bupropion/naltrexone (Rx)

>10%

Nausea (32.5%)

Constipation (19.2%)

Headache (17.6%)

Vomiting (10.7%)

1-10%

Dizziness (9.9%)

Insomnia (9.2%)

Dry mouth (8.1%)

Diarrhea (7.1%)

Anxiety (4.2%)

Hot flash (4.2%)

Fatigue (4%)

Tremor (4%)

Upper abdominal pain (3.5%)

Viral gastroenteritis (3.5%)

Influenza (3.4%)

Tinnitus (3.3%)

Urinary tract infection (3.3%)

Hypertension (3.2%)

Abdominal pain (2.8%)

Hyperhidrosis (2.6%)

Irritability (2.6%)

Increased blood pressure (2.4%)

Dysgeusia (2.4%)

Rash (2.4%)

Muscle strain (2.2%)

Palpitations (2.1%)

Frequency Not Defined

Tachycardia

Myocardial infarction

Vertigo

Motion sickness

Lower abdominal pain

Eructation

Lip swelling

Hematochezia

Hernia

Feeling jittery

Thirst

Feeling hot

Asthenia

Cholecystitis

Pneumonia

Staphylococcal infection

Kidney infection

Increased creatinine clearance

Increased hepatic enzymes

Decreased hematocrit

Dehydration

Intervertebral disc protrusion

Jaw pain

Disturbance in attention

Lethargy

Intention tremor

Balance disorder

Memory impairment

Amnesia

Mental impairment

Presyncope

Abnormal dreams

Nervousness

Dissociation (feeling spacy)

Tension

Agitation

Mood swings

Vaginal hemorrhage

Irregular menstruation

Erectile dysfunction

Vulvovaginal dryness

Alopecia

Postmarketing Reports

Loss of consciousness, malaise

Contraindications

Uncontrolled hypertension

Seizure disorder or a history of seizures

Use of other bupropion-containing products

Bulimia or anorexia nervosa, which may increase risk of seizures

Long-term opioid or opiate agonists use or acute opiate withdrawal

Patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptic drugs

Within 14 days of monoamine oxidase inhibitor therapy

Hypersensitivity

Pregnancy

Cautions

Monitor patients for suicidal ideation or behavior and for unusual changes in behavior (see black box warning)

Discontinue therapy and do not restart if seizure occurs while on therapy; use caution when prescribing to patients with predisposing risk factors for seizures

Not for administration to patients receiving long-term opioids, owing to naltrexone component (opioid antagonist); discontinue therapy if long-term opiate therapy required

Following therapy, patients may be more sensitive to opioids, even at lower doses

A patient should not attempt to overcome naltrexone opioid blockade by administering large amounts of exogenous opioids; may lead to fatal overdose

Opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before therapy is initiated; opioid-free interval of a minimum of 7-10 days is recommended for patients previously dependent on short-acting opioids; patients transitioning from buprenorphine or methadone may need as long as 2 weeks

Blood pressure and pulse should be measured prior to starting therapy and should be monitored at regular intervals, particularly among patients with controlled hypertension prior to treatment

Discontinue therapy if symptoms or signs of acute hepatitis occur

Screen patients for a history of bipolar disorder and the presence of risk factors for bipolar disorder; therapy was not studied in patients receiving antidepressant medications patients with a history of bipolar disorder or recent hospitalization foor psychiatric illness were excluded from clinical trials

Angle-closure attack may occur in patients with anatomically narrow angles that do not have a patent iridectomy

Measure blood glucose levels prior to and during therapy; patients who develop hypoglycemia after initiating Contrave therapy should adjust antidiabetic drug regimen

Use caution in patients with history of tumor or infection of the brain or spine

Initiation of therapy in patients receiving linezolid or intravenous (IV) methylene blue

Use caution in hepatic impairment

May precipitate a manic, mixed, or hypomanic episode; risk higher in patients with bipolar disorders or have risk factors for bipolar disorder, including family history of bipolar disorder, suicide, or depression; not FDA approved for bipolar depression

