Generic Name: bupropion/naltrexone
Brand Name: Contrave
Drug Class: Antidepressants, Dopamine Reuptake Inhibitors; Opioid Antagonists
What is bupropion/naltrexone, and what is it used for?
Bupropion/naltrexone is a combination medication used for chronic weight management in overweight and obese adults, in addition to increased physical activity and a reduced-calorie diet. Bupropion and naltrexone are used as single agents to treat other conditions, but the combination product is used in weight management to reduce appetite and increase energy expenditure. Bupropion is an antidepressant drug used to treat depression and to aid smoking cessation, while naltrexone is an opioid antagonist used to treat opioid and alcohol dependence.
Bupropion and naltrexone have effects on brain regions that regulate appetite and energy expenditure, and the reward system which reinforces behaviors that produce pleasure.
Bupropion is a dopamine reuptake inhibitor that increases dopamine and norepinephrine levels in the brain, two chemicals (neurotransmitters) involved in appetite regulation and energy expenditure, in addition to multiple other functions. Naltrexone binds to opioid receptors and prevents feedback from the reward system that reinforces overeating behavior.
Bupropion increases dopamine and norepinephrine levels in the brain by preventing their reabsorption (reuptake), a normal process in the brain. Dopamine stimulates nerve cells (neurons) known as pro-opiomelanocortin (POMC) neurons in the hypothalamus, which reduces appetite and increases metabolic rate and energy expenditure. Naltrexone binds to the opioid receptors in the POMC neurons preventing feedback inhibition of these neurons and further increasing POMC activity.
Bupropion/naltrexone is approved by the FDA as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults with an initial body mass index (BMI) of:
- 30 kg/m2 or greater (obese) or
- 27 kg/m2 or greater (overweight) in the presence of at least one weight-related comorbidity such as hypertension, type 2 diabetes mellitus, or dyslipidemia
Warnings
- Do not use bupropion/naltrexone in patients with any of the following conditions:
- Uncontrolled high blood pressure (hypertension)
- Seizure disorder or history of seizures
- Eating disorders such as anorexia nervosa or bulimia, it can increase the risk for seizures
- Do not use bupropion/naltrexone in patients with known allergy to bupropion, naltrexone or any other component of the formulation. There are reports of severe allergic (anaphylactic/anaphylactoid) reactions and life-threatening skin reactions such as Stevens-Johnson syndrome with bupropion use. Advise patients to discontinue treatment and report if they develop any hypersensitivity reactions.
- Do not use bupropion/naltrexone in pregnant women. Apprise the woman of the potential hazard of maternal weight loss to the fetus, if the drug is used during pregnancy or a woman becomes pregnant while using this drug.
- Do not use bupropion/naltrexone concurrently with other bupropion containing products.
- Do not use bupropion/naltrexone in patients who chronically use opioids, opioid agonists, or opioid partial agonists, or those in acute opiate withdrawal.
- Do not use bupropion/naltrexone concurrently or within 14 days of treatment with monoamine oxidase inhibitor (MAOI) class of antidepressant drugs, or other reversible MAOIs such as linezolid or intravenous methylene blue, it can increase the risk of hypertensive episodes.
- Do not use bupropion/naltrexone in patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates or antiepileptic drugs.
- Bupropion is an antidepressant drug and antidepressant drugs including bupropion are known to increase the risk for suicidal thoughts and behavior, particularly in children and young adults treated for major depressive disorder.
- Bupropion/naltrexone combination is not approved for the treatment of depressive disorders or other psychiatric disorders.
- Bupropion/naltrexone is not approved for use in pediatric patients.
- Prescribe the smallest quantity to reduce risk of overdose and suicide.
- Monitor all patients closely for the emergence of suicidal thoughts or behavior, particularly in the early phase of treatment, and during dose changes.
- Caution patients and their family and caregivers of the risk for suicidality. Advise family and caregivers to monitor the patient for emergence of anxiety, agitation, irritability or any unusual changes in behavior and report immediately.
