Overdose
Human Overdose Experience
Overdoses of up to 30 grams 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.
Overdosage Management
Consult a Certified Poison Control Center for up-to-date
guidance and advice. Telephone numbers for certified poison control centers are
listed in the Physicians' Desk Reference (PDR). Call 1-800-222-1222 or refer to
www.poison.org.
There are no known antidotes for bupropion. In case of an
overdose, provide supportive care, including close medical supervision and
monitoring. Consider the possibility of multiple drug overdose.
Contraindications
- WELLBUTRIN XL is contraindicated in patients with seizure
disorder.
- WELLBUTRIN XL is contraindicated in patients with a
current or prior diagnosis of bulimia or anorexia nervosa as a higher incidence
of seizures was observed in such patients treated with WELLBUTRIN XL.
- WELLBUTRIN XL is contraindicated in patients undergoing
abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and
antiepileptic drugs.
- The use of MAOIs (intended to treat psychiatric
disorders) concomitantly with WELLBUTRIN XL or within 14 days of discontinuing
treatment with WELLBUTRIN XL is contraindicated. There is an increased risk of
hypertensive reactions when WELLBUTRIN XL is used concomitantly with MAOIs. The
use of WELLBUTRIN XL within 14 days of discontinuing treatment with an MAOI is
also contraindicated. Starting WELLBUTRIN XL in a patient treated with
reversible MAOIs such as linezolid or intravenous methylene blue is
contraindicated.
- WELLBUTRIN XL is contraindicated in patients with known
hypersensitivity to bupropion or other ingredients of WELLBUTRIN XL.
Anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been
reported.
Undesirable effects
The following adverse reactions are discussed in greater
detail in other sections of the labeling:
- Suicidal thoughts and behaviors in children, adolescents,
and young adults
- Neuropsychiatric symptoms and suicide risk in smoking
cessation treatment
- Seizure
- Hypertension
- Activation of mania or hypomania
- Psychosis and other neuropsychiatric events
- Angle-Closure Glaucoma
- Hypersensitivity reactions
Clinical Trials Experience
Because clinical trials are conducted under widely
varying conditions, adverse reaction rates observed in the clinical trials of a
drug cannot be directly compared to rates in the clinical trials of another
drug and may not reflect the rates observed in clinical practice.
Commonly Observed Adverse Reactions In Controlled
Clinical Trials Of Sustained-Release Bupropion Hydrochloride
Adverse reactions that occurred in at least 5% of
patients treated with bupropion HCl sustained-release (300 mg and 400 mg per
day) and at a rate at least twice the placebo rate are listed below.
300 mg/day of bupropion HCl sustained-release: anorexia,
dry mouth, rash, sweating, tinnitus, and tremor.
400 mg/day of bupropion HCl sustained-release: abdominal
pain, agitation, anxiety, dizziness, dry mouth, insomnia, myalgia, nausea,
palpitation, pharyngitis, sweating, tinnitus, and urinary frequency.
WELLBUTRIN XL has been demonstrated to have similar
bioavailability both to the immediate-release and sustained-release
formulations of bupropion. The information included under this subsection and
under subsection 6.2 is based primarily on data from controlled clinical trials
with the sustained-release and extended-release formulations of bupropion
hydrochloride.
Major Depressive Disorder
Adverse Reactions Leading to Discontinuation of
Treatment with Bupropion HCl Immediate-Release, Bupropion HCl
Sustained-Release, and Bupropion HCl Extended-Release in Major Depressive
Disorder Trials
In placebo-controlled clinical trials with bupropion HCl
sustained-release, 4%, 9%, and 11% of the placebo, 300 mg/day and 400 mg/day
groups, respectively, discontinued treatment because of adverse reactions. The
specific adverse reactions leading to discontinuation in at least 1% of the 300
mg/day or 400 mg/day groups and at a rate at least twice the placebo rate are
listed in Table 2.
Table 2: Treatment Discontinuation Due to Adverse
Reactions in Placebo-Controlled Trials in MDD
| Adverse Reaction Term |
Placebo
(n=385) |
Bupropion HCl Sustained-Release 300 mg/day
(n=376) |
Bupropion HCl Sustained-Release 400 mg/day
(n=114) |
| Rash |
0.0% |
2.4% |
0.9% |
| Nausea |
0.3% |
0.8% |
1.8% |
| Agitation |
0.3% |
0.3% |
1.8% |
| Migraine |
0.3% |
0.0% |
1.8% |
In clinical trials with
bupropion HCl immediate-release, 10% of patients and volunteers discontinued
due to an adverse reaction. Reactions resulting in discontinuation (in addition
to those listed above for the sustained-release formulation) included vomiting,
seizures, and sleep disturbances.
Adverse Reactions Occurring
at an Incidence of > 1% in Patients Treated with Bupropion HCl
Immediate-Release or Bupropion HCl Sustained-Release in MDD
Table 3 summarizes the adverse reactions that occurred in
placebo-controlled trials in patients treated with bupropion HCl
sustained-release 300 mg/day and 400 mg/day. These include reactions that
occurred in either the 300 mg or 400 mg group at an incidence of 1% or more and
were more frequent than in the placebo group.
