Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/3479
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WELLBUTRIN SR (Tablet, Coated)
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General Dosing Considerations: It is particularly
important to administer WELLBUTRIN SR 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 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. WELLBUTRIN SR should
be swallowed whole and not crushed, divided, or chewed.<br/>Initial Treatment: The usual adult
target dose for WELLBUTRIN SR Tablets is 300 mg/day, given
as 150 mg twice daily. Dosing with WELLBUTRIN SR 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 150 mg twice daily, may
be made as early as day 4 of dosing. There should be an interval of
at least 8 hours between successive doses.<br/>Increasing the Dosage Above
300 mg/day: As with other
antidepressants, the full antidepressant effect of WELLBUTRIN SR
Tablets may not be evident until 4 weeks of treatment or longer.
An increase in dosage to the maximum of 400 mg/day, given as
200 mg twice daily, may be considered for patients in whom no
clinical improvement is noted after several weeks of treatment at
300 mg/day.<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. In a study in which patients with major depressive
disorder, recurrent type, who had responded during 8 weeks of
acute treatment with WELLBUTRIN SR were assigned randomly to
placebo or to the same dose of WELLBUTRIN SR (150 mg twice
daily) during 44 weeks of maintenance treatment as they had received
during the acute stabilization phase, longer-term efficacy was demonstrated
(see CLINICAL TRIALS under CLINICAL PHARMACOLOGY). Based on these
limited data, it is unknown whether or not the dose of WELLBUTRIN SR
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/>Dosage Adjustment for Patients
with Impaired Hepatic Function: WELLBUTRIN SR
should be used with extreme caution in patients with severe hepatic
cirrhosis. The dose should not exceed 100 mg every day or 150 mg
every other day in these patients. WELLBUTRIN SR 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 SR
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 SR (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 SR Tablets are supplied for oral administration
as 100-mg (blue), 150-mg (purple), and 200-mg (light pink), film-coated,
sustained-release tablets. Each tablet contains the labeled amount
of bupropion hydrochloride and the inactive ingredients: carnauba
wax, cysteine hydrochloride, hypromellose, magnesium stearate, microcrystalline
cellulose, polyethylene glycol, polysorbate 80, and titanium dioxide
and is printed with edible black ink. In addition, the 100-mg tablet
contains FD&C Blue No. 1 Lake, the 150-mg tablet contains
FD&C Blue No. 2 Lake and FD&C Red No. 40 Lake, and
the 200-mg tablet contains FD&C Red No. 40 Lake.
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| dailymed-instance:clinicalP... |
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 chronic dosing with WELLBUTRIN SR
Tablets 150 mg twice daily to the immediate-release formulation
of bupropion at 100 mg 3 times daily, peak plasma concentrations
of bupropion at steady state for WELLBUTRIN SR Tablets were approximately
85% of those achieved with the immediate-release formulation. There
was equivalence for bupropion AUCs, as well as equivalence for both
peak plasma concentration and AUCs for all 3 of the detectable bupropion
metabolites. Thus, at steady state, WELLBUTRIN SR Tablets, given
twice daily, and the immediate-release formulation of bupropion, given
3 times daily, are essentially bioequivalent for both bupropion and
the 3 quantitatively important metabolites.<br/>Absorption: Following oral administration of WELLBUTRIN SR
Tablets to healthy volunteers, peak plasma concentrations of bupropion
are achieved within 3 hours. Food increased Cand
AUC of bupropion by 11% and 17%, respectively, indicating that there
is no clinically significant food effect.<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). Following a single dose in humans, peak plasma concentrations
of hydroxybupropion occur approximately 6 hours after administration
of WELLBUTRIN SR 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 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 plasmaconcentration 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 SR is contraindicated in patients
with a seizure disorder. WELLBUTRIN SR
is contraindicated in patients treated with ZYBAN (bupropion hydrochloride) Sustained-Release Tablets; WELLBUTRIN (bupropion hydrochloride), the immediate-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 SR 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 SR is contraindicated in patients undergoing abrupt
discontinuation of alcohol or sedatives (including benzodiazepines). The concurrent administration of WELLBUTRIN SR
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 SR
Tablets. WELLBUTRIN SR is contraindicated
in patients who have shown an allergic response to bupropion or the
other ingredients that make up WELLBUTRIN SR Tablets.
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WELLBUTRIN SR
Sustained-Release Tablets, 100 mg of bupropion hydrochloride,
are blue, round, biconvex, film-coated tablets printed with���WELLBUTRIN SR 100���in bottles of 60 (NDC 0173-0947-55) tablets. WELLBUTRIN SR Sustained-Release Tablets, 150 mg of
bupropion hydrochloride, are purple, round, biconvex, film-coated
tablets printed with "WELLBUTRIN SR 150" in bottles of 60
(NDC 0173-0135-55) tablets. WELLBUTRIN SR
Sustained-Release Tablets, 200 mg of bupropion hydrochloride,
are light pink, round, biconvex, film-coated tablets printed with���WELLBUTRIN SR 200���in bottles of 60 (NDC 0173-0722-00)
tablets. Store
at controlled room temperature, 20��to 25��C (68��to
77��F)[see USP]. Dispense
in a tight, light-resistant container as defined in the USP.