- Serious neuropsychiatric symptoms including depression and mania, psychosis, hallucinations, paranoia, delusions, hostility, agitation, aggression, homicidal ideation, anxiety, panic and suicidal ideation and behavior have been reported with the use of bupropion as a smoking cessation aid.
- Bupropion/naltrexone is not approved for use as a smoking cessation aid.
- Monitor patients for neuropsychiatric reactions and advise them to report such symptoms immediately.
- Suicidality and depression have been reported with naltrexone use in the treatment of opioid dependence, although causal relationship has not been established.
- Bupropion use carries a dose-related risk for seizures. Consider the patient’s risk factors for seizures before starting bupropion/naltrexone. Strictly follow dosing recommendations to reduce the risk of seizure. Discontinue bupropion/naltrexone if the patient experiences seizures during treatment.
- Use bupropion/naltrexone with caution in patients with conditions that increase the risk for seizures including:
- History of head trauma or prior seizure, severe stroke, arteriovenous malformation, central nervous system tumor or infection, or metabolic disorders such as 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.
- Do not use bupropion/naltrexone in patients receiving long-term opioid therapy because naltrexone is an opioid antagonist.
- If chronic opioid therapy is required, discontinue bupropion/naltrexone.
- If intermittent opioid therapy is required, discontinue bupropion/naltrexone temporarily. Lower opioid doses may be required, because a patient may be more sensitive to opioids even at lower doses, after discontinuation of naltrexone.
- Caution patients that they should not attempt to overcome naltrexone opioid blockade with large doses of opioids because it can lead to life-threatening or fatal overdose.
- Opioid-dependent patients should be opioid-free for at least 7 to 10 days in the case of short-acting opioids (including tramadol) and for at least 2 weeks, if transitioning from buprenorphine or methadone.
- Bupropion/naltrexone can increase the resting heart rate and blood pressure. Evaluate pulse and blood pressure before starting bupropion/naltrexone and avoid prescribing to patients with uncontrolled hypertension. In patients with controlled hypertension, monitor blood pressure and heart rate regularly during treatment.
- Naltrexone is associated with liver injury and hepatitis. Evaluate patients who show symptoms of liver injury and discontinue bupropion/naltrexone in case of acute hepatis. Advise patients to report any liver-related symptoms promptly.
- Bupropion, like other antidepressants, can precipitate a manic, mixed or hypomanic episode, and the risk is higher in patients with bipolar disorder or at risk for bipolar disorder. Screen patients for a history of bipolar disorder and presence of risk factors for bipolar disorder. Bupropion/naltrexone is not approved for treatment of bipolar depression.
- Use with caution in patients with anatomically narrow angles in the eye which slow down fluid drainage. Use of bupropion can cause pupil dilation which may trigger an angle closure attack.
- Weight loss can increase the risk of dangerously low glucose levels (hypoglycemia) in patients with diabetes mellitus type II, treated with insulin and/or insulin secretagogues such as sulfonylureas. Evaluate blood glucose levels in patients with diabetes before starting treatment with bupropion/naltrexone, monitor during treatment and adjust antidiabetic drug dosages as required.
SLIDESHOW
See SlideshowWhat are the side effects of bupropion/naltrexone?