Table 3: Adverse Reactions
in Placebo-Controlled Trials in Patients with MDD
Body System/
Adverse Reaction |
Placebo
(n=385) |
Bupropion HCl Sustained-Release 300 mg/day
(n=376) |
Bupropion HCl Sustained-Release 400 mg/day
(n=114) |
| Body (General) |
| Headache |
23% |
26% |
25% |
| Infection |
6% |
8% |
9% |
| Abdominal pain |
2% |
3% |
9% |
| Asthenia |
2% |
2% |
4% |
| Chest pain |
1% |
3% |
4% |
| Pain |
2% |
2% |
3% |
| Fever |
— |
1% |
2% |
| Cardiovascular |
| Palpitation |
2% |
2% |
6% |
| Flushing |
— |
1% |
4% |
| Migraine |
1% |
1% |
4% |
| Hot flashes |
1% |
1% |
3% |
| Digestive |
| Dry mouth |
7% |
17% |
24% |
| Nausea |
8% |
13% |
18% |
| Constipation |
7% |
10% |
5% |
| Diarrhea |
6% |
5% |
7% |
| Anorexia |
2% |
5% |
3% |
| Vomiting |
2% |
4% |
2% |
| Dysphagia |
0% |
0% |
2% |
| Musculoskeletal |
| Myalgia |
3% |
2% |
6% |
| Arthralgia |
1% |
1% |
4% |
| Arthritis |
0% |
0% |
2% |
| Twitch |
— |
1% |
2% |
| Nervous System |
| Insomnia |
6% |
11% |
16% |
| Dizziness |
5% |
7% |
11% |
| Agitation |
2% |
3% |
9% |
| Anxiety |
3% |
5% |
6% |
| Tremor |
1% |
6% |
3% |
| Nervousness |
3% |
5% |
3% |
| Somnolence |
2% |
2% |
3% |
| Irritability |
2% |
3% |
2% |
| Memory decreased |
1% |
— |
3% |
| Paresthesia |
1% |
1% |
2% |
| Central nervous system stimulation |
1% |
2% |
1% |
| Respiratory |
| Pharyngitis |
2% |
3% |
11% |
| Sinusitis |
2% |
3% |
1% |
| Increased cough |
1% |
1% |
2% |
| Skin |
| Sweating |
2% |
6% |
5% |
| Rash |
1% |
5% |
4% |
| Pruritus |
2% |
2% |
4% |
| Urticaria |
0% |
2% |
1% |
| Special Senses |
| Tinnitus |
2% |
6% |
6% |
| Taste perversion |
— |
2% |
4% |
| Blurred vision or diplopia |
2% |
3% |
2% |
| Urogenital |
| Urinary frequency |
2% |
2% |
5% |
| Urinary urgency |
0% |
— |
2% |
| Vaginal hemorrhage1 |
— |
0% |
2% |
| Urinary tract infection |
—2 |
1% |
0% |
1Incidence based on the number of female patients.
2Hyphen denotes adverse reactions occurring in greater than 0 but
less than 0.5% of patients |
The following additional
adverse reactions occurred in controlled trials of bupropion HCl
immediate-release (300 to 600 mg per day) at an incidence of at least 1% more
frequently than in the placebo group were: cardiac arrhythmia (5% vs. 4%),
hypertension (4% vs. 2%), hypotension (3% vs. 2%), menstrual complaints (5% vs.
1%), akathisia (2% vs. 1%), impaired sleep quality (4% vs. 2%), sensory
disturbance (4% vs. 3%), confusion (8% vs. 5%), decreased libido (3% vs. 2%),
hostility (6% vs. 4%), auditory disturbance (5% vs. 3%), and gustatory
disturbance (3% vs. 1%).
Seasonal Affective Disorder
In placebo-controlled clinical trials in SAD, 9% of
patients treated with WELLBUTRIN XL and 5% of patients treated with placebo
discontinued treatment because of adverse reactions. The adverse reactions
leading to discontinuation in at least 1% of patients treated with bupropion
and at a rate numerically greater than the placebo rate were insomnia (2% vs.
< 1%) and headache (1% vs. < 1%).
Table 4 summarizes the adverse reactions that occurred in
patients treated with WELLBUTRIN XL for up to approximately 6 months in 3
placebo-controlled trials. These include reactions that occurred at an
incidence of 2% or more and were more frequent than in the placebo group.
Table 4: Adverse Reactions in Placebo-Controlled
Trials in Patients with SAD
System Organ Class/
Preferred Term |
Placebo
(n=511) |
Bupropion HCl Extended-Release
(n=537) |
| Gastrointestinal Disorder |
| Dry mouth |
15% |
26% |
| Nausea |
8% |
13% |
| Constipation |
2% |
9% |
| Flatulence |
3% |
6% |
| Abdominal pain |
< 1% |
2% |
| Nervous System Disorders |
| Headache |
26% |
34% |
| Dizziness |
5% |
6% |
| Tremor |
< 1% |
3% |
| Infections and Infestations |
| Nasopharyngitis |
12% |
13% |
| Upper respiratory tract infection |
8% |
9% |
| Sinusitis |
4% |
5% |
| Psychiatric Disorders |
| Insomnia |
13% |
20% |
| Anxiety |
5% |
7% |
| Abnormal dreams |
2% |
3% |
| Agitation |
< 1% |
2% |
| Musculoskeletal and Connective Tissue Disorders |
| Myalgia |
2% |
3% |
| Pain in extremity |
2% |
3% |
| Respiratory, Thoracic, and Mediastinal Disorders |
| Cough |
3% |
4% |
| General Disorders and Administration Site Conditions |
| Feeling jittery |
2% |
3% |
| Skin and Subcutaneous Tissue Disorders |
| Rash |
2% |
3% |
| Metabolism and Nutrition Disorders |
| Decreased appetite |
1% |
4% |
| Reproductive System and Breast Disorders |
| Dysmenorrhea |
< 1% |
2% |
| Ear and Labyrinth Disorders |
| Tinnitus |
< 1% |
3% |
| Vascular Disorders |
| Hypertension |
0% |
2% |
Changes In Body Weight
Table 5 presents the incidence of body weight changes ( ≥ 5 lbs) in the short-term MDD trials using bupropion
HCl sustained-release. There was a dose-related decrease in body weight.
Table 5: Incidence of Weight
Gain or Weight Loss ( ≥ 5 lbs) in
MDD Trials Using Bupropion HClSustained-Release
| Weight Change |
Bupropion HCl Sustained-Release 300 mg/day
(n=339) |
Bupropion HCl Sustained-Release 400 mg/day
(n=112) |
Placebo
(n=347) |
| Gained > 5 lbs |
3% |
2% |
4% |
| Lost > 5 lbs |
14% |
19% |
6% |
Table 6 presents the incidence of body weight changes ( ≥ 5 lbs) in the 3 SAD trials using bupropion HCl
extended-release. A higher proportion of subjects in the bupropion group (23%)
had a weight loss ≥ 5 lbs, compared to the placebo group (11%). These were
relatively long-term trials (up to 6 months).
Table 6: Incidence of Weight
Gain or Weight Loss ( ≥ 5 lbs) in
SAD Trials Using Bupropion HCl Extended-Release
| Weight Change |
Bupropion HCl Extended-Release 150 to 300 mg/day
(n=537) |
Placebo
(n=511) |
| Gained > 5 lbs |
11% |
21% |
| Lost > 5 lbs |
23% |
11% |
Postmarketing Experience
The following adverse reactions
have been identified during post-approval use of WELLBUTRIN XL. Because these
reactions are reported voluntarily from a population of uncertain size, it is
not always possible to reliably estimate their frequency or establish a causal
relationship to drug exposure.
Body (General)
Chills, facial edema, edema,
peripheral edema, musculoskeletal chest pain, photosensitivity, and malaise.
