Naltrexone and wellbutrin weight loss

Editor’s note: On Dec. 7, 2010, an FDA advisory committee recommended approval of Contrave. The FDA is expected to make its final decision in early 2011.

June 8, 2009 — A new weight loss drug looks good in late-stage clinical trials.

The drug is Contrave, from Orexigen Therapeutics Inc. It’s a combination of two existing drugs: The antidepressant Wellbutrin and the addiction drug naltrexone.

Contrave doesn’t work in the belly. It works in the hypothalamus, the brain’s central thermostat that controls appetite, temperature, and how the body burns energy.

It’s already known that people lose weight soon after starting Wellbutrin treatment. But this effect soon wears off, and people regain weight. That’s where the naltrexone comes in, says endocrinologist Dennis D. Kim, MD, MBA, Orexigen’s senior vice president for medical affairs.

“Naltrexone comes in and lifts the brake on the Wellbutrin effect,” Kim tells WebMD. “So you have a synergistic effect to signal the hypothalamus to reduce food intake. Weight decrease is maintained over time.”

That sounds good in theory. But does it work?

The drug was tested in a clinical trial that enrolled nearly 700 obese people — 90% of them women, with an average weight of 223 pounds. All study participants enrolled in an intensive weight loss program that included counseling, diet, and exercise. Two-thirds of the study participants also took Contrave.

Just under 60% of the participants stayed in the program for 56 weeks.

The intensive weight loss program worked well. After 56 weeks, they had an overall weight loss of just over 5% of their body weight — 11 to 16 pounds. Moreover, 11% of participants who finished the study lost more than 15% of their body weight.

But those who took Contrave did even better. After 56 weeks, they lost 9.3% of their body weight — 20 to 25 pounds. And more than 29% of them lost more than 15% of their body weight.

Nausea, usually mild or moderate, was a frequent side effect of Contrave treatment. More patients on Contrave also reported mild-to-moderate headaches and constipation. All these side effects tended to occur early in the study.

REDUCE HUNGER AND HELP CONTROL CRAVINGS TO LOSE WEIGHT AND KEEP IT OFF.

Indication

CONTRAVE is a prescription weight-loss medicine that may help some adults with a body mass index (BMI) of 30 kg/m2 or greater (obese), or adults with a BMI of 27 kg/m2 or greater (overweight) with at least one weight-related medical problem such as high blood pressure, high cholesterol, or type 2 diabetes, lose weight and keep the weight off.

  • CONTRAVE should be used with a reduced-calorie diet and increased physical activity
  • It is not known if CONTRAVE changes your risk of heart problems or stroke or of death due to heart problems or stroke
  • It is not known if CONTRAVE is safe and effective when taken with other prescription, over-the-counter, or herbal weight-loss products

CONTRAVE is not approved to treat depression or other mental illnesses, or to help people quit smoking (smoking cessation).

Please see Full Prescribing Information, including Medication Guide, for CONTRAVE.

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088.

One of the ingredients in CONTRAVE, bupropion, may increase the risk of suicidal thinking in children, adolescents, and young adults. CONTRAVE patients should be monitored for suicidal thoughts and behaviors. In patients taking bupropion for smoking cessation, serious neuropsychiatric adverse events have been reported. CONTRAVE is not approved for use in children under the age of 18.

Stop taking CONTRAVE and call a healthcare provider right away if you have any of the following symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying; attempts to commit suicide; depression; anxiety; feeling agitated or restless; panic attacks; trouble sleeping (insomnia); irritability; aggression, anger, or violence; acting on dangerous impulses; an extreme increase in activity and talking (mania); other unusual changes in behavior or mood.

Do not take CONTRAVE if you have uncontrolled high blood pressure; have or have had seizures; use other medicines that contain bupropion such as WELLBUTRIN, APLENZIN or ZYBAN; have or have had an eating disorder; are dependent on opioid pain medicines or use medicines to help stop taking opioids such as methadone or buprenorphine, or are in opiate withdrawal; drink a lot of alcohol and abruptly stop drinking; are allergic to any of the ingredients in CONTRAVE; or are pregnant or planning to become pregnant.

Before taking CONTRAVE, tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. Do not take any other medicines while you are taking CONTRAVE unless your healthcare provider says it is okay.

