Source:http://www4.wiwiss.fu-berlin.de/dailymed/resource/drugs/2546
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ZYBAN (Tablet, Coated)
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| dailymed-instance:dosage |
Usual Dosage for Adults: The recommended
and maximum dose of ZYBAN is 300 mg/day, given as 150 mg
twice daily. Dosing should begin at 150 mg/day given every day
for the first 3 days, followed by a dose increase for most patients
to the recommended usual dose of 300 mg/day. There should be
an interval of at least 8 hours between successive doses. Doses
above 300 mg/day should not be used (see WARNINGS). ZYBAN should be
swallowed whole and not crushed, divided, or chewed. Treatment with
ZYBAN should be initiated while the patient
is still smoking, since approximately 1 week of treatment
is required to achieve steady-state blood levels of bupropion. Patients
should set a���target quit date���within the first 2 weeks
of treatment with ZYBAN, generally in the second week. Treatment with
ZYBAN should be continued for 7 to 12 weeks; longer treatment
should be guided by the relative benefits and risks for individual
patients. If a patient has not made significant progress towards abstinence
by the seventh week of therapy with ZYBAN, it is unlikely that he
or she will quit during that attempt, and treatment should probably
be discontinued. Conversely, a patient who successfully quits after
7 to 12 weeks of treatment should be considered for ongoing therapy
with ZYBAN. Dose tapering of ZYBAN is not required when discontinuing
treatment. It is important that patients continue to receive counseling
and support throughout treatment with ZYBAN, and for a period of time
thereafter.<br/>Individualization of Therapy: Patients are more likely to quit smoking and remain
abstinent if they are seen frequently and receive support from their
physicians or other healthcare professionals. It is important to ensure
that patients read the instructions provided to them and have their
questions answered. Physicians should review the patient's
overall smoking cessation program that includes treatment with ZYBAN.
Patients should be advised of the importance of participating in the
behavioral interventions, counseling, and/or support services to be
used in conjunction with ZYBAN. See information for patients at the
end of the package insert. The goal of therapy
with ZYBAN is complete abstinence. If a patient has not made significant
progress towards abstinence by the seventh week of therapy with ZYBAN,
it is unlikely that he or she will quit during that attempt, and treatment
should probably be discontinued. Patients who
fail to quit smoking during an attempt may benefit from interventions
to improve their chances for success on subsequent attempts. Patients
who are unsuccessful should be evaluated to determine why they failed.
A new quit attempt should be encouraged when factors that contributed
to failure can be eliminated or reduced, and conditions are more favorable.<br/>Maintenance: Nicotine dependence is a chronic condition. Some
patients may need continuous treatment. Systematic evaluation of ZYBAN
300 mg/day for maintenance therapy demonstrated that treatment
for up to 6 months was efficacious. Whether to continue treatment
with ZYBAN for periods longer than 12 weeks for smoking cessation
must be determined for individual patients.<br/>Combination Treatment With
ZYBAN and a Nicotine Transdermal System (NTS): Combination treatment with ZYBAN and NTS may be
prescribed for smoking cessation. The prescriber should review the
complete prescribing information for both ZYBAN and NTS before using
combination treatment. See also CLINICAL TRIALS for methods and dosing
used in the ZYBAN and NTS combination trial. Monitoring for treatment-emergent
hypertension in patients treated with the combination of ZYBAN and
NTS is recommended.<br/>Dosage Adjustment for Patients
with Impaired Hepatic Function: ZYBAN 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. ZYBAN should be used with caution in
patients with hepatic impairment (including mild to moderate hepatic
cirrhosis) and a reduced frequency of dosing 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: ZYBAN should
be used with caution in patients with renal impairment and a reduced
frequency of dosing should be considered (see CLINICAL PHARMACOLOGY
and PRECAUTIONS).
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| dailymed-instance:descripti... |
ZYBAN (bupropion hydrochloride) Sustained-Release
Tablets are a non-nicotine aid to smoking cessation. ZYBAN is chemically
unrelated to nicotine or other agents currently used in the treatment
of nicotine addiction. Initially developed and marketed as an antidepressant
(WELLBUTRIN [bupropion hydrochloride] Tablets and WELLBUTRIN SR [bupropion
hydrochloride] Sustained-Release Tablets), ZYBAN is also 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 (��)-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: ZYBAN Tablets are supplied for oral administration as 150-mg (purple),
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
andis printed with edible black ink. In addition, the 150-mg tablet
contains FD&C Blue No. 2 Lake and FD&C Red No. 40
Lake.