Common side effects of bupropion/naltrexone include:
- Nausea
- Vomiting
- Constipation
- Dry mouth
- Diarrhea
- Upper abdominal pain
- Viral gastroenteritis
- Abdominal pain
- Taste disorder (dysgeusia)
- Headache
- Dizziness
- Insomnia
- Anxiety
- Irritability
- Hot flush
- Excessive sweating (hyperhidrosis)
- Fatigue
- Tremor
- Influenza
- Urinary tract infection
- Ringing in the ears (tinnitus)
- Increase in heart rate
- Increase in blood pressure
- Excessively high blood pressure (hypertension)
- Palpitations
- Rash
- Muscle strain
Less common side effects of bupropion/naltrexone include:
- Rapid heart rate (tachycardia)
- Heart attack (myocardial infarction)
- Lower abdominal pain
- Belching (eructation)
- Hernia
- Blood in stool (hematochezia)
- Lip swelling
- Gallbladder inflammation (cholecystitis)
- Staphylococcal infection
- Pneumonia
- Kidney infection
- Urinary urgency
- Dehydration
- Thirst
- Feeling hot
- Increase in blood creatinine levels
- Elevated liver enzymes
- Decrease in hematocrit
- Jaw pain
- Intervertebral disc protrusion
- Motion sickness
- Vertigo
- Lethargy
- Weakness (asthenia)
- Intention tremor
- Balance disorder
- Feeling faint (presyncope)
- Fainting (syncope)
- Disturbance in attention
- Memory impairment
- Amnesia
- Mental impairment
- Feeling jittery
- Feeling abnormal
- Nervousness
- Tension
- Agitation
- Mood swings
- Abnormal dreams
- Dissociation
- Anxiety
- Depression
- Sleep disorders
- Hair loss (alopecia)
- Irregular menstruation
- Vaginal hemorrhage
- Vulvovaginal dryness
- Erectile dysfunction
- Suicidal ideation and behavior
- Seizures
- Hypersensitivity reactions including:
- Angle-closure glaucoma, in patients with narrow angles in the eye
Call your doctor immediately if you experience any of the following symptoms or serious side effects while using this drug:
- Serious heart symptoms include fast or pounding heartbeats, fluttering in your chest, shortness of breath, and sudden dizziness;
- Severe headache, confusion, slurred speech, severe weakness, vomiting, loss of coordination, feeling unsteady;
- Severe nervous system reaction with very stiff muscles, high fever, sweating, confusion, fast or uneven heartbeats, tremors, and feeling like you might pass out; or
- Serious eye symptoms include blurred vision, tunnel vision, eye pain or swelling, or seeing halos around lights.
This is not a complete list of all side effects or adverse reactions that may occur from the use of this drug. Call your doctor for medical advice about serious side effects or adverse reactions. You may also report side effects or health problems to the FDA at 1-800-FDA-1088.
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What is the dosage for bupropion/naltrexone?
Extended-release tablet
- 90 mg/8 mg
Adult:
- Indicated as an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adults as defined by initial body mass index (BMI) and risk factors
BMI
- BMI 30 kg/m² and above (obese), or
- BMI 27 kg/m² and above (overweight) in presence of at least 1 weight-related comorbidity (e.g., hypertension, type 2 diabetes, or dyslipidemia)
Dose escalation
- Week 1: 1 tablet orally once every morning
- Week 2: 1 tablet orally once every morning and 1 tablet every evening
- Week 3: 2 tablets orally once every morning and 1 tablet every evening
- Week 4 and onward: 2 tablets orally once every morning and 2 tablet every evening
- Not to exceed total daily dose of 360 mg bupropion/32 mg naltrexone (i.e., 2 tablets twice daily)
Dosage Modifications
- Coadministration with CYP2B6 inhibitors (e.g., ticlopidine or clopidogrel): Not to exceed 1 tablet twice daily
Hepatic impairment
- Mild to moderate: 2 tablets (one tablet each morning and evening)
- Severe hepatic impairment: Not recommended
Renal impairment
- Mild: Not studied
- Moderate-to-severe: Not to exceed 1 tablet twice daily
- End-stage renal disease: Not recommended
Dosing Considerations
- Clinical response should be observed by 3 months of treatment
- Discontinue therapy if clinically meaningful weight loss (5% or more) not exhibited after 3 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:
Safety and efficacy not established
Overdose
- There is no clinical experience with bupropion/naltrexone overdose.
- The most serious adverse effects from bupropion/naltrexone overdose are likely related to bupropion overdose.
- Bupropion overdose symptoms include seizure, hallucinations, loss of consciousness, rapid heart rate (sinus tachycardia), ECG changes such as electrical conduction disturbances including QRS prolongation, or irregular heart rhythms.
- Severe overdose can cause multiple uncontrolled seizures, low heart rate (bradycardia), cardiac failure and cardiac arrest resulting in death.
- When bupropion was part of multiple drug overdoses, symptoms reported were fever, muscle rigidity, muscle breakdown (rhabdomyolysis), low blood pressure (hypotension), stupor, coma, and respiratory failure.
