Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/1874
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WELLBUTRIN XL (Tablet)
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| dailymed-instance:dosage |
General Dosing Considerations: It is particularly important to administer WELLBUTRIN XL
Tablets in a manner most likely to minimize the risk of seizure (see
WARNINGS). 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 temporaryreduction 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. WELLBUTRIN XL
should be swallowed whole and not crushed, divided, or chewed. WELLBUTRIN XL
may be taken without regard to meals.<br/>Major Depressive Disorder:<br/>Initial Treatment: The usual adult target dose for WELLBUTRIN XL
Tablets is 300 mg/day, given once daily in the morning. Dosing
with WELLBUTRIN XL Tablets should begin at 150 mg/day given
as a single daily dose in the morning. If the 150-mg initial dose
is adequately tolerated, an increase to the 300-mg/day target dose,
given as once daily, may be made as early as day 4 of dosing. There
should be an interval of at least 24 hours between successive
doses.<br/>Increasing the Dosage Above
300 mg/day: As with other antidepressants, the full antidepressant
effect of WELLBUTRIN XL Tablets may not be evident until 4 weeks
of treatment or longer. An increase in dosage to the maximum of 450 mg/day,
given as a single dose, may be considered for patients in whom no
clinical improvement is noted after several weeks of treatment at
300 mg/day.<br/>Maintenance Treatment: It is generally agreed that acute episodes of depression
require several months or longer of sustained pharmacological therapy
beyond response to the acute episode. It is unknown whether or not
the dose of WELLBUTRIN XL needed for maintenance treatment is
identical to the dose needed to achieve an initial response. Patients
should be periodically reassessed to determine the need for maintenance
treatment and the appropriate dose for such treatment.<br/>Seasonal Affective Disorder: For the prevention of seasonal major depressive
episodes associated with seasonal affective disorder, WELLBUTRIN XL
should generally be initiated in the autumn prior to the onset of
depressive symptoms. Treatment should continue through the winter
season and should be tapered and discontinued in early spring. The
timing of initiation and duration of treatment should be individualized
based on the patient's historical pattern of seasonal major depressive
episodes. Patients whose seasonal depressive episodes are infrequent
or not associated with significant impairment should not generally
be treated prophylactically. Dosing with
WELLBUTRIN XL Tablets should begin at 150 mg/day given as
a single daily dose in the morning. If the 150-mg initial dose is
adequately tolerated, the dose of WELLBUTRIN XL should be increased
to the 300-mg/day dose after 1 week. If the 300-mg dose is not
adequately tolerated, the dose can be reduced to 150 mg/day.
The usual adult target dose for WELLBUTRIN XL Tablets is 300 mg/day,
given once daily in the morning. For patients
taking 300 mg/day during the autumn-winter season, the dose should
be tapered to 150 mg/day for 2 weeks prior to discontinuation. Doses of WELLBUTRIN XL above 300 mg/day have
not been studied for the prevention of seasonal major depressive episodes.<br/>Switching Patients from WELLBUTRIN
Tablets or from WELLBUTRIN SR Sustained-Release Tablets: When switching patients from WELLBUTRIN Tablets
to WELLBUTRIN XL or from WELLBUTRIN SR Sustained-Release Tablets
to WELLBUTRIN XL, give the same total daily dose when possible.
Patients who are currently being treated with WELLBUTRIN Tablets at
300 mg/day (for example, 100 mg 3 times a day) may be switched
to WELLBUTRIN XL 300 mg once daily. Patients who are currently
being treated with WELLBUTRIN SR Sustained-Release Tablets at 300 mg/day
(for example, 150 mg twice daily) may be switched to WELLBUTRIN
XL 300 mg once daily.<br/>Dosage Adjustment for Patients
With Impaired Hepatic Function: WELLBUTRIN XL should be used with extreme caution
in patients with severe hepatic cirrhosis. The dose should not exceed
150 mg every other day in these patients. WELLBUTRIN XL
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 XL 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 XL (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 molecular 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 XL Tablets are supplied for oral administration as
150-mg and 300-mg, creamy-white to pale yellow extended-release tablets.
Each tablet contains the labeled amount of bupropion hydrochloride
and the inactive ingredients: ethylcellulose aqueous dispersion (NF),
glyceryl behenate, methacrylic acid copolymer dispersion (NF), polyvinyl
alcohol, polyethylene glycol, povidone, silicon dioxide, and triethyl
citrate. The tablets are printed with edible black ink. The insoluble shell of the extended-release tablet
may remain intact during gastrointestinal transit and is eliminated
in the feces.
