bupropion/naltrexone (Contrave)

Dosing and uses of Contrave (bupropion/naltrexone)

• Adult
• Pediatric

 

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