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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. The mechanism by
which ZYBAN enhances the ability of patients to abstain from smoking
is unknown. However, 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. Bupropion follows biphasic pharmacokinetics best described
by a 2-compartment model. The terminal phase has a mean half-life
(��% CV) of about 21 hours (��20%), while the distribution
phase has a mean half-life of 3 to 4 hours.<br/>Absorption: Bupropion has not been administered intravenously
to humans; therefore, the absolute bioavailability of ZYBAN Sustained-Release
Tablets in humans has not been determined. In rat and dog studies,
the bioavailability of bupropion ranged from 5% to 20%. Following oral administration of ZYBAN to healthy volunteers,
peak plasma concentrations of bupropion are achieved within 3 hours.
The mean peak concentration (C) values were 91 and
143 ng/mL from 2 single-dose (150-mg) studies. At steady state,
the mean Cfollowing a 150-mg dose every 12 hours
is 136 ng/mL. In a single-dose study, food
increased the Cof bupropion by 11% and the extent of
absorption as defined by area under the plasma concentration-time
curve (AUC) by 17%. The mean time to peak concentration (T) was prolonged by 1 hour. This effect was of no clinical significance.<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. The volume of distribution (V/F) estimated
from a single 150-mg dose given to 17 subjects is 1,950 L (20% CV).<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 resultsin 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 ZYBAN Tablets. Peak plasma concentrations of hydroxybupropion are
approximately 10 times the peak level of the parent drug at steadystate.
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: The mean
(��% CV) apparent clearance (Cl/F) estimated from 2 single-dose
(150-mg) studies are 135 (��20%) and 209 L/hr (��21%).
Following chronic dosing of 150 mg of ZYBAN every 12 hours
for 14 days (n = 34), the mean Cl/F at steady state
was 160 L/hr (��23%). The mean elimination half-life of bupropion
estimated from a series of studies is approximately 21 hours.
Estimates of the half-lives of the metabolites determined from a multiple-dose
study were 20 hours (��25%) for hydroxybupropion, 37 hours
(��35%) for threohydrobupropion, and 33 hours (��30%)
for erythrohydrobupropion. Steady-state plasma concentrations of bupropion
and metabolites are reached within 5 and 8 days, respectively. 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. The fraction of the oral dose
of bupropion excreted unchanged was only 0.5%. 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 ZYBAN, there was no statistically significant
difference in C, half-life, T, AUC, or
clearance of bupropion or its major metabolites between smokers and
nonsmokers. In a study comparing the treatment
combination of ZYBAN and nicotine transdermal system (NTS) versus
ZYBAN alone, no statistically significant differences were observed
between the 2 treatment groups of combination ZYBAN and NTS (n = 197)
and ZYBAN alone (n = 193) in the plasma concentrations of
bupropion or its active metabolites at weeks 3 and 6.<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
that there were no statistically significant differences in the pharmacokinetics
of bupropion and its active metabolites in 9 patients with mild to
moderate hepatic cirrhosis compared to 8 healthy volunteers. However,
more variability was observed in some of the pharmacokinetic parameters
for bupropion (AUC, C, and T) and its
active metabolites (t) in patients with mild to moderate
hepatic cirrhosis. In addition, in patients with severe hepatic cirrhosis,
the bupropion Cand AUC were substantially increased
(mean difference: by approximately 70% and 3-fold, respectively) and
more variable when compared to values in healthy volunteers; the mean
bupropion half-life was also longer (29 hours in patients with severe
hepatic cirrhosis vs. 19 hours in healthy subjects). For the metabolite
hydroxybupropion, the mean Cwas approximately 69% lower.For
the combined amino-alcohol isomers threohydrobupropion and erythrohydrobupropion,
the mean Cwas approximately 31% lower. The mean AUC
increased by 28% for hydroxybupropion and 50% for threo/erythrohydrobupropion.The
median Twas observed 19 hours later for hydroxybupropion
and 21 hours later for threo/erythrohydrobupropion. The mean half-lives
for hydroxybupropion and threo/erythrohydrobupropion were increased
2- and 4-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, compared to healthy normal volunteers,
was revealed.<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 a day 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 thatthe 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.