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Pharmacodynamics: 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. While the mechanism
of action of bupropion, as with other antidepressants, is unknown,
it is presumed that this action is mediated by noradrenergic and/or
dopaminergic mechanisms.<br/>Pharmacokinetics: Bupropion is a racemic mixture. The pharmacologic
activity and pharmacokinetics of the individual enantiomers have not
been studied. 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. In a study comparing 14-day dosing with WELLBUTRIN XL
Tablets 300 mg once daily to the immediate-release formulation
of bupropion at 100 mg 3 times daily, equivalence was demonstrated
for peak plasma concentration and area under the curve for bupropion
and the 3 metabolites (hydroxybupropion, threohydrobupropion,
and erythrohydrobupropion). Additionally, in a study comparing 14-day
dosing with WELLBUTRIN XL Tablets 300 mg once daily to the
sustained-release formulation of bupropion at 150 mg 2 times
daily, equivalence was demonstrated for peak plasma concentration
and area under the curve for bupropion and the 3 metabolites.<br/>Absorption: Following oral administration of WELLBUTRIN XL
Tablets to healthy volunteers, time to peak plasma concentrations
for bupropion was approximately 5 hours and food did not affect
the Cor AUC of bupropion.<br/>Distribution: In vitro tests show that bupropion is 84% bound
to human plasma proteins 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 the plasma concentrations of the metabolites 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). In humans, peak plasma concentrations of hydroxybupropion
occur approximately 7 hours after administration of WELLBUTRIN XL.
Following administration of WELLBUTRIN XL, peak plasma concentrations
of hydroxybupropion are approximately 7 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 13 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, approximately 33 (��10) and
37 (��13) hours, respectively, and steady-state AUCs are
1.4 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 bupropion excreted unchanged was only
0.5%, a finding consistent with the extensive metabolism of bupropion.<br/>Population 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 to urinary 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 patients 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 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 with bupropion 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 was
no statistically significant difference in C, half-life,
T, AUC, or clearance of bupropion or its active metabolites
between smokers and nonsmokers.
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WELLBUTRIN XL is contraindicated in patients
with a seizure disorder. WELLBUTRIN XL
is contraindicated in patients treated with ZYBAN (bupropion hydrochloride) Sustained-Release Tablets; WELLBUTRIN (bupropion hydrochloride), the immediate-release formulation;
WELLBUTRIN SR (bupropion hydrochloride), the sustained-release
formulation; or any other medications that contain bupropion because
the incidence of seizure is dose dependent. WELLBUTRIN XL is contraindicated in patients with a current
or prior diagnosis of bulimia or anorexia nervosa because of a higher
incidence of seizures noted in patients treated for bulimia with the
immediate-release formulation of bupropion. WELLBUTRIN XL is contraindicated in patients undergoing
abrupt discontinuation of alcohol or sedatives (including benzodiazepines). The concurrent administration of WELLBUTRIN XL
Tablets 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 XL
Tablets. WELLBUTRIN XL is contraindicated
in patients who have shown an allergic response to bupropion or the
other ingredients that make up WELLBUTRIN XL Tablets.
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| dailymed-instance:supply |
WELLBUTRIN XL Extended-Release Tablets,
150 mg of bupropion hydrochloride, are creamy-white to pale yellow,
round, tablets printed with���WELLBUTRIN XL 150���in bottles of 30 tablets (NDC 0173-0730-01) and 90 (NDC 0173-0730-02). WELLBUTRIN XL Extended-Release Tablets, 300 mg
of bupropion hydrochloride, are creamy-white to pale yellow, round,
tablets printed with���WELLBUTRIN XL 300���in bottles
of 30 (NDC 0173-0731-01). Store at 25��C (77��F); excursions permitted
to 15-30��C (59-86��F) [see USP Controlled Room Temperature].
