Included as part of the PRECAUTIONS section.
Suicidal Thoughts And Behaviors In Children, Adolescents,
And Young Adults
Patients with 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
Pooled analyses of short-term, placebo-controlled trials
of antidepressant drugs (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 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 (Years)
||Drug-Placebo Difference in Number of Cases of Suicidality per 1000 Patients Treated
|Increases Compared to Placebo
| < 18
||14 additional cases
||5 additional cases
|Decreases Compared to Placebo
||1 fewer case
| > 65
||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, ie, 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 [see BOXED WARNING and Use in Specific Populations].
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 MDD 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
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 MDD 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 [see PATIENT INFORMATION]. Prescriptions for FORFIVO XL should be written for the
smallest quantity of tablets consistent with good patient management, in order
to reduce the risk of overdose.
Neuropsychiatric Adverse Events And Suicide Risk In
Smoking Cessation Treatment
FORFIVO XL is not approved for smoking cessation
treatment, but bupropion hydrochloride sustained-release is approved for this
use. Serious neuropsychiatric adverse events have been reported in patients
taking bupropion for smoking cessation. These postmarketing reports have included
changes in mood (including depression and mania), psychosis, hallucinations,
paranoia, delusions, homicidal ideation, aggression, hostility, agitation,
anxiety, and panic, as well as suicidal ideation, suicide attempt, and
completed suicide [see ADVERSE REACTIONS]. Some patients who stopped
smoking may have been experiencing symptoms of nicotine withdrawal, including
depressed mood. Depression, rarely including suicidal ideation, has been
reported in smokers undergoing a smoking cessation attempt without medication.
However, some of these adverse events occurred in patients taking bupropion who
continued to smoke.
Neuropsychiatric adverse events occurred in patients
without and with pre-existing psychiatric disease; some patients experienced
worsening of their psychiatric illnesses. Observe patients for the occurrence
of neuropsychiatric adverse events. Advise patients and caregivers that the
patient should stop taking FORFIVO XL and contact a healthcare provider
immediately if agitation, depressed mood, or changes in behavior or thinking
that are not typical for the patient are observed, or if the patient develops
suicidal ideation or suicidal behavior. In many postmarketing cases, resolution
of symptoms after discontinuation of bupropion was reported. However, the symptoms
persisted in some cases; therefore, ongoing monitoring and supportive care
should be provided until symptoms resolve.
Bupropion can cause seizure. The risk of seizure is dose
related. FORFIVO XL should be discontinued and not restarted in patients who
experience a seizure while on treatment.
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 FORFIVO XL.
FORFIVO XL is contraindicated in patients with a seizure disorder or conditions
that increase the risk of seizure (eg, severe head injury, arteriovenous
malformation, central nervous system [CNS] tumor or CNS infection, severe
stroke, anorexia nervosa or bulimia, or abrupt discontinuation of alcohol,
benzodiazepines, barbiturates, and antiepileptic drugs) [see CONTRAINDICATIONS].
The following conditions can also increase the risk of seizure: concomitant use
of other medications that lower the seizure threshold (eg, other bupropion products,
antipsychotics, tricyclic antidepressants, theophylline, and systemic corticosteroids),
metabolic disorders (eg, hypoglycemia, hyponatremia, severe hepatic impairment,
and hypoxia), or use of illicit drugs (eg, 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, use of benzodiazepines,
sedatives/hypnotics, or opiates.
Incidence Of Seizure With Bupropion Use
The incidence of seizure with bupropion extended-release
has not been formally evaluated in clinical trials. In studies using bupropion
hydrochloride sustained-release up to 300 mg/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 patients) with bupropion hydrochloride
immediate-release in the range of 300 to 450 mg/day.
Additional data accumulated for bupropion
immediate-release suggests that the estimated seizure incidence increases
almost tenfold between 450 and 600 mg/day. The 600-mg dose is twice the usual
adult dose and one and one-third the maximum recommended daily dose (450 mg) of
FORFIVO XL. This disproportionate increase in seizure incidence with dose
incrementation calls for caution in dosing.
Treatment with FORFIVO XL can result in elevated blood
pressure and hypertension. Assess blood pressure before initiating treatment
with FORFIVO XL, and monitor periodically during treatment. The risk of
hypertension is increased if FORFIVO XL is used concomitantly with MAOIs or
other drugs that increase dopaminergic or noradrenergic activity [see CONTRAINDICATIONS].