Some patients who stopped smoking reported to have experienced symptoms of nicotine withdrawal, including depressed mood; depression, rarely including suicidal ideation, 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 reported in patients without and with pre-existing psychiatric disease; some patients experienced worsening of their psychiatric illnesses; observe patients for occurrence of neuropsychiatric adverse events; patient should stop therapy and contact healthcare provider immediately if agitation, depressed mood, or changes in behavior or thinking that are not typical for patient are observed, or if patient develops suicidal ideation or suicidal behavior; symptoms may persist after discontinuation of therapy; in some cases; monitoring and supportive care should be provided until symptoms resolve

Pregnancy

Weight loss offers no benefit to a pregnant patient and may cause fetal harm; when a pregnancy is recognized, advise pregnant patient of risk to fetus, and discontinue therapy; available pharmacovigilance data and data from clinical trials with individual components of combination drug use in pregnant patients have not demonstrated a drug-associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes

Bupropion

• Data from epidemiological studies of pregnant patients exposed to bupropion in first trimester have not identified an increased risk of congenital malformations overall
• When bupropion was administered to pregnant rats during organogenesis, there was no evidence of fetal malformations at doses up to approximately 20 times maximum recommended human dose (MRHD) of 360 mg/day
• When given to pregnant rabbits during organogenesis, non-dose–related increases in incidence of fetal malformations, and skeletal variations were observed at doses approximately twice the MRHD and greater; decreased fetal weights were seen at doses 5 times MRHD and greater

Naltrexone

• Limited case report data of pregnant patients exposed to naltrexone in first trimester have not identified an increased risk of congenital malformations overall; daily oral administration of naltrexone during period of organogenesis has been shown to increase incidence of early fetal loss in rats and rabbits at doses ≥15 times and ≥60 times MRHD of 32 mg/day respectively
• There was no evidence of fetal malformations in rats and rabbits at doses up to approximately 100 and 200 times the MHRD, respectively
• Appropriate weight gain based on pre-pregnancy weight is currently recommended for all pregnant patients, including those who are already overweight or obese, due to obligatory weight gain that occurs in maternal tissues during pregnancy

Lactation

Data from published literature report the presence of bupropion and its metabolites in human milk

Limited data from postmarketing reports with bupropion use during lactation have not identified a clear association of adverse effects on a breastfed infant

Naltrexone and its major metabolite, 6 β-naltrexol, are present in human milk; there are no data on bupropion, naltrexone, or their metabolites on milk production; the developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and any potential adverse effects on breastfed infant from drug combination or from mother’s underlying condition

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Bupropion: Increases dopamine activity in the brain, which appears to lead to a reduction in appetite and increase in energy expenditure by increasing activity of pro-opiomelanocortin (POMC) neurons

Naltrexone: Blocks opioid receptors on the POMC neurons, preventing feedback inhibition of these neurons and further increasing POMC activity

Combination may regulate activity in the dopamine reward system of the brain that helps control food cravings and overeating behaviors

Absorption

Naltrexone

• Peak time: 2 hr

Bupropion

• Peak time: 3 hr

Metabolism

Naltrexone

• Hepatic

Bupropion

• Hepatic, via CYP2B6

Distribution

Naltrexone

• Protein bound: 21%

Bupropion

• Protein bound: 84%

Elimination

Naltrexone

• Excretion: Urine (53-79%)
• Half-life: 5 hr

Bupropion

• Excretion: Urine (87%); feces (10%)
• Half-life: 21 hr

Oral Administration

Take by mouth in the morning and evening

Do not crush, chew, or cut tablets

Doses >32 mg/360 mg per day not recommended

Do not administer with high-fat meal as it may result in significant increase in bupropion and naltrexone exposure

Therapy may cause elevation in blood pressure or heart rate, especially during initial 3 months of therapy; patients with hypertension should be monitored closely