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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 SR or any other antidepressant
in a child, adolescent, or young adult must balance this risk with
the clinical need. Short-term studiesdid not show an increase in
the 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 SR 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:FD&C_Blue_No._1_lake,
dailymed-ingredient:carnauba_wax,
dailymed-ingredient:cysteine_hydrochloride,
dailymed-ingredient:edible_black_ink,
dailymed-ingredient:hypromellose,
dailymed-ingredient:magnesium_stearate,
dailymed-ingredient:microcrystalline_cellulose,
dailymed-ingredient:polyethylene_glycol,
dailymed-ingredient:polysorbate_80,
dailymed-ingredient:titanium_dioxide
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| dailymed-instance:precautio... |
General:<br/>Agitation and Insomnia: Patients
in placebo-controlled trials with WELLBUTRIN SR Tablets experienced
agitation, anxiety, and insomnia as shown in Table 2. In clinical studies, these symptoms were sometimes
of sufficient magnitude to require treatment with sedative/hypnotic
drugs. Symptoms were sufficiently severe
to require discontinuation of treatment in 1% and 2.6% of patients
treated with 300 and 400 mg/day, respectively, of WELLBUTRIN SR
Tablets and 0.8% of patients treated with placebo.<br/>Psychosis, Confusion, and
Other Neuropsychiatric Phenomena: Depressed patients treated with an immediate-release
formulation of bupropion or with WELLBUTRIN SR Tablets 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 SR is expected to pose
similar risks.<br/>Altered Appetite and Weight: In placebo-controlled
studies, patients experienced weight gain or weight loss as shown
in Table 3. 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 SR 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 SR 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 SR 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 welltolerated 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 SR should be used with extreme caution
in patients with severe hepatic cirrhosis. In these patients, a reduced
frequency and/or dose is required. WELLBUTRIN SR 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 SR 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 SR 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 SR is available for WELLBUTRIN
SR. 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. Thecomplete
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 SR.<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, sincechanges 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 SR contains the same active ingredient
found in ZYBAN, used as an aid to smoking cessation treatment, and
that WELLBUTRIN SR should not be used in combination with ZYBAN
or any other medications that contain bupropion hydrochloride (such
as WELLBUTRIN, the immediate-release formulation and WELLBUTRIN XL,
the extended-release formulation). As dose
is increased during initial titration to doses above 150 mg/day,
patients should be instructed to take WELLBUTRIN SR Tablets in
2 divided doses, preferably with at least 8 hours between
successive doses, to minimize the risk of seizures. Patients should be told that WELLBUTRIN SR 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 SR Tablets may impair their ability to perform tasks
requiring judgment or motor and cognitive skills. Consequently, until
they are reasonably certain that WELLBUTRIN SR 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 SR. 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 SR
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 SR
Tablets whole so that the release rate is not altered. Do not chew,
divide, or crush tablets.<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 SR 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 wellas 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 WELLBUTRIN SR 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 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 lowerend 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 SR
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 SR
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 WELLBUTRIN SR. The consumption of alcohol
during treatment with WELLBUTRIN SR 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 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 SR
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 SR, 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 SR 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 SR 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 SR
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). No overall 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 SR, 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 SR (Tablet, Coated)
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| 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 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 well as the emergence of suicidality, and to report
such symptoms immediately to healthcare providers. Such monitoring
should include dailyobservation by families and caregivers. Prescriptions for WELLBUTRIN SR 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 todetermine 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 SR is not
approved for use in treating bipolar depression. Patients should be made aware that
WELLBUTRIN SR contains the same active ingredient found in ZYBAN,
used as an aid to smoking cessation treatment, and that WELLBUTRIN SR
should not be used in combination with ZYBAN, or any other medications
that contain bupropion, such as WELLBUTRIN (bupropion hydrochloride),
the immediate-release formulation or WELLBUTRIN XL (bupropion hydrochloride),
the extended-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 SR. WELLBUTRIN SR should be discontinued and
not restarted in patients who experience a seizure while on treatment. 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.
The 450-mg/day upper limit of this dose range is close to the currently
recommended maximum dose of 400 mg/day for WELLBUTRIN SR
Tablets. This seizure incidence (0.4%) may exceed that of other marketed
antidepressants and WELLBUTRIN SR Tablets up to 300 mg/day
by as much as 4-fold. This relative risk is only an approximate estimate
because no direct comparative studies have been conducted. 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, which is twice the usual adult dose and one
and one-half the maximum recommended daily dose (400 mg) of WELLBUTRIN SR
Tablets. This disproportionate increase in seizure incidence with
dose incrementation calls for caution in dosing. Data for WELLBUTRIN SR
Tablets revealed a seizure incidence of approximately 0.1% (i.e.,
3 of 3,100 patients followed prospectively) in patients treated at
doses in a range of 100 to 300 mg/day. It is not possible to
know if the lower seizure incidence observed in this study involving
the sustained-release formulation of bupropion resulted from the different
formulation or the lower dose used.However, as noted above, the immediate-release
and sustained-release formulations are bioequivalent with regard to
both rate and extent of absorption during steady state (the most pertinent
condition to estimating seizure incidence), since most observed seizures
occur under steady-state conditions.<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 SR 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 SR 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 100 mg every day
or 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... |
WELLBUTRIN SR 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 depressed inpatients and in one
6-week controlled trial of depressed outpatients whose diagnoses corresponded
most closely to the Major Depression category of the APA Diagnostic
and Statistical Manual (DSM) (see CLINICAL PHARMACOLOGY). 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 WELLBUTRIN SR in maintaining an antidepressant response
for up to 44 weeks following 8 weeks of acute treatment
was demonstrated in a placebo-controlled trial (see CLINICAL PHARMACOLOGY).
Nevertheless, the physician who elects to use WELLBUTRIN SR 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 SR
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