Included as part of the PRECAUTIONS section.
Suicidal Behavior And Ideation
CONTRAVE contains bupropion, a dopamine and
norepinephrine re-uptake inhibitor that is similar to some drugs used for the
treatment of depression; therefore, the following precautions pertaining to
these products should be considered when treating patients with CONTRAVE.
Patients with major depressive disorder, 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.
In placebo-controlled clinical trials with CONTRAVE for
the treatment of obesity in adult patients, no suicides or suicide attempts
were reported in studies up to 56 weeks duration with CONTRAVE (equivalent to
bupropion doses of 360 mg/day). In these same studies, suicidal ideation was
reported by 3 (0.20%) of 1,515 patients treated with placebo compared with 1
(0.03%) of 3,239 treated with CONTRAVE.
Pooled analyses of short-term placebo-controlled trials
of antidepressant drugs (selective serotonin re-uptake 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
clinical trials did not show an increase in the risk of suicidality with
antidepressants compared with placebo in adults beyond age 24; there was a
reduction with antidepressants compared with placebo in adults aged 65 and
The pooled analyses of placebo-controlled trials of
antidepressant drugs in children and adolescents with MDD, obsessive compulsive
disorder (OCD), or other psychiatric disorders included a total of 24
short-term trials of nine 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 two 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 2.
Table 2: Risk Differences in the Number of Suicidality
Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants
in Pediatric and Adult Subjects
||Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated
|Increases Compared to Placebo
| < 18
||14 additional cases
|18 to 24
||5 additional cases
|Decreases Compared to Placebo
|25 to 64
||1 fewer case
| > 65
||6 fewer cases
No suicides occurred in any of the antidepressant
pediatric trials. There were suicides in the adult antidepressant trials, but
the number was not sufficient to reach any conclusion about drug effect on
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 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. This warning applies to CONTRAVE
because one of its components, bupropion, is a member of an antidepressant
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 anxiety, 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 CONTRAVE 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
CONTRAVE is not approved for smoking cessation treatment,
but 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 Suicidal Behavior and Ideation]. 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 CONTRAVE 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.
Depression, suicide, attempted suicide and suicidal
ideation have been reported in the postmarketing experience with naltrexone
used in the treatment of opioid dependence. No causal relationship has been
Bupropion, a component of CONTRAVE, can cause seizures.
The risk of seizure is dose-related. The incidence of seizure in patients
receiving CONTRAVE in clinical trials was approximately 0.1% vs 0% on placebo.
CONTRAVE should be discontinued and not restarted in patients who experience a
seizure while being treated with CONTRAVE.
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 CONTRAVE.
CONTRAVE is contraindicated in patients with a seizure disorder, current or
prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt
discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic
drugs. Caution should be used when prescribing CONTRAVE to patients with
predisposing factors that may increase the risk of seizure including:
- history of head trauma or prior seizure, severe stroke,
arteriovenous malformation, central nervous system tumor or infection, or
metabolic disorders (e.g., hypoglycemia, hyponatremia, severe hepatic
impairment, and hypoxia)
- excessive use of alcohol or sedatives, addiction to
cocaine or stimulants, or withdrawal from sedatives
- patients with diabetes treated with insulin and/or oral
diabetic medications (sulfonylureas and meglitinides) that may cause
- concomitant administration of medications that may lower
the seizure threshold, including other bupropion products, antipsychotics,
tricyclic antidepressants, theophylline, systemic steroids
Recommendations For Reducing The Risk of Seizure
experience with bupropion suggests that the risk of seizure may be minimized by
adhering to the recommended dosing recommendations [see DOSAGE AND
ADMINISTRATION], in particular:
- the total daily dose of CONTRAVE does not exceed 360 mg
of the bupropion component (i.e., four tablets per day)
- the daily dose is administered in divided doses (twice
- the dose is escalated gradually
- no more than two tablets are taken at one time
- coadministration of CONTRAVE with high-fat meals is
avoided [see DOSAGE AND ADMINISTRATION and CLINICAL PHARMACOLOGY]
- if a dose is missed, a patient should wait until the next
scheduled dose to resume the regular dosing schedule
Patients Receiving Opioid Analgesics
Vulnerability To Opioid Overdose
CONTRAVE should not be administered to patients receiving
chronic opioids, due to the naltrexone component, which is an opioid receptor
antagonist [see CONTRAINDICATIONS]. If chronic opiate therapy is
required, CONTRAVE treatment should be stopped. In patients requiring
intermittent opiate treatment, CONTRAVE therapy should be temporarily
discontinued and lower doses of opioids may be needed. Patients should be
alerted that they may be more sensitive to opioids, even at lower doses, after
CONTRAVE treatment is discontinued.