Cardiovascular
Postural hypotension,
hypertension, stroke, vasodilation, syncope, complete atrioventricular block,
extrasystoles, myocardial infarction, phlebitis, and pulmonary embolism.
Digestive
Abnormal liver function, bruxism, gastric reflux,
gingivitis, glossitis, increased salivation, jaundice, mouth ulcers,
stomatitis, thirst, edema of tongue, colitis, esophagitis, gastrointestinal
hemorrhage, gum hemorrhage, hepatitis, intestinal perforation, liver damage,
pancreatitis, and stomach ulcer.
Endocrine
Hyperglycemia, hypoglycemia, and syndrome of
inappropriate antidiuretic hormone secretion.
Hemic And Lymphatic
Ecchymosis, anemia, leukocytosis, leukopenia, lymphadenopathy,
pancytopenia, and thrombocytopenia. Altered PT and/or INR, associated with
hemorrhagic or thrombotic complications, were observed when bupropion was
coadministered with warfarin.
Metabolic And Nutritional
Glycosuria.
Musculoskeletal
Leg cramps, fever/rhabdomyolysis, and muscle weakness.
Nervous System
Abnormal coordination, depersonalization, emotional
lability, hyperkinesia, hypertonia, hypesthesia, vertigo, amnesia, ataxia,
derealization, abnormal electroencephalogram (EEG), aggression, akinesia,
aphasia, coma, dysarthria, dyskinesia, dystonia, euphoria, extrapyramidal
syndrome, hypokinesia, increased libido, neuralgia, neuropathy, paranoid
ideation, restlessness, suicide attempt, and unmasking tardive dyskinesia.
Respiratory
Bronchospasm and pneumonia.
Skin
Maculopapular rash, alopecia, angioedema, exfoliative
dermatitis, and hirsutism.
Special Senses
Accommodation abnormality, dry eye, deafness, increased
intraocular pressure, angle-closure glaucoma, and mydriasis.
Urogenital
Impotence, polyuria, prostate disorder, abnormal
ejaculation, cystitis, dyspareunia, dysuria, gynecomastia, menopause, painful
erection, salpingitis, urinary incontinence, urinary retention, and vaginitis.
Therapeutic indications
Major Depressive Disorder
WELLBUTRIN XL® (bupropion hydrochloride extended-release
tablets) is indicated for the treatment of major depressive disorder (MDD), as
defined by the Diagnostic and Statistical Manual (DSM).
The efficacy of the immediate-release
formulation of bupropion was established in two 4-week controlled inpatient
trials and one 6-week controlled outpatient trial of adult patients with MDD.
The efficacy of the sustained-release formulation of bupropion in the
maintenance treatment of MDD was established in a long-term (up to 44 weeks),
placebo-controlled trial in patients who had responded to bupropion in an
8-week study of acute treatment.
Seasonal Affective Disorder
WELLBUTRIN XL is indicated for
the prevention of seasonal major depressive episodes in patients with a
diagnosis of seasonal affective disorder (SAD).
The efficacy of bupropion hydrochloride extended-release
tablets in the prevention of seasonal major depressive episodes was established
in 3 placebo-controlled trials in adult outpatients with a history of MDD with
an autumn-winter seasonal pattern as defined in the DSM.
Pharmacokinetic properties
Bupropion is a racemic mixture. The pharmacologic
activity and pharmacokinetics of the individual enantiomers have not been
studied.
Following chronic dosing, the mean steady-state plasma
concentration of bupropion was reached within 8 days. The mean elimination
half-life (±SD) of bupropion 21 (±9) hours.
In a study comparing 14-day dosing with WELLBUTRIN XL,
300 mg once-daily to the immediate-release formulation of bupropion at 100 mg 3
times daily, equivalence was demonstrated for peak plasma concentration and
area under the curve for bupropion and the three metabolites (hydroxybupropion,
threohydrobupropion, and erythrohydrobupropion). Additionally, in a study
comparing 14-day dosing with WELLBUTRIN XL 300 mg once daily to the
sustained-release formulation of bupropion at 150 mg 2 times daily, equivalence
was demonstrated for peak plasma concentration and area under the curve for
bupropion and the three metabolites.
Absorption
Following single oral administration of WELLBUTRIN XL
tablets to healthy volunteers, the median time to peak plasma concentrations
for bupropion was approximately 5 hours. The presence of food did not affect
the peak concentration or area under the curve of bupropion.
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 of bupropion.
Metabolism
Bupropion is extensively metabolized in humans. Three
metabolites are 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 CYP2B6 is the principal
isoenzyme involved in the formation of hydroxybupropion, while cytochrome P450
enzymes 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.
At steady state, peak plasma concentration of
hydroxybupropion occurred approximately 7 hours after administration of
WELLBUTRIN XL, and it was approximately 7 times the peak level of the parent
drug. The elimination half-life of hydroxybupropion is approximately 20 (±5)
hours, and its AUC at steady state is about 13 times that of bupropion. The
times to peak concentrations for the erythrohydrobupropion and
threohydrobupropion metabolites are similar to that of hydroxybupropion.
However, the elimination half-lives of erythrohydrobupropion and
threohydrobupropion are longer, approximately 33 (±10) and 37 (±13) hours,
respectively, and steady-state AUCs were 1.4 and 7 times that of bupropion,
respectively.
Bupropion and its metabolites exhibit linear kinetics
following chronic administration of 300 to 450 mg/day.
Elimination
Following oral administration of 200 mg of 14C-bupropion
in humans, 87% and 10% of the radioactive dose were recovered in the urine and
feces, respectively. Only 0.5% of the oral dose was excreted as unchanged
bupropion.
Date of revision of the text
Aug 2016
Name of the medicinal product
Wellbutrin XL
Fertility, pregnancy and lactation
Pregnancy Category C
Risk Summary
Data from epidemiological studies including pregnant
women exposed to bupropion in the first trimester indicate no increased risk of
congenital malformations overall. All pregnancies regardless of drug exposure
have a background rate of 2% to 4% for major malformations and 15% to 20% for
pregnancy loss. No clear evidence of teratogenic activity was found in
reproductive developmental studies conducted in rats and rabbits. However, in
rabbits, slightly increased incidences of fetal malformations and skeletal
variations were observed at doses approximately equal to the maximum
recommended human dose (MRHD) and greater and decreased fetal weights were seen
at doses twice the MRHD and greater. WELLBUTRIN XL should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Clinical Considerations
Consider the risk of untreated depression when discontinuing
or changing treatment with antidepressant medications during pregnancy and
postpartum.