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ZYBAN is contraindicated
in patients with a seizure disorder. ZYBAN is
contraindicated in patients treated with WELLBUTRIN (bupropion hydrochloride),
the immediate-release formulation; WELLBUTRIN SR (bupropion hydrochloride),
the sustained-release formulation; WELLBUTRIN XL (bupropion hydrochloride),
the extended-release formulation; or any other medications that contain
bupropion because the incidence of seizure is dose dependent. ZYBAN 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. ZYBAN is contraindicated in patients undergoing abrupt discontinuation
of alcohol or sedatives (including benzodiazepines). The concurrent administration of ZYBAN 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 ZYBAN. ZYBAN is contraindicated in patients
who have shown an allergic response to bupropion or the other ingredients
that make up ZYBAN.
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ZYBAN Sustained-Release
Tablets, 150 mg of bupropion hydrochloride, are purple, round,
biconvex, film-coated tablets printed with���ZYBAN 150���in bottles of 60 (NDC 0173-0556-02) tablets and the ZYBAN Advantage
Pack containing 1 bottle of 60 (NDC 0173-0556-01)
tablets. Store at
controlled room temperature, 20��to 25��C (68��to 77��F)
(see USP). Dispense in tight, light-resistant containers as defined
in the USP.
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| dailymed-instance:inactiveI... |
dailymed-ingredient:FD&C_Blue_No._2_lake,
dailymed-ingredient:FD&C_Red_No._40_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/>Allergic Reactions: Anaphylactoid/anaphylactic reactions characterized
by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring
medical treatment have been reported at a rate of about 1 to 3 per
thousand in clinical trials of ZYBAN. 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 ZYBAN 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/>Insomnia: In the
dose-response smoking cessation trial, 29% of patients treated with
150 mg/day of ZYBAN and 35% of patients treated with 300 mg/day
of ZYBAN experienced insomnia, compared to 21% of placebo-treated
patients. Symptoms were sufficiently severe to require discontinuation
of treatment in 0.6% of patients treated with ZYBAN and none of the
patients treated with placebo. In the comparative
trial, 40% of the patients treated with 300 mg/day of ZYBAN,
28% of the patients treated with 21 mg/day of NTS, and 45% of
the patients treated with the combination of ZYBAN and NTS experienced
insomnia compared to 18% of placebo-treated patients. Symptoms were
sufficiently severe to require discontinuation of treatment in 0.8%
of patients treated with ZYBAN and none of the patients in the other
3 treatment groups. Insomnia may be minimized
by avoiding bedtime doses and, if necessary, reduction in dose.<br/>Psychosis, Confusion, and
Other Neuropsychiatric Phenomena: In clinical trials with ZYBAN conducted in nondepressed
smokers, the incidence of neuropsychiatric side effects was generally
comparable to placebo. Depressed patients treated with bupropion in
depression trials 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 individuals.
The sustained-release formulation of bupropion is expected to pose
similar risks. There were no reports of activation of psychosis or
mania in clinical trials with ZYBAN conducted in nondepressed smokers.<br/>Depression and Nicotine Withdrawal: Depressed mood
may be a symptom of nicotine withdrawal. Depression, rarely including
suicidal ideation, has been reported in patients undergoing a smoking
cessation attempt (see WARNINGS: Clinical
Worsening and Suicide Risk).<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 ZYBAN, 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 ZYBAN and
NTS. In this study, 6.1% of patients treated with the combination
of ZYBAN and NTS had treatment-emergent hypertension compared to 2.5%,
1.6%, and 3.1% of patients treated with ZYBAN, 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 ZYBAN 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: ZYBAN
should be used with extreme caution in patients with severe hepatic
cirrhosis. In these patients, a reduced frequency of dosing is required.
