bupropion/naltrexone (Contrave)
Classes: Antidepressants, Dopamine Reuptake Inhibitors; Opioid Antagonists
Dosing and uses of Contrave (bupropion/naltrexone)
Adult dosage forms and strengths
bupropion/naltrexone
extended release tablet
- 90mg/8mg
Obesity
For use as adjunct to reduced-calorie diet and increased physical activity for long-term weight management in adults with initial body mass index of ≥30 kg/m² (obese) or ≥27 kg/m² (overweight) in presence of at least 1 weight-related comorbidity (eg, hypertension, type 2 diabetes, or dyslipidemia)
1 tablet (90mg/8mg) initially week 1; increase by 1 tablet/day each subsequent week until daily maintenance dose of 2 tablets twice daily (360 mg bupropion/32 mg naltrexone) is achieved at the start of week 4
Administration
- Take by mouth in the morning and evening
- Do not crush, chew, or cut tablets
- Doses >32mg/360mg 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
Dosage modifications
Coadministration with CYP2B6 inhibitors (eg, ticlopidine or clopidogrel): Not to exceed 1 tablet BId
Hepatic impairment: Not to exceed 1 tablet daily
Renal impairment
- Mild: Not studied
- Moderate-to-severe: Not to exceed 1 tablet BID
- End-stage renal disease: Not recommended
Dosing Considerations
Clinical response should be observed by 4 months of treatment
Discontinue therapy if clinically meaningful weight loss (≥5%) not exhibited after 4 months; other weight management strategies should be considered
Effect on cardiovascular morbidity not established
Safety and efficacy when used in combination with other weight-loss products, including over-the-counter drugs and herbal preparations, not established
Do not administer within 14 days of taking a monoamine oxidase inhibitor for depression
Recommendations to reduce risk of seizure
- Bupropion component may increase the risk of seizures
- Do not exceed 360 mg bupropion component (4 tablets daily)
- Administer daily dose in divided doses (twice daily)
- Escalate dose gradually
- Do not take more than 2 tablets at one time
- Avoid coadministration with high-fat meals
- If dose is missed, wait until next scheduled dose to resume regular dosing schedule
Pediatric dosage forms and strengths
Safety and efficacy not established
Contrave (bupropion/naltrexone) adverse (side) effects
>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
Warnings
Black Box Warning
Not approved for treatment of major depressive disorder or psychiatric disorders
Antidepressants like bupropion increase the risk of suicidal thoughts and behavior in children, adolescents, and young adults in short-term trials but were not seen in patients ≥24 years and a lower risk was seen in patients ≥65 years; patients of all ages in Contrave therapy should be monitored closely for suicidal thoughts and behaviors
Serious neuropsychiatric reactions reported in patients taking bupropion for smoking cessation that occurred during therapy or while discontinuing therapy; patients on Contrave therapy should be monitored for neuropsychiatric reactions
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 Contrave therapy; use caution when prescribing Contrave 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 Contrave 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 Contrave 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 Contrave 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
Pregnancy and lactation
Pregnancy category: X
Lactation: Not recommended
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.
Pharmacology of Contrave (bupropion/naltrexone)
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