An attempt by a patient to overcome any naltrexone opioid
blockade by administering large amounts of exogenous opioids is especially
dangerous and may lead to a fatal overdose or life-threatening opioid
intoxication (e.g., respiratory arrest, circulatory collapse). Patients should
be told of the serious consequences of trying to overcome the opioid blockade.
Precipitated Opioid Withdrawal
The symptoms of spontaneous opioid withdrawal, which are
associated with the discontinuation of opioid in a dependent individual, are
uncomfortable, but they are not generally believed to be severe or necessitate
hospitalization. However, when withdrawal is precipitated abruptly, the
resulting withdrawal syndrome can be severe enough to require hospitalization.
To prevent occurrence of either precipitated withdrawal in patients dependent
on opioids or exacerbation of a pre-existing subclinical withdrawal symptoms,
opioid-dependent patients, including those being treated for alcohol
dependence, should be opioid-free (including tramadol) before starting CONTRAVE
treatment. An opioid-free interval of a minimum of 7 to 10 days is recommended
for patients previously dependent on short-acting opioids, and those patients
transitioning from buprenorphine or methadone may need as long as two weeks.
Patients should be made aware of the risks associated with precipitated
withdrawal and encouraged to give an accurate account of last opioid use.
Increase In Blood Pressure And Heart Rate
CONTRAVE can cause an increase in systolic and/or
diastolic blood pressure as well as an increase in resting heart rate. In
clinical practice with other bupropion-containing products, hypertension, in
some cases severe and requiring acute treatment, has been reported. The
clinical significance of the increases in blood pressure and heart rate
observed with CONTRAVE treatment is unclear, especially for patients with
cardiac and cerebrovascular disease, since patients with a history of
myocardial infarction or stroke in the previous 6 months, life-threatening
arrhythmias, or congestive heart failure were excluded from CONTRAVE clinical
trials. Blood pressure and pulse should be measured prior to starting therapy
with CONTRAVE and should be monitored at regular intervals consistent with
usual clinical practice, particularly among patients with controlled
hypertension prior to treatment [see DOSAGE AND ADMINISTRATION].
CONTRAVE should not be given to patients with uncontrolled hypertension [see
Among patients treated with CONTRAVE in
placebo-controlled clinical trials, mean systolic and diastolic blood pressure
was approximately 1 mmHg higher than baseline at Weeks 4 and 8, similar to
baseline at Week 12, and approximately 1 mmHg below baseline between Weeks 24
and 56. In contrast, among patients treated with placebo, mean blood pressure
was approximately 2 to 3 mmHg below baseline throughout the same time points,
yielding statistically significant differences between the groups at every
assessment during this period. The largest mean differences between the groups
were observed during the first 12 weeks (treatment difference +1.8 to +2.4 mmHg
systolic, all p < 0.001; +1.7 to +2.1 mmHg diastolic, all p < 0.001).
For heart rate, at both Weeks 4 and 8, mean heart rate
was statistically significantly higher (2.1 bpm) in the CONTRAVE group compared
with the placebo group; at Week 52, the difference between groups was +1.7 bpm
(p < 0.001).
In an ambulatory blood pressure monitoring substudy of
182 patients, the mean change from baseline in systolic blood pressure after 52
weeks of treatment was -0.2 mmHg for the CONTRAVE group and -2.8 mmHg for the
placebo group (treatment difference, +2.6 mmHg, p=0.08); the mean change in
diastolic blood pressure was +0.8 mmHg for the CONTRAVE group and -2.1 mmHg for
the placebo group (treatment difference, +2.9 mmHg, p=0.004).
A greater percentage of subjects had adverse reactions
related to blood pressure or heart rate in the CONTRAVE group compared to the
placebo group (6.3% vs 4.2%, respectively), primarily attributable to adverse
reactions of Hypertension/Blood Pressure Increased (5.9% vs 4.0%,
respectively). These events were observed in both patients with and without
evidence of preexisting hypertension. In a trial that enrolled individuals with
diabetes, 12.0% of patients in the CONTRAVE group and 6.5% in the placebo group
had a blood pressure-related adverse reaction.