ZYBAN should be used with caution in patients with hepatic impairment
(including mild to moderate hepatic cirrhosis) and reduced frequency
of dosing 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. ZYBAN should be used with
caution in patients with renal impairment and a reduced frequency
of dosing 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: Although ZYBAN is not indicated for treatment of
depression, it contains the same active ingredient as the antidepressant
medications WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN XL. Prescribers
or other health professionals should inform patients, their families,
and their caregivers about the benefits and risks associated with
treatment with ZYBAN 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 ZYBAN
is available for ZYBAN. 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 ZYBAN.<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 ZYBAN contains the same
active ingredient found in WELLBUTRIN, WELLBUTRIN SR, and WELLBUTRIN
XL used to treat depression and that ZYBAN should not be used in conjunction
with WELLBUTRIN, the immediate-release formulation; WELLBUTRIN SR,
the sustained-release formulation;WELLBUTRIN XL, the extended-release
formulation; or any other medications that contain bupropion hydrochloride.<br/>Laboratory Tests: There are no specific laboratory tests recommended.<br/>Drug Interactions: In vitro studies indicate that bupropion is primarily
metabolized to hydroxybupropion by the CYP2B6 isoenzyme. Therefore,
the potential exists for a drug interaction between ZYBAN 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. Few systemicdata have been collected on the metabolism of ZYBAN following concomitant
administration with other drugs or, alternatively, the effect of concomitant
administration of ZYBAN on the metabolism of other drugs. 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.
However, following chronic administration of bupropion, 100 mg
t.i.d to 8 healthy male volunteers for 14 days, there was no evidence
of induction of its own metabolism. Because bupropion is extensively
metabolized, the coadministration of other drugs may affect its clinical
activity. In particular, certain drugs may induce the metabolism of
bupropion (e.g., carbamazepine, phenobarbital, phenytoin), while other
drugs may inhibit the metabolism of bupropion (e.g., cimetidine).
The effects of concomitant administration ofcimetidine on the pharmacokinetics
of bupropion and its active metabolites were studied in 24 healthy
young male volunteers. Following oral administration of two 150-mg
ZYBAN tablets with and without 800 mg of cimetidine, the pharmacokinetics
of bupropion and its hydroxy metabolite were unaffected. However,
there were 16% and 32% increases, respectively, in the AUC and Cof the combined moieties of threohydro- and erythrohydro-
bupropion.<br/>Drugs Metabolized by Cytochrome
P450IID6 (CYP2D6): Many drugs, including most antidepressants (SSRIs,
many tricyclics), beta-blockers, antiarrhythmics, and antipsychotics
are metabolized by the CYP2D6 isoenzyme. Although bupropion is not
metabolized by this isoenzyme, bupropion and hydroxybupropion are
inhibitors of the CYP2D6 isoenzyme in vitro. In a study of 15male
subjects (ages 19 to 35 years) who were extensive metabolizers of
the CYP2D6 isoenzyme, daily doses of bupropion given as 150 mg
twice daily followed by a single dose of 50 mg desipramine increased
the C, AUC, and tof desipramine by an
average of approximately 2-, 5- and 2-fold, respectively. The effect
was present for at least 7 days after the last dose of bupropion.
Concomitant use of bupropion with other drugs metabolized by CYP2D6
has not been formally studied. Therefore, coadministration
of bupropion with drugs that are metabolized by CYP2D6 isoenzyme including
certain antidepressants (e.g., nortriptyline, imipramine, desipramine,
paroxetine, fluoxetine, sertraline), antipsychotics (e.g., haloperidol,
risperidone, thioridazine), beta-blockers (e.g., metoprolol), and
Type 1C antiarrhythmics (e.g., propafenone, flecainide), should be
approached with caution and should be initiated at the lower end of
the dose range of the concomitant medication. If bupropion is added
to the treatment regimen of a patient already receiving a drug metabolized
by CYP2D6, the need to decrease the dose of the original medication
should be considered, particularly for those concomitant medications
with a narrow therapeutic index.<br/>MAO Inhibitors: Studies in animals demonstrate that the acute toxicity
of bupropion is enhanced by the MAO inhibitor phenelzine (see CONTRAINDICATIONS).<br/>Levodopa and Amantadine: Limited clinical data suggest a higher incidence
of adverse experiences in patients receiving bupropion concurrently
with either levodopa or amantadine. Administration of ZYBAN 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 ZYBAN and agents (e.g., antipsychotics, antidepressants,
theophylline, systemic steroids, etc.) that lower seizure threshold
should be undertaken only with extreme caution (see WARNINGS).<br/>Nicotine Transdermal System: (see PRECAUTIONS: Cardiovascular Effects).<br/>Smoking Cessation: Physiological changes resulting from smoking cessation
itself, with or without treatment with ZYBAN, may alter the pharmacokinetics
of some concomitant medications, which may require dosage adjustment.
