WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
Suicidality and Antidepressant Drugs
CONTRAVE® is not approved for use in the treatment of
major depressive disorder or other psychiatric disorders. CONTRAVE
contains bupropion, the same active ingredient as some other
antidepressant medications (including, but not limited to,
WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and APLENZIN).
Antidepressants increased the risk of suicidal thoughts and
behavior in children, adolescents, and young adults in short-term
trials. These trials did not show an increase in the risk of
suicidal thoughts and behavior with antidepressant use in subjects
over age 24; there was a reduction in risk with antidepressant use
in subjects aged 65 and older. In patients of all ages who are
started on CONTRAVE, monitor closely for worsening, and for the
emergence of suicidal thoughts and behaviors. Advise families and
caregivers of the need for close observation and communication
with the prescriber. CONTRAVE is not approved for use in pediatric
patients.
Contraindications
CONTRAVE is contraindicated in: uncontrolled hypertension; seizure
disorder or a history of seizures; use of other bupropion-containing
products; bulimia or anorexia nervosa, which increase the risk for
seizure; chronic opioid or opiate agonist (eg, methadone) or partial
agonist (eg, buprenorphine) use, or acute opiate withdrawal; patients
undergoing an abrupt discontinuation of alcohol, benzodiazepines,
barbiturates, and antiepileptic drugs; use during/within 14 days
following treatment with monoamine oxidase inhibitors (MAOIs), as
there is an increased risk of hypertensive reactions when CONTRAVE is
used concomitantly with MAOIs, including reversible MAOIs such as
linezolid or intravenous methylene blue; known allergy to any
component of CONTRAVE, as anaphylactoid/anaphylactic reactions and
Stevens-Johnson syndrome have been reported.
WARNINGS AND PRECAUTIONS
Suicidal Behavior and Ideation
All patients being treated with antidepressants for any indication
should be monitored and observed 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.
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 suicidality, anxiety,
agitation, irritability, unusual changes in behavior, and other
symptoms, 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
Cessation Treatment
CONTRAVE is not approved for smoking cessation. 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.
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.
Seizures
Bupropion, a component of CONTRAVE, can cause seizures. The risk of
seizure is dose-related. Discontinue treatment and do not restart
CONTRAVE in patients who experience a seizure. Use caution when
prescribing CONTRAVE to patients with an elevated risk of seizure,
including: history of head trauma or prior seizure, severe stroke,
arteriovenous malformation, central nervous system tumor or infection,
or metabolic disorders (eg, 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
hypoglycemia; concomitant administration of medications that may lower
the seizure threshold, including other bupropion products,
antipsychotics, tricyclic antidepressants, theophylline, and systemic
steroids.
Clinical experience with bupropion suggests that the risk of seizure
may be minimized by adhering to the recommended dosing
recommendations, in particular: the total daily dose of CONTRAVE does
not exceed 360 mg of the bupropion component (ie, four tablets per
day); the daily dose is administered in divided doses (twice daily);
the dose is escalated gradually; no more than two tablets are taken at
one time; coadministration of CONTRAVE with high-fat meals is avoided;
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. 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: 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 (BP) and Heart Rate (HR)
CONTRAVE can cause an increase in systolic BP, diastolic BP, and/or
resting HR. These events were observed in both patients with and
without evidence of preexisting hypertension. In clinical practice
with other bupropion-containing products, hypertension, in some cases
severe and requiring acute treatment, has been reported. 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.
Allergic Reactions
Anaphylactoid/anaphylactic reactions and symptoms suggestive of
delayed hypersensitivity have been reported with bupropion, as well as
rare spontaneous reports of erythema multiforme, Stevens-Johnson
syndrome, and anaphylactic shock. Instruct patients to discontinue
CONTRAVE and consult a healthcare provider if they develop an allergic
or anaphylactoid/anaphylactic reaction (eg, skin rash, pruritus,
hives, chest pain, edema, or shortness of breath) during treatment.
Hepatotoxicity
Cases of hepatitis, clinically significant liver dysfunction, and
transient asymptomatic hepatic transaminase elevations have been
observed with naltrexone exposure. Warn patients of the risk of
hepatic injury and advise them 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.
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 history of
bipolar disorder and the presence of risk factors for bipolar disorder
(eg, family history of bipolar disorder, suicide, or depression).
CONTRAVE is not approved for use in treating bipolar depression.
Angle-Closure Glaucoma
The pupillary dilation that occurs following use of many
antidepressant drugs, including bupropion, may trigger an
angle-closure attack in a patient with anatomically narrow angles who
does not have a patent iridectomy.
Hypoglycemia with Use of Antidiabetic Medications
Weight loss may increase the risk of hypoglycemia in patients with
type 2 diabetes mellitus treated with insulin and/or insulin
secretagogues (eg, 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 that are non-glucose-dependent
should be considered to mitigate the risk of hypoglycemia.
Adverse Reactions
Most common adverse reactions (≥5%) include: nausea (32.5%),
constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness
(9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%).
Drug Interactions
Use caution and consider dose reduction of drugs metabolized by CYP2D6
when using with CONTRAVE. Avoid concomitant use with MAOIs and CYP2B6
inducers. Reduce CONTRAVE dose when taken with CYP2B6 inhibitors. Dose
CONTRAVE with caution when used with drugs that lower seizure
threshold. Use caution and monitor for CNS toxicity when using
CONTRAVE concomitantly with dopaminergic drugs (levodopa and
amantadine). CONTRAVE can cause false positive urine test results for
amphetamines.