Tell your healthcare provider about all of your medical conditions including if you have: depression or other mental illnesses; attempted suicide; seizures; head injury; tumor or infection of brain or spine; low blood sugar or low sodium; liver or kidney problems; high blood pressure; heart attack, heart problems, or stroke; eating disorder; drinking a lot of alcohol; prescription medicine or street drug abuse; are 65 or older; diabetes; pregnant; or breastfeeding.

CONTRAVE may cause serious side effects, including:

  • Seizures. There is a risk of having a seizure when you take CONTRAVE. If you have a seizure, stop taking CONTRAVE, tell your healthcare provider right away.
  • Risk of opioid overdose. Do not take large amounts of opioids, including opioid-containing medicines, such as heroin or prescription pain pills, to try to overcome the opioid-blocking effects of naltrexone.
  • Sudden opioid withdrawal. Do not use any type of opioid for at least 7 to 10 days before starting CONTRAVE.
  • Severe allergic reactions. Stop taking CONTRAVE and get medical help immediately if you have any signs and symptoms of severe allergic reactions: rash, itching, hives, fever, swollen lymph glands, painful sores in your mouth or around your eyes, swelling of your lips or tongue, chest pain, or trouble breathing.
  • Increases in blood pressure or heart rate.
  • Liver damage or hepatitis. Stop taking CONTRAVE if you have any symptoms of liver problems: stomach area pain lasting more than a few days, dark urine, yellowing of the whites of your eyes, or tiredness.
  • Manic episodes.
  • Visual problems (angle-closure glaucoma). Signs and symptoms may include: eye pain, changes in vision, swelling or redness in or around the eye.
  • Increased risk of low blood sugar (hypoglycemia) in people with type 2 diabetes mellitus who also take medicines to treat their diabetes (such as insulin or sulfonylureas).

The most common side effects of CONTRAVE include nausea, constipation, headache, vomiting, dizziness, trouble sleeping, dry mouth, and diarrhea.

These are not all the possible side effects of CONTRAVE. Tell your healthcare provider about any side effect that bothers you or does not go away.

Bupropion-Naltrexone

Bupropion is an antidepressant medicine that can also decrease appetite. Naltrexone is usually given to block the effects of narcotics or alcohol in people with addiction problems. Naltrexone may also curb hunger and food cravings.

Bupropion and naltrexone is a combination medicine used to help manage weight in obese or overweight adults with weight-related medical problems. This medicine is used together with diet and exercise.

Bupropion and naltrexone will not treat any weight-related medical condition, such as high blood pressure, diabetes, or high cholesterol.

Contrave is not approved to treat depression or other psychiatric conditions, or to help you quit smoking.

Bupropion and naltrexone may also be used for purposes not listed in this medication guide.

You should not use this medicine if you have uncontrolled high blood pressure, seizures, an eating disorder, opioid addiction, if you are pregnant, if you take narcotic medicine or other forms of bupropion, or if you have suddenly stopped using alcohol, seizure medication, or a sedative.

Tell your doctor about all your current medicines and any you start or stop using. Many drugs can interact with bupropion and naltrexone, and some drugs should not be used together.

Some young people have thoughts about suicide when first taking bupropion. Stay alert to changes in your mood or symptoms. Report any new or worsening symptoms to your doctor.

Do not use this medicine if you are pregnant. Weight loss during pregnancy can harm an unborn baby, even if you are overweight. Tell your doctor right away if you become pregnant.

You should not use this medicine if you are allergic to bupropion or naltrexone, or if you have:

  • untreated or uncontrolled high blood pressure;
  • an eating disorder (anorexia or bulimia);
  • a history of seizures;
  • opioid addiction or withdrawal (or if you take methadone or buprenorphine);
  • if you take other forms of bupropion (Wellbutrin, Aplenzin, Budeprion, Forfivo, Zyban, and others); or
  • if you have suddenly stopped using alcohol, seizure medication, or a sedative such as Xanax, Valium, Fiorinal, Klonopin, and others).

Do not use an MAO inhibitor within 14 days before or 14 days after you take bupropion and naltrexone. A dangerous drug interaction could occur. MAO inhibitors include isocarboxazid, linezolid, phenelzine, rasagiline, selegiline, and tranylcypromine.