Blood concentrations of concomitant medications that are extensively
metabolized, such as theophylline and warfarin, may be expected to
increase following smoking cessation due to de-induction of hepatic
enzymes.<br/>Alcohol: In post-marketing experience, there have been rare
reports of adverse neuropsychiatric events or reduced alcohol tolerance
in patients who were drinking alcohol during treatment with ZYBAN.
The consumption of alcohol during treatment with ZYBAN 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 per day, respectively.
These doses are approximately 10 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 per day (approximately
3 to 10 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 cytogenic studies. A fertility
study in rats at doses up to 300 mg/kg 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 14 and 10 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 2 times 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 10 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. ZYBAN should
be used during pregnancy only if the potential benefit justifies the
potential risk to the fetus. Pregnant smokers should be encouraged
to attempt cessation using educational and behavioral interventions
before pharmacological approaches are used. To monitor fetal outcomes of pregnant women exposed to ZYBAN, 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 ZYBAN on labor and delivery in humans
is unknown.<br/>Nursing Mothers: Bupropion and
its metabolites are secreted in human milk. Because of the potential
for serious adverse reactions in nursing infants from ZYBAN, 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 ZYBAN 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 ZYBAN, 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).
|
| dailymed-instance:genericMe... |
bupropion hydrochloride
|
| dailymed-instance:fullName |
ZYBAN (Tablet, Coated)
|
| 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 patientsduring 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 reductionwith 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 4. No suicides occurred in any of these pediatric
trials. There were suicides in the adult trials, but the number was
not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to
longer-term use, i.e., beyond several months. However, there is substantial
evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence
of depression. All
patients being treated with antidepressants for any indication should
be monitored appropriately and observed closely for clinical worsening,
suicidality, and unusual changes in behavior, especially during the
initial few months of a course of drug therapy, or at times of dose
changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia,
irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor
restlessness), hypomania, and mania, have been reported in adult and
pediatric patients being treated with antidepressants for major depressive
disorder as well as for other indications, both psychiatric and nonpsychiatric.
Although a causal link between the emergence of such symptoms and
either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms
may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen,
including possibly discontinuing the medication, in patients whose
depression is persistently worse, or who are experiencing emergent
suicidality or symptoms that might be precursors to worsening depression
or suicidality, especially if these symptoms are severe, abrupt in
onset, or were not part of the patient's presenting symptoms. Families and caregivers of patients
being treated with antidepressants for major depressive disorder or
other indications, both psychiatric and nonpsychiatric, should be
alerted about the need to monitor patients for the emergence of agitation,
irritability, unusual changes in behavior, and the other symptoms
described above, as well as the emergence of suicidality, and to report
such symptoms immediately to healthcare providers. Such monitoring
should include daily observation by families and caregivers. Prescriptions for ZYBAN 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 ZYBAN is not approved for
use in treating bipolar depression. Patients should be made aware that ZYBAN contains
the same active ingredient found in WELLBUTRIN, WELLBUTRIN SR, and
WELLBUTRIN XL used to treat depression, and that ZYBAN should not
be used in combination with WELLBUTRIN (bupropion hydrochloride),
the immediate release formulation; WELLBUTRIN SR (bupropion hydrochloride),
the sustained-release formulation; WELLBUTRIN XL (bupropion hydrochloride),
theextended-release formulation; or any other medications that contain
bupropion.<br/>Seizures: Because the use of bupropion
is associated with a dose-dependent risk of seizures, clinicians should not prescribe doses over
300 mg/day for smoking cessation. The risk of seizures is also related to patient factors, clinical
situation, and concomitant medications, which must be considered in
selection of patients for therapy with ZYBAN. ZYBAN 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% (4/1,000) in depressed patients treated at doses in a range of
300 to 450 mg/day. In addition, the estimated seizure incidence
increases almost tenfold between 450 and 600 mg/day.<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 ZYBAN 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, antidepressants, theophylline,
systemic steroids, etc.) that lower seizure threshold.<br/>Hepatic Impairment: ZYBAN should be used with
extreme caution in patients with severe hepatic cirrhosis. In these
patients a reduced frequency of dosing is required, as peak bupropion
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.
|
| dailymed-instance:indicatio... |
ZYBAN is indicated as an aid to smoking cessation
treatment.
|
| dailymed-instance:represent... | |
| dailymed-instance:routeOfAd... | |
| dailymed-instance:name |
ZYBAN
|