Human Data
Data from an international bupropion Pregnancy registry
(675 first trimester exposures) and a retrospective cohort study using the
United Healthcare database (1,213 first trimester exposures) did not show an
increased risk for malformations overall.
No increased risk for cardiovascular malformations
overall has been observed after bupropion exposure during the first trimester.
The prospectively observed rate of cardiovascular malformations in pregnancies
with exposure to bupropion in the first trimester from the international
Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester
maternal bupropion exposures), which is similar to the background rate of
cardiovascular malformations (approximately 1%). Data from the United
Healthcare database and a case-controlled study (6,853 infants with
cardiovascular malformations and 5,753 with non-cardiovascular malformations)
from the National Birth Defects Prevention Study (NBDPS) did not show an
increased risk for cardiovascular malformations overall after bupropion
exposure during the first trimester.
Study findings on bupropion exposure during the first
trimester and risk left ventricular outflow tract obstruction (LVOTO) are
inconsistent and do not allow conclusions regarding possible association. The
United Healthcare database lacked sufficient power to evaluate this
association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR =
2.6; 95% CI 1.2, 5.7) and the Slone Epidemiology case control study did not
find increased risk for LVOTO.
Study findings on bupropion exposure during the first
trimester and risk for ventricular septal defect (VSD) are inconsistent and do
not allow conclusions regarding a possible association. The Slone Epidemiology
Study found an increased risk for VSD following first trimester maternal
bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not
find an increased risk for any other cardiovascular malformations studied
(including LVOTO as above). The NBDPS and United Healthcare database study did
not find an association between first trimester maternal bupropion exposure and
VSD.
For the findings of LVOTO and VSD, the studies were
limited by the small number of exposed cases, inconsistent findings among
studies, and the potential for chance findings from multiple comparisons in
case control studies.
Animal Data
In studies conducted in rats and rabbits, bupropion was
administered orally at doses of up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis),
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/m² basis)
and greater. Decreased fetal weights were observed 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/m² basis) prior to mating
and throughout pregnancy and lactation, there were no apparent adverse effects
on offspring development.
Qualitative and quantitative composition
Dosage Forms And Strengths
WELLBUTRIN XL Extended-Release Tablets, 150 mg of
bupropion hydrochloride, are creamy-white to pale yellow, round tablets printed
with “WELLBUTRIN XL 150”.
WELLBUTRIN XL Extended-Release Tablets, 300 mg of
bupropion hydrochloride, are creamy-white to pale yellow, round tablets printed
with “WELLBUTRIN XL 300”.
Storage And Handling
WELLBUTRIN XL® Extended-Release Tablets, 150 mg of
bupropion hydrochloride, are creamy-white to pale yellow, round tablets printed
with “WELLBUTRIN XL 150” in bottles of 30 tablets (NDC 0187-0730-30)
and 90 tablets (NDC 0187-0730-90).
WELLBUTRIN XL® Extended-Release Tablets, 300 mg of
bupropion hydrochloride, are creamy-white to pale yellow, round tablets printed
with “WELLBUTRIN XL 300” in bottles of 30 (NDC 0187-0731-30).
Store at 25°C (77°F); excursions permitted to 15°-30°C
(59°-86°F).
WELLBUTRIN XL Tablets may have an odor.
Manufactured for: Valeant Pharmaceuticals North America
LLC Bridgewater, NJ 08807 USA. By: Valeant Pharmaceuticals International, Inc.
Steinbach, MB R5G 1Z7 Canada. Revised: Aug 2016
Special warnings and precautions for use
WARNINGS
Included as part of the PRECAUTIONS section.
PRECAUTIONS
Suicidal Thoughts And Behaviors In Children, Adolescents,
And Young Adults
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 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 (Selective Serotonin Reuptake Inhibitors [SSRIs] and
others) show that these drugs increase the risk of suicidal thinking and
behavior (suicidality) in children, adolescents, and young adults (ages 18 to
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 4400 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
1000 patients treated) are provided in Table 1.
Table 1: Risk Differences in the Number of Suicidality
Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants
in Pediatric and Adult Patients
| Age Range |
Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated |
| Increases Compared to Placebo |
| < 18 years |
14 additional cases |
| 18-24 years |
5 additional cases |
| Decreases Compared to Placebo |
| 25-64 years |
1 fewer case |
| > 65 years |
6 fewer cases |
No suicides occurred in any of
the pediatric trials. There were suicides in the adult trials, but the number
was not sufficient to reach any conclusion about drug effect on suicide.
It is unknown whether the suicidality
risk extends to longer-term use, i.e., beyond several months. However, there is
substantial evidence from placebo-controlled maintenance trials in adults with
depression that the use of antidepressants can delay the recurrence of
depression.
All patients being treated
with antidepressants for any indication should be monitored appropriately and
observed closely for clinical worsening, suicidality, and unusual changes in
behavior, especially during the initial few months of a course of drug therapy,
or at times of dose changes, either increases or decreases.
The following symptoms, anxiety, agitation, panic
attacks, insomnia, irritability, hostility, aggressiveness, impulsivity,
akathisia (psychomotor restlessness), hypomania, and mania, have been reported
in adult and pediatric patients being treated with antidepressants for major
depressive disorder as well as for other indications, both psychiatric and
nonpsychiatric. Although a causal link between the emergence of such symptoms
and either the worsening of depression and/or the emergence of suicidal
impulses has not been established, there is concern that such symptoms may
represent precursors to emerging suicidality.
Consideration should be given to changing the therapeutic
regimen, including possibly discontinuing the medication, in patients whose
depression is persistently worse, or who are experiencing emergent suicidality
or symptoms that might be precursors to worsening depression or suicidality,
especially if these symptoms are severe, abrupt in onset, or were not part of
the patient's presenting symptoms.
Families and caregivers of patients being treated with
antidepressants for major depressive disorder or other indications, both
psychiatric and nonpsychiatric, should be alerted about the need to monitor
patients for the emergence of agitation, irritability, unusual changes in
behavior, and the other symptoms described above, as well as the emergence of
suicidality, and to report such symptoms immediately to healthcare providers.
Such monitoring should include daily observation by families and caregivers.
Prescriptions for WELLBUTRIN XL should be written for the smallest quantity of
tablets consistent with good patient management, in order to reduce the risk of
overdose.
Neuropsychiatric Symptoms And Suicide Risk In Smoking
Cessation Treatment
WELLBUTRIN XL is not approved for smoking cessation
treatment; however, bupropion HCl sustained-release is approved for this use.