Tell your doctor if you have ever had:

  • depression, bipolar disorder, or mental illness;
  • suicidal thoughts or actions;
  • a head injury;
  • a tumor or infection in your brain or spinal cord;
  • diabetes or low blood sugar;
  • low sodium levels;
  • liver or kidney disease;
  • heart disease, high blood pressure, heart attack, or stroke; or
  • drug addiction, or if you normally drink a lot of alcohol.

Some young people have thoughts about suicide when first taking bupropion. Your doctor should check your progress at regular visits. Your family or other caregivers should also be alert to changes in your mood or symptoms.

You should not breast-feed while using this medicine.

This medicine is not approved for use by anyone younger than 18 years old.

Naltrexone/Bupropion (Contrave) for Weight Loss

SAFETY

Safety concerns with bupropion include depression, hypertension, and risk of seizures, whereas acute opioid withdrawal and opioid overuse have been associated with naltrexone.1 Naltrexone/bupropion is labeled as increasing the risk of depression and suicidal behavior, based on studies of bupropion alone that showed an increase in the incidence of these events. However, clinical trials of the combination compared with placebo found no increase in depression and no increase in suicidality.2–4 Naltrexone/bupropion should not be given to children or adolescents. Because it may raise blood pressure and heart rate, it should not be used in patients with uncontrolled high blood pressure. It also should not be prescribed to patients with a known seizure disorder or those already taking opioids. The total daily dosage of naltrexone/bupropion should not exceed two tablets twice a day.1

Although one of the goals of weight loss is to decrease the risk of cardiovascular outcomes, patients with active cardiovascular disease, including significant heart failure, history of myocardial infarction, angina, or stroke, were excluded from premarketing studies. A large cardiovascular outcomes study that includes these patients is now ongoing. Bupropion is metabolized in the liver and its use may increase serum levels of some antidepressants, antipsychotics, beta blockers, and antiarrhythmics. Lower doses of these medications may be needed with concomitant use.1

Naltrexone/bupropion is pregnancy category X. Both components are excreted in breast milk and the medication should not be taken by breastfeeding mothers.1

TOLERABILITY

Gastrointestinal symptoms are common with naltrexone/bupropion. Up to one in three patients will report nausea and 19% will experience constipation, especially early in treatment. Headache, dizziness, and sleep disorders are also common.1 In premarketing studies, about 20% of patients discontinued treatment because of adverse effects.2–5

EFFECTIVENESS

Naltrexone/bupropion has been evaluated in three studies that enrolled more than 4,000 overweight or obese patients with hyperlipidemia or hypertension, and in one study of 505 patients with diabetes. In all studies, naltrexone/bupropion combined with a diet and exercise program for one year resulted in greater weight loss than placebo combined with a diet and exercise program.2–5 About four patients need to be treated with naltrexone/bupropion instead of placebo for one additional patient to achieve at least a 5% weight loss (number needed to treat = 4).2–4 Clinically significant weight loss was also achieved with placebo plus an intensive program of behavior modification, which supports the implementation of intensive interventions when these resources exist.4 In settings where these resources are not available, naltrexone/bupropion combined with less intensive lifestyle interventions may also achieve clinically significant weight loss for obese patients.2,3

Naltrexone/bupropion has not been compared with other pharmacologic approaches. It is unknown if weight gain occurs after stopping the medication, and patient-oriented outcomes such as the development of osteoarthritis, diabetes, hypertension, cardiovascular disease, and mortality have not been studied.

PRICE

Naltrexone/bupropion costs approximately $212 for a one-month supply.

SIMPLICITY

The dosing of naltrexone/bupropion must be titrated. In week 1, patients should take one 8/90-mg tablet once a day in the morning with a low-fat meal. In week 2, they should increase the daily dosage to one tablet in the morning and one tablet in the evening. During week 3, patients should increase the daily dosage to two tablets in the morning and one tablet in the evening, and in week 4 patients will reach the maximum recommended dosage of two tablets twice a day.1 Patients with moderate to severe renal impairment should be limited to one tablet twice daily, and patients with moderate hepatic impairment should be limited to one tablet daily.1 If patients do not lose 5% of their baseline body weight after 12 weeks, further treatment is unlikely to be beneficial and therapy should be discontinued.1 If patients achieve clinically significant weight loss after 12 weeks, therapy should be continued for up to one year. Naltrexone/bupropion has not been studied beyond 56 weeks.2–5

Bupropion / Naltrexone Dosage

Medically reviewed by Drugs.com. Last updated on Sep 20, 2019.