Data from a comparative trial of the sustained-release
formulation of bupropion hydrochloride, nicotine transdermal system (NTS), the
combination of sustained-release bupropion hydrochloride 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
hydrochloride 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 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 patients,
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 FORFIVO XL, screen patients for a history of bipolar disorder and the
presence of risk factors for bipolar disorder (eg, family history of bipolar
disorder, suicide, or depression). FORFIVO 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 FORFIVO XL if these reactions occur.
Angle-closure Glaucoma: The pupillary dilation that
occurs following use of many antidepressant drugs including FORFIVO XL may
trigger an angle closure attack in a patient with anatomically narrow angles
who does not have a patent iridectomy.
Anaphylactoid/anaphylactic reactions have occurred during
clinical trials with bupropion. Reactions have been characterized by symptoms
such as 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 FORFIVO XL and
consult a healthcare provider if they develop an allergic or
anaphylactoid/anaphylactic reaction (eg, 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
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 FORFIVO 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 FORFIVO XL” is available for FORFIVO
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 FORFIVO 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 Adverse Events and Suicide Risk In Smoking
Although FORFIVO XL is not indicated for smoking
cessation treatment, it contains the same active ingredient as ZYBAN® which is
approved for this use. Inform patients that some patients have experienced
changes in mood (including depression and mania), psychosis, hallucinations, paranoia,
delusions, homicidal ideation, aggression, hostility, agitation, anxiety, and
panic, as well as suicidal ideation and suicide when attempting to quit smoking
while taking bupropion. Instruct patients to discontinue FORFIVO XL and contact
a healthcare professional if they experience such symptoms.
Severe Allergic Reactions
Educate patients on the symptoms of hypersensitivity and
to discontinue FORFIVO XL if they have a severe allergic reaction.
Instruct patients to discontinue and not restart FORFIVO
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 avoid the use of alcohol.
Patients should be advised that taking FORFIVO 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-angle glaucoma 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 (eg,
iridectomy), if they are susceptible [see WARNINGS AND PRECAUTIONS].
Educate patients that FORFIVO XL contains the same active
ingredient (bupropion) found in ZYBAN, which is used as an aid to smoking
cessation treatment, and that FORFIVO XL should not be used in combination with
ZYBAN or any other medications that contain bupropion hydrochloride (such as
WELLBUTRIN XL, the extended-release formulation; 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 hydrochloride products for the immediate-, sustained-,
and extended-release formulations.
Potential For Cognitive And Motor Impairment
Advise patients that any CNS-active drug like FORFIVO 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 FORFIVO XL tablets do not adversely affect their performance, they should
refrain from driving an automobile or operating complex, hazardous machinery. FORFIVO
XL treatment may lead to decreased alcohol tolerance.
Counsel patients to notify their healthcare provider if
they are taking or plan to take any prescription or over-the-counter drugs,
because FORFIVO XL tablets and other drugs may affect each other's metabolism.
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.
Instruct patients to swallow FORFIVO XL tablets whole so
that the release rate is not altered. Instruct patients that FORFIVO XL tablets
should not be chewed, divided, or crushed. FORFIVO XL may be taken with or
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 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 Category C.
Data from epidemiological studies including pregnant
women exposed to bupropion in the first trimester indicate no increased risk of
congenital malformations. 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.
FORFIVO XL should be used during pregnancy only if the potential benefit
justifies the potential risk to the fetus.
Consider the risk of untreated depression when
discontinuing or changing treatment with antidepressant medications during
pregnancy and postpartum.
Data from the international bupropion Pregnancy Registry
(675 first-trimester exposures) and a retrospective cohort study using the
United Healthcare database (1213 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-control study (6853 infants with cardiovascular
malformations and 5753 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 for 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
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.
Bupropion and its metabolites are present in human milk.
In a lactation study of 10 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 FORFIVO
XL is administered to a nursing woman.
Safety and effectiveness in the pediatric population have
not been established. When considering the use of FORFIVO XL in a child or
adolescent, balance the potential risks with the clinical need [see BOXED
WARNING, and WARNINGS AND PRECAUTIONS].
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 of age
and 47 were ≥ 75 years of age. 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 [see DOSAGE AND ADMINISTRATION, Use in
Specific Populations, and CLINICAL PHARMACOLOGY].
Because there is no lower strength for FORFIVO XL,
FORFIVO XL is not recommended in patients with renal impairment [see CLINICAL
Because there is no lower strength for FORFIVO XL,
FORFIVO XL is not recommended in patients with hepatic impairment [see CLINICAL