- There is limited experience with naltrexone overdose. A small study with a daily dose of 800 mg naltrexone, which is equivalent to 25 times daily recommended dose, administered for a week did not produce evidence of toxicity.
- Animal studies with high doses of naltrexone caused salivation, depression/reduced activity, tremors, and convulsions.
- There are no known antidotes for bupropion/naltrexone. Bupropion/naltrexone overdose may be treated with symptomatic and supportive care, including maintaining adequate airway, oxygenation and ventilation, and monitoring of vital signs and cardiac rhythm.
What drugs interact with bupropion/naltrexone?
Inform your doctor of all medications you are currently taking, who can advise you on any possible drug interactions. Never begin taking, suddenly discontinue, or change the dosage of any medication without your doctor’s recommendation.
- Severe interactions of bupropion/naltrexone include:
- eliglustat
- isocarboxazid
- phenelzine
- pimozide
- rasagiline
- selegiline
- selegiline transdermal
- tranylcypromine
- Bupropion/naltrexone has serious interactions with at least 20 different drugs.
- Bupropion/naltrexone has moderate interactions with at least 66 different drugs.
- Bupropion/naltrexone has mild interactions with at least 19 different drugs.
The drug interactions listed above are not all of the possible interactions or adverse effects. For more information on drug interactions, visit the RxList Drug Interaction Checker.
It is important to always tell your doctor, pharmacist, or health care provider of all prescription and over-the-counter medications you use, as well as the dosage for each, and keep a list of the information. Check with your doctor or health care provider if you have any questions about the medication.
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Pregnancy and breastfeeding
- There are no adequate and well-controlled studies of bupropion/naltrexone use in pregnant women. Bupropion/naltrexone should not be used during pregnancy, because weight loss offers no potential benefit to a pregnant woman and may cause fetal harm. A minimum weight gain and no weight loss is currently recommended for all pregnant women including those who are overweight or obese.
- Bupropion and its metabolites, and naltrexone and its major metabolite 6-beta-naltrexol are present in breastmilk. Bupropion/naltrexone should not be used by nursing mothers.
What else should I know about bupropion/naltrexone?
- Take bupropion/naltrexone exactly as directed.
- Do not take other bupropion-containing drugs while taking bupropion/naltrexone.
- Bupropion can cause changes in mood, depression and mania, hallucinations, paranoia, psychosis, delusions, hostility, agitation, aggression, homicidal ideation, anxiety, panic, and suicidal thoughts and behavior. Report emergence of such symptoms immediately to your healthcare provider. If you are a caregiver, monitor the patient and report any unusual behavior to the treating physician.
- While undergoing bupropion/naltrexone treatment, seek medical attention immediately if you experience:
- Severe allergic reactions or skin reactions
- Liver related symptoms
- Seizures
- Increase in heart rate or/and blood pressure
- Eye problems
- Low blood sugar levels, if you are diabetic taking antidiabetic treatment
- Do not take any opioid while on treatment with bupropion/naltrexone, it can have serious and potentially fatal consequences. You must be off opioids for at least 7 to 10 days before starting treatment with bupropion/naltrexone. Do not take bupropion/naltrexone if you have symptoms of opioid withdrawal.
- Avoid or minimize alcohol use while on treatment with bupropion/naltrexone.
- Store bupropion/naltrexone safely out of reach of children.
- In case of overdose, seek immediate medical help or contact Poison Control.
Summary
Bupropion/naltrexone is a combination medication used for chronic weight management in overweight and obese adults, in addition to increased physical activity and a reduced-calorie diet. Common side effects of bupropion/naltrexone include nausea, vomiting, constipation, dry mouth, diarrhea, upper abdominal pain, viral gastroenteritis, abdominal pain, taste disorder (dysgeusia), headache, dizziness, insomnia, anxiety, irritability, hot flush, excessive sweating (hyperhidrosis), and others.
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Treatment & Diagnosis
Prevention & Wellness
Report Problems to the Food and Drug Administration
You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.
https://www.accessdata.fda.gov/drugsatfda_docs/label/2014/200063s000lbl.pdf
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4771085/
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https://www.sciencedirect.com/science/article/pii/S1043661814000449