Serious neuropsychiatric symptoms have been reported in patients taking
bupropion for smoking cessation. These have included changes in mood (including
depression and mania), psychosis, hallucinations, paranoia, delusions,
homicidal ideation, hostility, agitation, aggression, anxiety, and panic, as
well as suicidal ideation, suicide attempt, and completed suicide. Observe patients for the occurrence
of neuropsychiatric reactions. Instruct patients to contact a healthcare
professional if such reactions occur.
In many of these cases, a causal relationship to
bupropion treatment is not certain, because depressed mood can be a symptom of
nicotine withdrawal. However, some of the cases occurred in patients taking
bupropion who continued to smoke.
Seizure
WELLBUTRIN XL can cause seizure. The risk of seizure is
dose-related. The dose should not exceed 300 mg once daily. Increase the dose
gradually. Discontinue WELLBUTRIN XL and do not restart treatment if the
patient experiences a seizure.
The risk of seizures is also related to patient factors,
clinical situations, and concomitant medications that lower the seizure
threshold. Consider these risks before initiating treatment with WELLBUTRIN XL.
WELLBUTRIN XL is contraindicated in patients with a seizure disorder or
conditions that increase the risk of seizure (e.g., severe head injury,
arteriovenous malformation, CNS tumor or CNS infection, severe stroke, anorexia
nervosa or bulimia, or abrupt discontinuation of alcohol, benzodiazepines, barbiturates,
and antiepileptic drugs. The following
conditions can also increase the risk of seizure: concomitant use of other
medications that lower the seizure threshold (e.g., other bupropion products,
antipsychotics, tricyclic antidepressants, theophylline, and systemic
corticosteroids), metabolic disorders (e.g., hypoglycemia, hyponatremia, severe
hepatic impairment, and hypoxia), or use of illicit drugs (e.g., cocaine) or
abuse or misuse of prescription drugs such as CNS stimulants. Additional
predisposing conditions include diabetes mellitus treated with oral
hypoglycemic drugs or insulin, use of anorectic drugs, excessive use of
alcohol, benzodiazepines, sedative/hypnotics, or opiates.
Incidence Of Seizure With Bupropion Use
The incidence of seizure with WELLBUTRIN XL has not been
formally evaluated in clinical trials. In studies using bupropion HCl
sustained-release up to 300 mg per day the incidence of seizure was
approximately 0.1% (1/1000 patients). In a large prospective, follow-up study,
the seizure incidence was approximately 0.4% (13/3200) with bupropion HCl
immediate-release in the range of 300 mg to 450 mg per day.
Additional data accumulated for bupropion
immediate-release suggests that the estimated seizure incidence increases
almost tenfold between 450 and 600 mg/day. The risk of seizure can be reduced
if the WELLBUTRIN XL dose does not exceed 450 mg once daily and the titration
rate is gradual.
Hypertension
Treatment with WELLBUTRIN XL can result in elevated blood
pressure and hypertension.
Assess blood pressure before initiating treatment with
WELLBUTRIN XL, and monitor periodically during treatment. The risk of
hypertension is increased if WELLBUTRIN XL is used concomitantly with MAOIs or
other drugs that increase dopaminergic or noradrenergic activity.
Data from a comparative trial of the sustained-release
formulation of bupropion HCl, 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 trial, 6.1% of subjects treated with the combination of
sustained-release bupropion and NTS had treatment-emergent hypertension
compared to 2.5%, 1.6%, and 3.1% of subjects treated with sustained-release
bupropion, NTS, and placebo, respectively. The majority of these subjects had
evidence of pre-existing hypertension. Three subjects (1.2%) treated with the
combination of sustained-release bupropion and NTS and 1 subject (0.4%) treated
with NTS had study medication discontinued due to hypertension compared with
none of the subjects treated with sustained-release bupropion or placebo.
Monitoring of blood pressure is recommended in patients who receive the
combination of bupropion and nicotine replacement.
In the 3 trials of bupropion HCl extended-release in
seasonal affective disorder, there were significant elevations in blood pressure.
Hypertension was reported as an adverse reaction for 2% of the bupropion group
(11/537) and none in the placebo group (0/511). In the SAD trials, 2 patients
treated with bupropion discontinued from the study because they developed
hypertension. None of the placebo group discontinued because of hypertension.
The mean increase in systolic blood pressure was 1.3 mmHg in the bupropion
group and 0.1 mmHg in the placebo group. The difference was statistically
significant (p=0.013). The mean increase in diastolic blood pressure was 0.8
mmHg in the bupropion group and 0.1 mmHg in the placebo group. The difference
was not statistically significant (p=0.075). In the SAD trials, 82% of patients
were treated with 300 mg per day, and 18% were treated with 150 mg per day. The
mean daily dose was 270 mg per day. The mean duration of bupropion exposure was
126 days.
In a clinical trial of bupropion immediate-release in MDD
subjects with stable congestive heart failure (N=36), bupropion was associated
with an exacerbation of pre-existing hypertension in 2 subjects, leading to
discontinuation of bupropion treatment. There are no controlled studies
assessing the safety of bupropion in patients with a recent history of
myocardial infarction or unstable cardiac disease.
Activation Of Mania/Hypomania
Antidepressant treatment can precipitate a manic, mixed,
or hypomanic manic episode. The risk appears to be increased in patients with
bipolar disorder or who have risk factors for bipolar disorder. Prior to
initiating WELLBUTRIN XL, screen patients for a history of bipolar disorder and
the presence of risk factors for bipolar disorder (e.g., family history of
bipolar disorder, suicide, or depression). WELLBUTRIN XL is not approved for
the treatment of bipolar depression.
Psychosis And Other Neuropsychiatric Reactions
Depressed patients treated with bupropion have had a
variety of neuropsychiatric signs and symptoms, including delusions,
hallucinations, psychosis, concentration disturbance, paranoia, and confusion.
Some of these patients had a diagnosis of bipolar disorder. In some cases,
these symptoms abated upon dose reduction and/or withdrawal of treatment.
Discontinue WELLBUTRIN XL if these reactions occur.
Angle-Closure Glaucoma
Angle-Closure Glaucoma: The pupillary dilation that
occurs following use of many antidepressant drugs including WELLBUTRIN XL may
trigger an angle-closure attack in a patient with anatomically narrow angles
who does not have a patent iridectomy.
Hypersensitivity Reactions
Anaphylactoid/anaphylactic reactions have occurred during
clinical trials with bupropion. Reactions have been characterized by pruritus,
urticaria, angioedema, and dyspnea, requiring medical treatment. In addition,
there have been rare, spontaneous postmarketing reports of erythema multiforme,
Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion.