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| dailymed-instance:inactiveI... |
dailymed-ingredient:edible_black_ink,
dailymed-ingredient:ethylcellulose_aqueous_dispersion,
dailymed-ingredient:glyceryl_behenate,
dailymed-ingredient:methacrylic_acid_copolymer_dispersion,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:polyvinyl_alcohol,
dailymed-ingredient:povidone,
dailymed-ingredient:silicon_dioxide,
dailymed-ingredient:triethyl_citrate
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General:<br/>Agitation and Insomnia: Increased restlessness, agitation, anxiety, and insomnia,
especially shortly after initiation of treatment, have been associated
with treatment with bupropion. In 3 placebo-controlled clinical
trials of seasonal affective disorder with WELLBUTRIN XL, the
incidence of agitation, anxiety, and insomnia are shown in Table 2. Patients in placebo-controlled trials of major
depressive disorder with WELLBUTRIN SR, the sustained-release
formulation of bupropion, experienced agitation, anxiety, and insomnia
as shown in Table 3. In clinical studies of major depressive disorder,
these symptoms were sometimes of sufficient magnitude to require treatment
with sedative/hypnotic drugs. Symptoms in
these studies were sufficiently severe to require discontinuation
of treatment in 1% and 2.6% of patients treated with 300 and 400 mg/day,
respectively, of bupropion sustained-release tablets and 0.8% of patients
treated with placebo.<br/>Psychosis, Confusion, and
Other Neuropsychiatric Phenomena: Depressed patients treated with bupropion have been
reported to show a variety of neuropsychiatric signs and symptoms,
including delusions, hallucinations, psychosis, concentration disturbance,
paranoia, and confusion. In some cases, these symptoms 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 XL
is expected to pose similar risks.<br/>Altered Appetite and Weight: In 3 placebo-controlled clinical trials of seasonal
affective disorder with WELLBUTRIN XL, the percentage of patients
with weight gain or weight loss are shown in Table 4. In placebo-controlled studies of major depressive
disorder using WELLBUTRIN SR, the sustained-release formulation
of bupropion, patients experienced weight gain or weight loss as shown
in Table 5. In studies conducted with the immediate-release
formulation of bupropion, 35% of patients receiving tricyclic antidepressants
gained weight, compared to 9% of patients treated with the immediate-release
formulation of bupropion. If weight loss is a major presenting sign
of a patient's depressive illness, the anorectic and/or weight-reducing
potential of WELLBUTRIN XL Tablets 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 XL
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
of sustained-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 to hypertension 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 XL Tablets 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 XL should be used with extreme caution
in patients with severe hepatic cirrhosis. In these patients, a reduced
frequency and/or dose is required. WELLBUTRIN XL should be used
with caution in patients with hepatic impairment (including mild to
moderate hepatic cirrhosis) and reduced frequency and/or dose should
be considered in patients with mild to 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 XL
should be used with caution in patients with renal impairment and
a reduced frequency and/or dose shouldbe 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 XL 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 XL is available for WELLBUTRIN
XL. 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
XL.<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
should be 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 XL contains the same active ingredient
found in ZYBAN, used as an aid to smoking cessation treatment, and
that WELLBUTRIN XL 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,
the immediate-release formulation). Patients
should be told that WELLBUTRIN XL 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 XL Tablets may impair their ability to perform tasks
requiring judgment or motor and cognitive skills. Consequently, until
they are reasonably certain that WELLBUTRIN XL Tablets do 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 XL. 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 XL
Tablets 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. Patients should be advised to swallow WELLBUTRIN XL
Tablets whole so that the release rate is not altered. Do not chew,
divide, or crush tablets. Patients should
be advised that they may notice in their stool something that looks
like a tablet. This is normal. The medication in WELLBUTRIN XL
is contained in a non-absorbable shell that has been specially designed
to slowly release drug in the body. When this process is completed,
the empty shell is eliminated from the body.<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 XL and drugs that are 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 tablets of the sustained-release formulation of bupropion
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 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 beapproached 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 XL
Tablets to patients receiving either levodopa or amantadine concurrently
should be undertaken with caution, using small initial doses and gradual
dose increases.<br/>Drugs That Lower Seizure Threshold: Concurrent administration of WELLBUTRIN XL
Tablets 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 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 bupropion.
The consumption of alcohol during treatment with WELLBUTRIN XL
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.