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Applies to the following strengths: 90 mg-8 mg

Usual Adult Dose for:

  • Weight Loss

Additional dosage information:

  • Renal Dose Adjustments
  • Liver Dose Adjustments
  • Dose Adjustments
  • Precautions
  • Dialysis
  • Other Comments

Usual Adult Dose for Weight Loss

Each extended-release tablet contains naltrexone 8 mg/bupropion 90 mg:
Initial dose:
-Week 1: One tablet orally once a day in the morning
-Week 2: One tablet orally 2 times a day (morning and evening)
-Week 3: Two tablets orally once a day in the morning and 1 tablet orally once a day in the evening
-Week 4: Two tablets orally 2 times a day (morning and evening)
Maintenance dose: 2 tablets orally 2 times a day (morning and evening)
Maximum dose: 4 tablets/day (naltrexone 32 mg/Bupropion 360 mg)

-Discontinue therapy if a patient has not lost at least 5% of baseline body weight after 12 weeks at maintenance dose.
Uses: 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 comorbid condition (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia).

Renal Dose Adjustments

Mild renal impairment: No adjustment recommended
Moderate to Severe renal impairment: Maximum maintenance dose: 1 tablet orally 2 times a day (morning and evening)
ESRD: Not recommended

Liver Dose Adjustments

Hepatic Impairment: Maximum dose: 1 tablet orally once a day in the morning

Dose Adjustments

Elderly: Use caution; elderly patients are more likely to have impaired renal function, therefore, consider monitoring renal function
Concomitant Use of MAOIs: Contraindicated
-Allow at least 14 days between discontinuation of an MAOI and initiating therapy with this drug; conversely, allow at least 14 days after stopping this drug before initiating an MAOI
Concomitant Use with CYP450 2B6 Inhibitors:
-Maximum dose: 1 tablet orally 2 times a day (morning and evening)
Avoid Concomitant Use with CYP450 2B6 Inducers

Precautions

US BOXED WARNING: SUICIDAL THOUGHTS AND BEHAVIORS
-Suicidality and Antidepressant Drugs: This drug is not approved for use in the treatment of major depressive disorder or other psychiatric disorders. The drug contains bupropion, the same active ingredient in some antidepressant medications. Antidepressants increased the risk of suicidal thinking 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 years and there was a reduction in risk with antidepressant use in subjects aged 65 and older. In patients of all ages who start therapy, 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. This drug is not approved for use in pediatric patients.
CONTRAINDICATIONS:
-Uncontrolled hypertension
-Seizure disorder or a history of seizures
-Concomitant use of other bupropion-containing products
-Bulimia or anorexia nervosa
-Chronic opioid or opiate agonist or partial agonists use, or acute opiate withdrawal
-Patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs
-Concomitant, or use within 14 days of monoamine oxidase inhibitors (MAOI) including linezolid or IV methylene blue
-Known allergy to active substance or any product excipient
-Pregnancy
Safety and efficacy have not been established in patients younger than 18 years.
Consult WARNINGS section for additional precautions.