Anaphylactoid/anaphylactic reactions characterized by
symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical
treatment have been reported in clinical trials with bupropion. In addition,
there have been rare spontaneous postmarketing reports of erythema multiforme,
Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion.
Instruct patients to discontinue CONTRAVE and consult a healthcare provider if
they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin
rash, pruritus, hives, chest pain, edema, or shortness of breath) during
Arthralgia, myalgia, fever with rash, and other symptoms
suggestive of delayed hypersensitivity have been reported in association with
bupropion. These symptoms may resemble serum sickness.
Cases of hepatitis and clinically significant liver
dysfunction were observed in association with naltrexone exposure during
naltrexone clinical trials and in postmarketing reports for patients using
naltrexone. Transient, asymptomatic hepatic transaminase elevations were also
observed. When patients presented with elevated transaminases, there were often
other potential causative or contributory etiologies identified, including
pre-existing alcoholic liver disease, hepatitis B and/or C infection, and
concomitant usage of other potentially hepatotoxic drugs. Although clinically
significant liver dysfunction is not typically recognized as a manifestation of
opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to
systemic sequelae, including acute liver injury.
Patients should be warned of the risk of hepatic injury
and advised to seek medical attention if they experience symptoms of acute
hepatitis. Use of CONTRAVE should be discontinued in the event of symptoms
and/or signs of acute hepatitis.
In CONTRAVE clinical trials, there were no cases of
elevated transaminases greater than three times the upper limit of normal (ULN)
in conjunction with an increase in bilirubin greater than two times ULN.
Activation Of Mania
Bupropion, a component of CONTRAVE, is a drug used for
the treatment of depression. Antidepressant treatment can precipitate a manic,
mixed, or hypomanic episode. The risk appears to be increased in patients with
bipolar disorder or who have risk factors for bipolar disorder. Prior to
initiating CONTRAVE, 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). CONTRAVE is not approved for use in treating
bipolar depression. No activation of mania or hypomania was reported in the
clinical trials evaluating effects of CONTRAVE in obese patients; however,
patients receiving antidepressant medications and patients with a history of
bipolar disorder or recent hospitalization because of psychiatric illness were
excluded from CONTRAVE clinical trials.
The pupillary dilation that occurs following use of many
antidepressant drugs including bupropion, a component of CONTRAVE, may trigger
an angle-closure attack in a patient with anatomically narrow angles who does
not have a patent iridectomy.
Potential Risk Of Hypoglycemia In Patients With Type 2
Diabetes Mellitus On Antidiabetic Therapy
Weight loss may increase the risk of hypoglycemia in
patients with type 2 diabetes mellitus treated with insulin and/or insulin
secretagogues (e.g., sulfonylureas). Measurement of blood glucose levels prior
to starting CONTRAVE and during CONTRAVE treatment is recommended in patients
with type 2 diabetes. Decreases in medication doses for antidiabetic
medications which are non-glucose-dependent should be considered to mitigate
the risk of hypoglycemia. If a patient develops hypoglycemia after starting
CONTRAVE, appropriate changes should be made to the antidiabetic drug regimen.
Patient Counseling Information
See FDA-Approved Patient Labeling (Medication Guide)
Patient information is printed at the end of this insert.
This information and the instructions provided in the Medication Guide should
be discussed with patients.
Patients should be advised to take CONTRAVE exactly as
prescribed. Patients should be instructed to follow the dose escalation
schedule and not to take more than the recommended dose of CONTRAVE.
Patients should be made aware that CONTRAVE contains the
same active ingredient (bupropion) found in certain antidepressants and smoking
cessation products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR,
WELLBUTRIN XL, APLENZIN and ZYBAN) and that CONTRAVE should not be used in
combination with any other medications that contain bupropion.
Patients should be advised 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, suicide attempt,
and completed suicide when attempting to quit smoking while taking bupropion.
Instruct patients to discontinue CONTRAVE and contact a healthcare professional
if they experience such symptoms.
Patients should be advised of the potential serious risks
associated with the use of CONTRAVE, including suicidality, seizures, and
increases in blood pressure or heart rate.
Patients should be advised to call their healthcare provider
to report new or sudden changes in mood, behavior, thoughts, or feelings.
Patients should be advised that taking CONTRAVE 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 (e.g., iridectomy), if they are susceptible.
Patients should be educated on the symptoms of
hypersensitivity and to discontinue CONTRAVE if they have a severe allergic
reaction to CONTRAVE.