These doses are approximately 7 and 2 times the maximum recommended
human dose (MRHD), respectively, on a mg/mbasis. In the
rat study there was an increase in nodular proliferative lesions of
the liver at doses of 100 to 300 mg/kg/day (approximately 2 to
7 times the MRHD on a mg/mbasis); 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 positive response (2 to 3 times
control mutation rate) in 2 of 5 strains in the Ames bacterial
mutagenicity test and an increase in chromosomal aberrations in 1 of
3 in vivo rat bone marrow cytogenetic studies. A fertility study in rats at doses up to 300 mg/kg/day revealed
no evidence of impaired fertility.<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 congenial 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 XL
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 XL, 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 XL Tablets 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 XL Tablets, 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 XL
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 years old and
47 were���75 years old. In addition, several hundred patients
65 and over participated in clinical trials using the immediate-release
formulation of bupropion (depression studies). No overall differences
in safety or effectiveness were observed between these subjects and
younger subjects. 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 XL,
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 XL (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 andbehavior (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 antidepressant 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 wellas 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 XL 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 is unknown. 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 XL is not
approved for use in treating bipolar depression. Patients should be made aware that
WELLBUTRIN XL contains the same active ingredient found in ZYBAN,
used as an aid to smoking cessation treatment, and that WELLBUTRIN XL
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 (bupropion hydrochloride),
the immediate-release formulation.<br/>Seizures: Bupropion is associated
with a dose-related risk of seizures. The risk of seizures is also
related to patient factors, clinical situations, and concomitant medications,
which must be considered in selection of patients for therapy with
WELLBUTRIN XL. WELLBUTRIN XL should be discontinued and
not restarted in patients who experience a seizure while on treatment. As WELLBUTRIN XL
is bioequivalent to both the immediate-release formulation of bupropion
and to the sustained-release formulation of bupropion, the seizure
incidence with WELLBUTRIN XL, while not formally evaluated in
clinical trials, may be similar to that presented below for the immediate-release
and sustained-release formulations of bupropion. Data for
the immediate-release formulation of bupropion revealed a seizure
incidence of approximately 0.4% (i.e., 13 of 3,200 patients followed
prospectively) in patients treated at doses in a range of 300 to 450 mg/day.
This seizure incidence (0.4%) may exceed that of some other marketed
antidepressants. Additional data accumulated for the
immediate-release formulation of bupropion suggested that the estimated
seizure incidence increases almost tenfold between 450 and 600 mg/day.
The 600 mg dose is twice the usual adult dose and one and one-third
the maximum recommended daily dose (450 mg) of WELLBUTRIN XL
Tablets. This disproportionate increase in seizure incidence with
dose incrementation calls for caution in dosing.<br/>Recommendations for Reducing
the Risk of Seizure: Retrospective analysis
of clinical experience gained during the development of bupropion
suggests that the risk of seizure may be minimized if WELLBUTRIN XL
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 XL should
be used with extreme caution in patients with severe hepatic cirrhosis.
In these patients a reduced frequency and/or dose 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 150 mg every other
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... |
Major Depressive Disorder: WELLBUTRIN XL is indicated for the treatment
of major depressive disorder. The efficacy
of bupropion in the treatment of a major depressive episode was established
in two 4-week controlled trials of inpatients and in one 6-week controlled
trial of outpatients whose diagnoses corresponded most closely to
the Major Depression category of the APA Diagnostic and Statistical
Manual (DSM) (see CLINICAL TRIALS). A major
depressive episode (DSM-IV) implies the presence of 1) depressed mood
or 2) loss of interest or pleasure; in addition, at least 5 of the
following symptoms have been present during the same 2-week period
and represent a change from previous functioning: depressed mood,
markedly diminished interest or pleasure in usual activities, significant
change in weight and/or appetite, insomnia or hypersomnia, psychomotor
agitation or retardation, increased fatigue, feelings of guilt or
worthlessness, slowed thinking or impaired concentration, a suicide
attempt, or suicidal ideation. The efficacy
of bupropion in maintaining an antidepressant response for up to 44 weeks
following 8 weeks of acute treatment was demonstrated in a placebo-controlled
trial with the sustained-release formulation of bupropion (see CLINICAL
TRIALS). Nevertheless, the physician who elects to use WELLBUTRIN XL
for extended periods should periodically reevaluate the long-term
usefulness of the drug for the individual patient.<br/>Seasonal Affective Disorder: WELLBUTRIN XL is indicated for the prevention
of seasonal major depressive episodes in patients with a diagnosis
of seasonal affective disorder. The efficacy
of WELLBUTRIN XL for the prevention of seasonal major depressive
episodes was established in 3 controlled trials of adult outpatients
with a history of major depressive disorder with an autumn-winter
seasonal pattern as defined by Diagnostic and Statistical Manual of
Mental Disorders, 4th edition (DSM-IV) criteria (see CLINICAL TRIALS). Seasonal affective disorder is characterized by recurrent
major depressive episodes, most commonly occurring during the autumn
and/or winter months. Episodes may last up to 6 months in duration,
typically beginning in the autumn and remitting in the springtime.
Although patients with seasonal affective disorder may have depressive
episodes during other times of the year, the diagnosis of seasonal
affective disorder requires that the number of seasonal episodes substantially
outnumber the number of non-seasonal episodes during the individual's
lifetime.
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| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
WELLBUTRIN XL
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