Dialysis

ESRD: Not recommended

Other Comments

Administration advice:
-Take orally twice a day
-Swallow whole; do not cut, chew, or crush tablets
-Follow dose escalation schedule; do not take more than 2 tablets at any one time
-May take with food, but do not take with a high-fat meal
Missed dose: If a dose is missed, do not take an additional dose, but take the prescribed next dose at the usual time
General:
-It is unlikely that patients who do not respond with at least a 5% loss of baseline body weight after 12 weeks at the maintenance dose, will achieve and sustain clinically meaningful weight loss with continued use, therefore, discontinuation is recommended.
-This drug should not be used in opioid dependent patients due to the possibility of precipitating opioid withdrawal; an opioid free interval of 7 to 10 days is recommended for patients on short-acting opioids while an opioid free interval of up to 2 weeks may be needed for those on buprenorphine or methadone.
-The effect of this drug on cardiovascular morbidity and mortality has not been established.
-The safety and effectiveness of this drug in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.
Monitoring:
-Measure blood pressure and pulse prior to starting therapy and at regular intervals, particularly among patients with controlled hypertension.
-Measure blood glucose levels prior to and during treatment in patients with type 2 diabetes.
-Monitor patients closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months and with any change in dose.
-Prior to treatment initiation, screen patients for a history of/risk factors for bipolar disorder.
Patient Advice:
-Read the US FDA-approved Medication Guide.
-Patients should be instructed to follow the dose escalation schedule and not to take more than the recommended dose.
-Patients should understand that this drug contains an opioid antagonist and therefore should not be taken with opioid medications.
-Patients, families and caregivers should understand changes in behavior and mood may occur; their healthcare provider should be contacted promptly for any new or sudden changes in mood, behavior, thoughts, or feelings.
-Patients should discuss alcohol use with their healthcare provider; patients should avoid or minimize alcohol use and should avoid suddenly stopping alcohol if they drink a lot as this may increase the risk of having a seizure.

Further information

Always consult your healthcare provider to ensure the information displayed on this page applies to your personal circumstances.

Medical Disclaimer

More about bupropion / naltrexone

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Consumer resources

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  • Naltrexone and bupropion (Advanced Reading)

Other brands: Contrave

Professional resources

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Contrave

WARNINGS

Included as part of the PRECAUTIONS section.

PRECAUTIONS

Suicidal Behavior And Ideation

CONTRAVE contains bupropion, a dopamine and norepinephrine re-uptake inhibitor that is similar to some drugs used for the treatment of depression; therefore, the following precautions pertaining to these products should be considered when treating patients with CONTRAVE.

Patients with major depressive disorder, both adult and pediatric, may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking antidepressant medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern that antidepressants may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment.

In placebo-controlled clinical trials with CONTRAVE for the treatment of obesity in adult patients, no suicides or suicide attempts were reported in studies up to 56 weeks duration with CONTRAVE (equivalent to bupropion doses of 360 mg/day). In these same studies, suicidal ideation was reported by 3 (0.20%) of 1,515 patients treated with placebo compared with 1 (0.03%) of 3,239 treated with CONTRAVE.

Pooled analyses of short-term placebo-controlled trials of antidepressant drugs (selective serotonin re-uptake inhibitors and others) show that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18 to 24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term clinical trials did not show an increase in the risk of suicidality with antidepressants compared with placebo in adults beyond age 24; there was a reduction with antidepressants compared with placebo in adults aged 65 and older.

The pooled analyses of placebo-controlled trials of antidepressant drugs in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of nine antidepressant drugs in over 4,400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of two months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk differences (drug vs placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1,000 patients treated) are provided in Table 2.

Table 2: Risk Differences in the Number of Suicidality Cases by Age Group in the Pooled Placebo-Controlled Trials of Antidepressants in Pediatric and Adult Subjects

Age Range Drug-Placebo Difference in Number of Cases of Suicidality per 1,000 Patients Treated
Increases Compared to Placebo
< 18 14 additional cases
18 to 24 5 additional cases
Decreases Compared to Placebo
25 to 64 1 fewer case
> 65 6 fewer cases

No suicides occurred in any of the antidepressant pediatric trials. There were suicides in the adult antidepressant trials, but the number was not sufficient to reach any conclusion about drug effect on suicide.

It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled trials in adults with depression that the use of antidepressants can delay the recurrence of depression.

All patients being treated with antidepressants for any indication should be monitored appropriately and observed closely 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, either increases or decreases. This warning applies to CONTRAVE because one of its components, bupropion, is a member of an antidepressant class.

The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania, have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality.

Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients whose depression is persistently worse, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe, abrupt in onset, or were not part of the patient’s presenting symptoms.

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 anxiety, agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, 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 treatment, but 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. In many postmarketing cases, resolution of symptoms after discontinuation of bupropion was reported. However, the symptoms persisted in some cases, therefore, ongoing monitoring and supportive care should be provided until symptoms resolve.