Instruct patients to discontinue WELLBUTRIN XL and consult a healthcare
provider if they develop an allergic or anaphylactoid/anaphylactic reaction
(e.g., skin rash, pruritus, hives, chest pain, edema, and shortness of breath)
during treatment.
There are reports of arthralgia, myalgia, fever with rash
and other symptoms of serum sickness suggestive of delayed hypersensitivity.
Patient Counseling Information
Advise the patient to read the FDA-approved patient
labeling (Medication Guide).
Inform patients, their families, and their caregivers
about the benefits and risks associated with treatment with WELLBUTRIN XL and
counsel them in its appropriate use.
A patient Medication Guide about “Antidepressant
Medicines, Depression and Other Serious Mental Illnesses, and Suicidal Thoughts
or Actions,” “Quitting Smoking, Quit-Smoking Medications, Changes in Thinking
and Behavior, Depression, and Suicidal Thoughts or Actions,” and “What Other
Important Information Should I Know About WELLBUTRIN XL?” is available for
WELLBUTRIN XL. Instruct patients, their families, and their caregivers to read
the Medication Guide and 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.
Advise patients regarding the following issues and to
alert their prescriber if these occur while taking WELLBUTRIN XL.
Suicidal Thoughts And Behaviors
Instruct patients, their families, and/or their
caregivers 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.
Advise families and caregivers of patients to observe 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.
Neuropsychiatric Symptoms And Suicide Risk In Smoking
Cessation Treatment
Although WELLBUTRIN XL is not indicated for smoking
cessation treatment, it contains the same active ingredient as ZYBAN® which is
approved for this use. Advise patients, families and caregivers that quitting
smoking, with or without ZYBAN, may trigger nicotine withdrawal symptoms (e.g.,
including depression or agitation) or worsen pre-existing psychiatric illness.
Some patients have experienced changes in mood (including depression and
mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation,
aggression, anxiety, and panic, as well as suicidal ideation, suicide attempt,
and completed suicide when attempting to quit smoking while taking ZYBAN. If
patients develop agitation, hostility, depressed mood, or changes in thinking
or behavior that are not typical for them, or if patients develop suicidal
ideation or behavior, they should be urged to report these symptoms to their
healthcare provider immediately.
Severe Allergic Reactions
Educate patients on the symptoms of hypersensitivity and
to discontinue WELLBUTRIN XL if they have a severe allergic reaction.
Seizure
Instruct patients to discontinue and not restart
WELLBUTRIN XL if they experience a seizure while on treatment. Advise patients
that the excessive use or the abrupt discontinuation of alcohol, benzodiazepines,
antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure.
Advise patients to minimize or avoid the use of alcohol.
Angle-Closure Glaucoma
Patients should be advised that taking WELLBUTRIN XL can
cause mild pupillary dilation, which in susceptible individuals, can lead to an
episode of angle-closure glaucoma. Pre-existing glaucoma is almost always
open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be
treated definitively with iridectomy. Open-angleglaucoma is not a risk factor
for angle-closure glaucoma. Patients may wish to be examined to determine
whether they are susceptible to angle closure, and have a prophylactic
procedure (e.g., iridectomy), if they are susceptible.
Bupropion-Containing Products
Educate patients that WELLBUTRIN XL contains the same
active ingredient (bupropion) found in ZYBAN, which is used as an aid to
smoking cessation treatment, and that WELLBUTRIN XL should not be used in
combination with ZYBAN or any other medications that contain bupropion
hydrochloride (such as WELLBUTRIN SR, the sustained-release formulation,
WELLBUTRIN, the immediate-release formulation, and APLENZIN, a bupropion
hydrobromide formulation). In addition, there are a number of generic bupropion
HCl products for the immediate, sustained, and extended-release formulations.
Potential For Cognitive And Motor Impairment
Advise patients that any CNS-active drug like WELLBUTRIN
XL Tablets may impair their ability to perform tasks requiring judgment or
motor and cognitive skills. Advise patients that until they are reasonably
certain that WELLBUTRIN XL Tablets do not adversely affect their performance,
they should refrain from driving an automobile or operating complex, hazardous
machinery. WELLBUTRIN XL treatment may lead to decreased alcohol tolerance.
Concomitant Medications
Counsel patients to notify their healthcare provider if
they are taking or plan to take any prescription or over-the-counter drugs,
because WELLBUTRIN XL Tablets and other drugs may affect each other's
metabolism.
Pregnancy
Advise patients to notify their healthcare provider if
they become pregnant or intend to become pregnant during therapy.
Precautions For Nursing Mothers
Communicate with the patient and pediatric healthcare
provider regarding the infant's exposure to bupropion through human milk.
Instruct patients to immediately contact the infant's healthcare provider if
they note any side effect in the infant that concerns them or is persistent.
Administration Information
Instruct patients to swallow WELLBUTRIN XL Tablets whole
so that the release rate is not altered. Instruct patients if they miss a dose,
not to take an extra tablet to make up for the missed dose and to take the next
tablet at the regular time because of the dose-related risk of seizure.
Instruct patients that WELLBUTRIN XL tablets should be swallowed whole and not
crushed, divided, or chewed. WELLBUTRIN XL should be administered in the
morning and may be taken with or without food.
Nonclinical Toxicology
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Lifetime carcinogenicity studies were performed in rats
and mice at doses up to 300 and 150 mg/kg/day bupropion hydrochloride,
respectively. These doses are approximately 7 and 2 times the maximum
recommended human dose (MRHD), respectively, on a mg/m² basis. In
the rat study there was an increase in nodular proliferative lesions of the
liver at doses of 100 to 300 mg/kg/day of bupropion hydrochloride
(approximately 2 to 7 times the MRHD on a mg/m² basis); 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 one Ames bacterial mutagenicity
assay, but was negative in another. Bupropion produced 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.
Use In Specific Populations
Pregnancy
Pregnancy Category C
Risk Summary
Data from epidemiological studies including pregnant
women exposed to bupropion in the first trimester indicate no increased risk of
congenital malformations overall. All pregnancies regardless of drug exposure
have a background rate of 2% to 4% for major malformations and 15% to 20% for
pregnancy loss. No clear evidence of teratogenic activity was found in
reproductive developmental studies conducted in rats and rabbits. However, in
rabbits, slightly increased incidences of fetal malformations and skeletal
variations were observed at doses approximately equal to the maximum
recommended human dose (MRHD) and greater and decreased fetal weights were seen
at doses twice the MRHD and greater. WELLBUTRIN XL should be used during
pregnancy only if the potential benefit justifies the potential risk to the
fetus.