Patients should be told that CONTRAVE should be
discontinued and not restarted if they experience a seizure while on treatment.
Patients should be advised that the excessive use or
abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or
sedatives/hypnotics can increase the risk of seizure. Patients should be
advised to minimize or avoid use of alcohol.
Patients should be advised that if they previously used
opioids, they may be more sensitive to lower doses of opioids and at risk of
accidental overdose should they use opioids after CONTRAVE treatment is
discontinued or temporarily interrupted.
Patients should be advised that because naltrexone, a
component of CONTRAVE, can block the effects of opioids, they will not perceive
any effect if they attempt to self-administer any opioid drug in small doses
while on CONTRAVE. Further advise patients that the attempt to administer large
doses of any opioid or to bypass the blockade while on CONTRAVE may lead to
serious injury, coma, or death.
Patients should be off all opioids for a minimum of 7 to
10 days before starting CONTRAVE in order to avoid precipitation of withdrawal.
Advise patients they should not take CONTRAVE if they have any symptoms of
Patients should be advised to call their healthcare
provider if they experience increased blood pressure or heart rate.
Patients should be advised to notify their healthcare
provider if they are taking, or plan to take, any prescription or
over-the-counter drugs. Concern is warranted because CONTRAVE and other drugs
may affect each other's metabolism.
Patients should be advised to notify their healthcare
provider if they become pregnant, intend to become pregnant, or are breastfeeding
Patients with type 2 diabetes mellitus on antidiabetic
therapy should be advised to monitor their blood glucose levels and report
symptoms of hypoglycemia to their healthcare provider(s).
Patients should be advised to swallow CONTRAVE tablets
whole so that the release rate is not altered. Do not chew, divide, or crush
Carcinogenesis, Mutagenesis, Impairment Of Fertility
Studies to evaluate carcinogenesis, mutagenesis, or
impairment of fertility with the combined products in CONTRAVE have not been
conducted. The following findings are from studies performed individually with
naltrexone and bupropion. The potential carcinogenic, mutagenic and fertility
effects of the metabolite 6-beta-naltrexol are unknown. Safety margins were
estimated using body surface area exposure (mg/m²) based on a body weight of
In a two-year carcinogenicity study in rats with
naltrexone, there were small increases in the numbers of testicular
mesotheliomas in males and tumors of vascular origin in males and females. The
incidence of mesothelioma in males given naltrexone at a dietary dose of 100
mg/kg/day (approximately 50 times the recommended therapeutic dose on a mg/m² basis
for the naltrexone maintenance dose for CONTRAVE) was 6%, compared with a
maximum historical incidence of 4%. The incidence of vascular tumors in males
and females given dietary doses of 100 mg/kg/day was 4%, but only the incidence
in females was increased compared with a maximum historical control incidence
of 2%. There was no evidence of carcinogenicity in a two-year dietary study
with naltrexone in male and female mice.
Lifetime carcinogenicity studies of bupropion were
performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively.
These doses are approximately 15 and 3 times the maximum recommended human dose
(MRHD) of the bupropion component in CONTRAVE, 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 (approximately 5 to 15 times the MRHD of
the bupropion component in CONTRAVE 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.
There was limited evidence of a weak genotoxic effect of
naltrexone in one gene mutation assay in a mammalian cell line, in the
Drosophila recessive lethal assay, and in non-specific DNA repair tests with E.
coli. However, no evidence of genotoxic potential was observed in a range of
other in vitro tests, including assays for gene mutation in bacteria, yeast, or
in a second mammalian cell line, a chromosomal aberration assay, and an assay
for DNA damage in human cells. Naltrexone did not exhibit clastogenicity in an in
vivo mouse micronucleus assay.
Bupropion produced a positive response (two to three
times control mutation rate) in two of five strains in the Ames bacterial mutagenicity
test and an increase in chromosomal aberrations in one of three in vivo rat
bone marrow cytogenetic studies.
Naltrexone administered orally to rats caused a
significant increase in pseudopregnancy and a decrease in pregnancy rates in
rats at 100 mg/kg/day (approximately 50 times the MRHD of the naltrexone
component in CONTRAVE on a mg/m² basis). There was no effect on male fertility
at this dose level. The relevance of these observations to human fertility is
A fertility study of bupropion in rats at doses up to 300
mg/kg/day (approximately 15 times the MRHD of the bupropion component in
CONTRAVE on a mg/m² basis) revealed no evidence of impaired fertility.