Depression, suicide, attempted suicide and suicidal ideation have been reported in the postmarketing experience with naltrexone used in the treatment of opioid dependence. No causal relationship has been demonstrated.

Seizures

Bupropion, a component of CONTRAVE, can cause seizures. The risk of seizure is dose-related. The incidence of seizure in patients receiving CONTRAVE in clinical trials was approximately 0.1% vs 0% on placebo. CONTRAVE should be discontinued and not restarted in patients who experience a seizure while being treated with CONTRAVE.

The risk of seizures is also related to patient factors, clinical situations, and concomitant medications that lower the seizure threshold. Consider these risks before initiating treatment with CONTRAVE. CONTRAVE is contraindicated in patients with a seizure disorder, current or prior diagnosis of anorexia nervosa or bulimia, or undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs. Caution should be used when prescribing CONTRAVE to patients with predisposing factors that may increase the risk of seizure including:

  • history of head trauma or prior seizure, severe stroke, arteriovenous malformation, central nervous system tumor or infection, or metabolic disorders (e.g., 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, systemic steroids
Recommendations For Reducing The Risk of Seizure

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 (i.e., 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

The symptoms of spontaneous opioid withdrawal, which are associated with the discontinuation of opioid in a dependent individual, are uncomfortable, but they are not generally believed to be severe or necessitate hospitalization. However, when withdrawal is precipitated abruptly, the resulting withdrawal syndrome can be severe enough to require hospitalization. To prevent occurrence of either precipitated withdrawal in patients dependent on opioids or exacerbation of a pre-existing subclinical withdrawal symptoms, opioid-dependent patients, including those being treated for alcohol dependence, should be opioid-free (including tramadol) before starting CONTRAVE treatment. 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 And Heart Rate

CONTRAVE can cause an increase in systolic and/or diastolic blood pressure as well as an increase in resting heart rate. In clinical practice with other bupropion-containing products, hypertension, in some cases severe and requiring acute treatment, has been reported. The clinical significance of the increases in blood pressure and heart rate observed with CONTRAVE treatment is unclear, especially for patients with cardiac and cerebrovascular disease, since patients with a history of myocardial infarction or stroke in the previous 6 months, life-threatening arrhythmias, or congestive heart failure were excluded from CONTRAVE clinical trials. 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 . CONTRAVE should not be given to patients with uncontrolled hypertension .

Among patients treated with CONTRAVE in placebo-controlled clinical trials, mean systolic and diastolic blood pressure was approximately 1 mmHg higher than baseline at Weeks 4 and 8, similar to baseline at Week 12, and approximately 1 mmHg below baseline between Weeks 24 and 56. In contrast, among patients treated with placebo, mean blood pressure was approximately 2 to 3 mmHg below baseline throughout the same time points, yielding statistically significant differences between the groups at every assessment during this period. The largest mean differences between the groups were observed during the first 12 weeks (treatment difference +1.8 to +2.4 mmHg systolic, all p < 0.001; +1.7 to +2.1 mmHg diastolic, all p < 0.001).

For heart rate, at both Weeks 4 and 8, mean heart rate was statistically significantly higher (2.1 bpm) in the CONTRAVE group compared with the placebo group; at Week 52, the difference between groups was +1.7 bpm (p < 0.001).

In an ambulatory blood pressure monitoring substudy of 182 patients, the mean change from baseline in systolic blood pressure after 52 weeks of treatment was -0.2 mmHg for the CONTRAVE group and -2.8 mmHg for the placebo group (treatment difference, +2.6 mmHg, p=0.08); the mean change in diastolic blood pressure was +0.8 mmHg for the CONTRAVE group and -2.1 mmHg for the placebo group (treatment difference, +2.9 mmHg, p=0.004).

A greater percentage of subjects had adverse reactions related to blood pressure or heart rate in the CONTRAVE group compared to the placebo group (6.3% vs 4.2%, respectively), primarily attributable to adverse reactions of Hypertension/Blood Pressure Increased (5.9% vs 4.0%, respectively). These events were observed in both patients with and without evidence of preexisting hypertension. In a trial that enrolled individuals with diabetes, 12.0% of patients in the CONTRAVE group and 6.5% in the placebo group had a blood pressure-related adverse reaction.