Clinical Considerations
Consider the risk of untreated depression when discontinuing
or changing treatment with antidepressant medications during pregnancy and
postpartum.
Human Data
Data from an international bupropion Pregnancy registry
(675 first trimester exposures) and a retrospective cohort study using the
United Healthcare database (1,213 first trimester exposures) did not show an
increased risk for malformations overall.
No increased risk for cardiovascular malformations
overall has been observed after bupropion exposure during the first trimester.
The prospectively observed rate of cardiovascular malformations in pregnancies
with exposure to bupropion in the first trimester from the international
Pregnancy Registry was 1.3% (9 cardiovascular malformations/675 first-trimester
maternal bupropion exposures), which is similar to the background rate of
cardiovascular malformations (approximately 1%). Data from the United
Healthcare database and a case-controlled study (6,853 infants with
cardiovascular malformations and 5,753 with non-cardiovascular malformations)
from the National Birth Defects Prevention Study (NBDPS) did not show an
increased risk for cardiovascular malformations overall after bupropion
exposure during the first trimester.
Study findings on bupropion exposure during the first
trimester and risk left ventricular outflow tract obstruction (LVOTO) are
inconsistent and do not allow conclusions regarding possible association. The
United Healthcare database lacked sufficient power to evaluate this
association; the NBDPS found increased risk for LVOTO (n = 10; adjusted OR =
2.6; 95% CI 1.2, 5.7) and the Slone Epidemiology case control study did not
find increased risk for LVOTO.
Study findings on bupropion exposure during the first
trimester and risk for ventricular septal defect (VSD) are inconsistent and do
not allow conclusions regarding a possible association. The Slone Epidemiology
Study found an increased risk for VSD following first trimester maternal
bupropion exposure (n = 17; adjusted OR = 2.5; 95% CI: 1.3, 5.0) but did not
find an increased risk for any other cardiovascular malformations studied
(including LVOTO as above). The NBDPS and United Healthcare database study did
not find an association between first trimester maternal bupropion exposure and
VSD.
For the findings of LVOTO and VSD, the studies were
limited by the small number of exposed cases, inconsistent findings among
studies, and the potential for chance findings from multiple comparisons in
case control studies.
Animal Data
In studies conducted in rats and rabbits, bupropion was
administered orally at doses of up to 450 and 150 mg/kg/day, respectively
(approximately 11 and 7 times the MRHD, respectively, on a mg/m² basis),
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/m² basis)
and greater. Decreased fetal weights were observed 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/m² basis) prior to mating
and throughout pregnancy and lactation, there were no apparent adverse effects
on offspring development.
Nursing Mothers
Bupropion and its metabolites are present in human milk.
In a lactation study of ten women, levels of orally dosed bupropion and its
active metabolites were measured in expressed milk. The average daily infant
exposure (assuming 150 mL/kg daily consumption) to bupropion and its active
metabolites was 2% of the maternal weight-adjusted dose. Exercise caution when
WELLBUTRIN XL is administered to a nursing woman.
Pediatric Use
Safety and effectiveness in the pediatric population have
not been established. When considering the use of WELLBUTRIN XL in a child or
adolescent, balance the potential risks with the clinical need.
Geriatric Use
Of the approximately 6000 patients who participated in clinical
trials with bupropion hydrochloride sustained-release tablets (depression and
smoking cessation studies), 275 were ≥ 65 years old and 47 were ≥ 75
years old. In addition, several hundred patients ≥ 65 years of age
participated in clinical trials using the immediate-release formulation of
bupropion hydrochloride (depression studies). No overall differences in safety
or effectiveness were observed between these subjects and younger subjects.
Reported clinical experience has not identified differences in responses
between the elderly and younger patients, but greater sensitivity of some older
individuals cannot be ruled out.
Bupropion is extensively metabolized in the liver to
active metabolites, which are further metabolized and excreted by the kidneys.
The risk of adverse reactions may be greater in patients with impaired renal
function. Because elderly patients are more likely to have decreased renal
function, it may be necessary to consider this factor in dose selection; it may
be useful to monitor renal function.
Renal Impairment
Consider a reduced dose and/or dosing frequency of
WELLBUTRIN XL in patients with renal impairment (Glomerular Filtration Rate:
< 90 mL/min). Bupropion and its metabolites are cleared renally and may
accumulate in such patients to a greater extent than usual. Monitor closely for
adverse reactions that could indicate high bupropion or metabolite exposures.
Hepatic Impairment
In patients with moderate to severe hepatic impairment
(Child-Pugh score: 7 to 15), the maximum WELLBUTRIN XL dose is 150 mg every
other day. In patients with mild hepatic impairment (Child-Pugh score: 5 to 6),
consider reducing the dose and/or frequency of dosing.
Dosage (Posology) and method of administration
General Instructions For Use
To minimize the risk of seizure, increase the dose
gradually.
WELLBUTRIN XL should be swallowed whole and not crushed,
divided, or chewed.
WELLBUTRIN XL should be administered in the morning and
may be taken with or without food.
Dosage For Major Depressive Disorder (MDD)
The recommended starting dose for MDD is 150 mg once
daily in the morning. After 4 days of dosing, the dose may be increased to the
target dose of 300 mg once daily in the morning.
It is generally agreed that acute episodes of depression
require several months or longer of antidepressant treatment beyond the
response in the acute episode. It is unknown whether the WELLBUTRIN XL dose
needed for maintenance treatment is identical to the dose that provided an
initial response. Periodically reassess the need for maintenance treatment and
the appropriate dose for such treatment.
Dosage For Seasonal Affective Disorder (SAD)
The recommended starting dose for SAD is 150 mg once
daily. After 7 days of dosing, the dose may be increased to the target dose of
300 mg once daily in the morning. Doses above 300 mg of bupropion HCl
extended-release were not assessed in the SAD trials.
For the prevention of seasonal MDD episodes associated
with SAD, initiate WELLBUTRIN XL in the autumn, prior to the onset of depressive
symptoms. Continue treatment through the winter season. Taper and discontinue
WELLBUTRIN XL in early spring. For patients treated with 300 mg per day,
decrease the dose to 150 mg once daily before discontinuing WELLBUTRIN XL.
Individualize the timing of initiation, and duration of treatment should be
individualized, based on the patient's historical pattern of seasonal MDD
episodes.
