whether any of the symptoms described
above represent such a conversion isunknown. However, prior to initiating
treatment with an antidepressant, patients with depressive symptoms
should be adequately screened to determine if they are at risk for
bipolar disorder; such screening should include a detailed psychiatric
history, including a family history of suicide, bipolar disorder,
and depression. It should be noted that WELLBUTRIN is not approved
for use in treating bipolar depression. Patients should be made aware that WELLBUTRIN contains
the same active ingredient found in ZYBAN, used as an aid to smoking
cessation treatment, and that WELLBUTRIN should not be used in combination
with ZYBAN, or any other medications that contain bupropion, such
as WELLBUTRIN SR (bupropion hydrochloride), the sustained-release
formulation or WELLBUTRIN XL (bupropion hydrochloride), the extended-release
formulation.<br/>Seizures: Bupropion is associated
with seizures in approximately 0.4% (4/1,000) of patients treated
at doses up to 450 mg/day. This incidence of seizures may exceed
that of other marketed antidepressants by as much as 4-fold. This
relative risk is only an approximate estimate because no direct comparative
studies have been conducted. The estimated seizure incidence for WELLBUTRIN
increases almost tenfold between 450 and 600 mg/day, which is
twicethe usually required daily dose (300 mg) and one and one-third
the maximum recommended daily dose (450 mg). Given the wide variability
among individuals and their capacity to metabolize and eliminate drugs
this disproportionate increase in seizure incidence with dose incrementation
calls for caution in dosing. During the initial development, 25 among approximately
2,400 patients treated with WELLBUTRIN experienced seizures. At the
time of seizure, 7 patients were receiving daily doses of 450 mg
or below for an incidence of 0.33% (3/1,000) within the recommended
dose range. Twelve patients experienced seizures at 600 mg/day
(2.3% incidence); 6 additional patients had seizures at daily
doses between 600 and 900 mg (2.8% incidence). A separate, prospective study
was conducted to determine the incidence of seizure during an 8-week
treatment exposure in approximately 3,200 additional patients who
received daily doses of up to 450 mg. Patients were permitted
to continue treatment beyond 8 weeks if clinically indicated.
Eight seizures occurred during the initial 8-week treatment period
and 5 seizures were reported in patients continuing treatment beyond
8 weeks, resulting in a total seizure incidence of 0.4%. The risk of seizure
appears to be strongly associated with dose. Sudden and large increments
in dose may contribute to increased risk. While many seizures occurred
early in the course of treatment, some seizures did occur after several
weeks at fixed dose. WELLBUTRIN should be discontinued and not restarted
in patients who experience a seizure while on treatment. The risk of seizure
is also related to patient factors, clinical situations, and concomitant
medications, which must be considered in selection of patients for
therapy with WELLBUTRIN. Recommendations for Reducing the Risk of
Seizure: Retrospective analysis
of clinical experience gained during the development of WELLBUTRIN
suggests that the risk of seizure may be minimized if WELLBUTRIN should be administered
with extreme caution to patients with a history of seizure, cranial
trauma, or other predisposition(s) toward seizure, or patients treated
with other agents (e.g., antipsychotics, other antidepressants, theophylline,
systemic steroids, etc.) that lower seizure threshold.<br/>Hepatic Impairment: WELLBUTRIN should be used
with extreme caution in patients with severe hepatic cirrhosis. In
these patients a reduced dose and/or frequency is required, as peak
bupropion, as well as AUC, levels are substantially increased and
accumulation is likely to occur in such patients to a greater extent
than usual. The dose should not exceed 75 mg once a day in these
patients (see CLINICAL PHARMACOLOGY, PRECAUTIONS, and DOSAGE AND ADMINISTRATION).<br/>Potential for Hepatotoxicity: In rats receiving large doses of bupropion chronically,
there was an increase in incidence of hepatic hyperplastic nodules
and hepatocellular hypertrophy. In dogs receiving large doses of bupropion
chronically, various histologic changes were seen in the liver, and
laboratory tests suggesting mild hepatocellular injury were noted.
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| dailymed-instance:indicatio... |
WELLBUTRIN is indicated for the treatment of major
depressive disorder. A physician considering WELLBUTRIN for the management
of a patient's first episode of depression should be aware
that the drug may cause generalized seizures in a dose-dependent manner
with an approximate incidence of 0.4% (4/1,000). This incidence of
seizures may exceed that of other marketed antidepressants by as much
as 4-fold. This relative risk is only an approximate estimate because
no direct comparative studies have been conducted (see WARNINGS). The efficacy of WELLBUTRIN has been established in 3 placebo-controlled
trials, including 2 of approximately 3 weeks' duration
in depressed inpatients and one of approximately 6 weeks'
duration in depressed outpatients. The depressive disorder of the
patients studied corresponds most closely to the Major Depression
category of the APA Diagnostic and Statistical Manual III. Major Depression implies a prominent and relatively persistent
depressed or dysphoric mood that usually interferes with daily functioning
(nearly every day for at least 2 weeks); it should include at
least 4 of the following 8 symptoms: change in appetite, change
in sleep, psychomotor agitation or retardation, loss of interest in
usual activities or decrease in sexual drive, increased fatigability,
feelings of guilt or worthlessness, slowed thinking or impaired concentration,
and suicidal ideation or attempts. Effectiveness
of WELLBUTRIN in long-term use, that is, for more than 6 weeks,
has not been systematically evaluated in controlled trials. Therefore,
the physician who elects to use WELLBUTRIN for extended periods should
periodically reevaluate the long-term usefulness of the drug for the
individual patient.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
WELLBUTRIN
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