Switching Patients From WELLBUTRIN Tablets Or From
WELLBUTRIN SR Sustained-Release Tablets
When switching patients from WELLBUTRIN Tablets to
WELLBUTRIN XL or from WELLBUTRIN SR Sustained-Release Tablets to WELLBUTRIN XL,
give the same total daily dose when possible.
To Discontinue WELLBUTRIN XL, Taper The Dose
When discontinuing treatment in patients treated with WELLBUTRIN
XL 300 mg once daily, decrease the dose to 150 mg once daily prior to
discontinuation.
Dosage Adjustment In Patients With Hepatic Impairment
In patients with moderate to severe hepatic impairment
(Child-Pugh score: 7 to 15), the maximum dose is 150 mg every other day. In
patients with mild hepatic impairment (Child-Pugh score: 5 to 6), consider
reducing the dose and/or frequency of dosing.
Dose Adjustment In Patients With Renal Impairment
Consider reducing the dose and/or frequency of WELLBUTRIN
in patients with renal impairment (Glomerular Filtration Rate less than 90
mL/min).
Switching A Patient To Or From A Monoamine Oxidase
Inhibitor (MAOI) Antidepressant
At least 14 days should elapse between discontinuation of
an MAOI intended to treat depression and initiation of therapy with WELLBUTRIN
XL. Conversely, at least 14 days should be allowed after stopping WELLBUTRIN XL
before starting an MAOI antidepressant.
Use Of WELLBUTRIN XL With Reversible MAOIs Such As
Linezolid Or Methylene Blue
Do not start WELLBUTRIN XL in a patient who is being
treated with a reversible MAOI such as linezolid or intravenous methylene blue.
Drug interactions can increase risk of hypertensive reactions. In a patient who
requires more urgent treatment of a psychiatric condition, non-pharmacological
interventions, including hospitalization, should be considered.
In some cases, a patient already receiving therapy with
WELLBUTRIN XL may require urgent treatment with linezolid or intravenous
methylene blue. If acceptable alternatives to linezolid or intravenous
methylene blue treatment are not available and the potential benefits of
linezolid or intravenous methylene blue treatment are judged to outweigh the
risks of hypertensive reactions in a particular patient, WELLBUTRIN XL should
be stopped promptly, and linezolid or intravenous methylene blue can be
administered. The patient should be monitored for 2 weeks or until 24 hours
after the last dose of linezolid or intravenous methylene blue, whichever comes
first. Therapy with WELLBUTRIN XL may be resumed 24 hours after the last dose of
linezolid or intravenous methylene blue.
The risk of administering methylene blue by
non-intravenous routes (such as oral tablets or by local injection) or in
intravenous doses much lower than 1 mg per kg with WELLBUTRIN XL is unclear.
The clinician should, nevertheless, be aware of the possibility of a drug
interaction with such use.
Interaction with other medicinal products and other forms of interaction
Potential for Other Drugs to Affect WELLBUTRIN XL
In vitro studies indicate that bupropion is primarily
metabolized to hydroxybupropion by CYP2B6. Therefore, the potential exists for
drug interactions between WELLBUTRIN XL and drugs that are inhibitors or
inducers of CYP2B6. In addition, in vitro studies suggest that paroxetine,
sertraline, norfluoxetine, fluvoxamine, and nelfinavir inhibit the
hydroxylation of bupropion.
Inhibitors Of CYP2B6
Ticlopidine and Clopidogrel: In a study in healthy
male volunteers, clopidogrel 75 mg once daily or ticlopidine 250 mg twice daily
increased exposures (Cmax and AUC) of bupropion by 40% and 60% for clopidogrel,
by 38% and 85% for ticlopidine, respectively. The exposures of hydroxybupropion
were decreased.
Prasugrel: In healthy subjects, prasugrel
increased bupropion Cmax and AUC values by 14% and 18%, respectively, and
decreased Cmax and AUC values of hydroxybupropion by 32% and 24%, respectively.
Cimetidine: Following oral administration of
bupropion 300 mg with and without cimetidine 800 mg in 24 healthy young male
volunteers, the pharmacokinetics of bupropion and hydroxybupropion were
unaffected. However, there were 16% and 32% increases in the AUC and Cmax,
respectively, of the combined moieties of threohydrobupropion and
erythrohydrobupropion.
Citalopram: Citalopram did not affect the
pharmacokinetics of bupropion and its three metabolites.
Inducers Of CYP2B6
Ritonavir and Lopinavir: In a healthy volunteer
study, ritonavir 100 mg twice daily reduced the AUC and Cmax of bupropion by
22% and 21%, respectively. The exposure of the hydroxybupropion metabolite was
decreased by 23%, the threohydrobupropion decreased by 38%, and the
erythrohydrobupropion decreased by 48%. In a second healthy volunteer study,
ritonavir 600 mg twice daily decreased the AUC and Cmax of bupropion by 66% and
62%, respectively. The exposure of the hydroxybupropion metabolite was
decreased by 78%, the threohydrobupropion decreased by 50%, and the
erythrohydrobupropion decreased by 68%.
In another healthy volunteer study, lopinavir 400
mg/ritonavir 100 mg twice daily decreased bupropion AUC and Cmax by 57%. The
AUC and Cmax of hydroxybupropion metabolite were decreased by 50% and 31%,
respectively.
Efavirenz: In a study of healthy volunteers,
efavirenz 600 mg once daily for 2 weeks reduced the AUC and Cmax of bupropion
by approximately 55% and 34%, respectively. The AUC of hydroxybupropion was
unchanged, whereas Cmax of hydroxybupropion was increased by 50%.
Carbamazepine, Phenobarbital, Phenytoin: While not
systematically studied, these drugs may induce the metabolism of bupropion.
Potential for WELLBUTRIN XL to Affect Other Drugs
Animal data indicated that bupropion may be an inducer of
drug-metabolizing enzymes in humans. In a study of 8 healthy male volunteers,
following a 14-day administration of bupropion 100 mg three times per day,
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.
Drugs Metabolized By CYP2D6
In vitro, bupropion and hydroxybupropion are CYP2D6
inhibitors. In a clinical study of 15 male subjects (ages 19 to 35 years) who
were extensive metabolizers of CYP2D6, bupropion given as 150 mg twice daily
followed by a single dose of 50 mg desipramine increased the Cmax, AUC, and
T½ of 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.
Citalopram: Although citalopram is not primarily
metabolized by CYP2D6, in one study bupropion increased the Cmax and AUC of
citalopram by 30% and 40%, respectively.
Lamotrigine: Multiple oral doses of bupropion had
no statistically significant effects on the single-dose pharmacokinetics of
lamotrigine in 12 healthy volunteers.