Allergic Reactions

Anaphylactoid/anaphylactic reactions characterized by symptoms such as pruritus, urticaria, angioedema, and dyspnea requiring medical treatment have been reported in clinical trials with bupropion. In addition, there have been rare spontaneous postmarketing reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock associated with bupropion. Instruct patients to discontinue CONTRAVE and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction (e.g., skin rash, pruritus, hives, chest pain, edema, or shortness of breath) during treatment.

Arthralgia, myalgia, fever with rash, and other symptoms suggestive of delayed hypersensitivity have been reported in association with bupropion. These symptoms may resemble serum sickness.

Hepatotoxicity

Cases of hepatitis and clinically significant liver dysfunction were observed in association with naltrexone exposure during naltrexone clinical trials and in postmarketing reports for patients using naltrexone. Transient, asymptomatic hepatic transaminase elevations were also observed. When patients presented with elevated transaminases, there were often other potential causative or contributory etiologies identified, including pre-existing alcoholic liver disease, hepatitis B and/or C infection, and concomitant usage of other potentially hepatotoxic drugs. Although clinically significant liver dysfunction is not typically recognized as a manifestation of opioid withdrawal, opioid withdrawal that is precipitated abruptly may lead to systemic sequelae, including acute liver injury.

Patients should be warned of the risk of hepatic injury and advised 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.

In CONTRAVE clinical trials, there were no cases of elevated transaminases greater than three times the upper limit of normal (ULN) in conjunction with an increase in bilirubin greater than two times ULN.

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 a history of bipolar disorder and the presence of risk factors for bipolar disorder (e.g., family history of bipolar disorder, suicide, or depression). CONTRAVE is not approved for use in treating bipolar depression. No activation of mania or hypomania was reported in the clinical trials evaluating effects of CONTRAVE in obese patients; however, patients receiving antidepressant medications and patients with a history of bipolar disorder or recent hospitalization because of psychiatric illness were excluded from CONTRAVE clinical trials.

Angle-Closure Glaucoma

The pupillary dilation that occurs following use of many antidepressant drugs including bupropion, a component of CONTRAVE, may trigger an angle-closure attack in a patient with anatomically narrow angles who does not have a patent iridectomy.

Potential Risk Of Hypoglycemia In Patients With Type 2 Diabetes Mellitus On Antidiabetic Therapy

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (e.g., 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 which are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia. If a patient develops hypoglycemia after starting CONTRAVE, appropriate changes should be made to the antidiabetic drug regimen.

Patient Counseling Information

See FDA-Approved Patient Labeling (Medication Guide)

Patient information is printed at the end of this insert. This information and the instructions provided in the Medication Guide should be discussed with patients.

Patients should be advised to take CONTRAVE exactly as prescribed. Patients should be instructed to follow the dose escalation schedule and not to take more than the recommended dose of CONTRAVE.

Patients should be made aware that CONTRAVE contains the same active ingredient (bupropion) found in certain antidepressants and smoking cessation products (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, APLENZIN and ZYBAN) and that CONTRAVE should not be used in combination with any other medications that contain bupropion.

Patients should be advised that some patients have experienced 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 when attempting to quit smoking while taking bupropion. Instruct patients to discontinue CONTRAVE and contact a healthcare professional if they experience such symptoms.

Patients should be advised of the potential serious risks associated with the use of CONTRAVE, including suicidality, seizures, and increases in blood pressure or heart rate.

Patients should be advised to call their healthcare provider to report new or sudden changes in mood, behavior, thoughts, or feelings.

Patients should be advised that taking CONTRAVE can cause mild pupillary dilation, which in susceptible individuals, can lead to an episode of angle-closure glaucoma. Pre-existing glaucoma is almost always open-angle glaucoma because angle-closure glaucoma, when diagnosed, can be treated definitively with iridectomy. Open-angle glaucoma is not a risk factor for angle-closure glaucoma. Patients may wish to be examined to determine whether they are susceptible to angle closure, and have a prophylactic procedure (e.g., iridectomy), if they are susceptible.

Patients should be educated on the symptoms of hypersensitivity and to discontinue CONTRAVE if they have a severe allergic reaction to CONTRAVE.

Patients should be told that CONTRAVE should be discontinued and not restarted if they experience a seizure while on treatment.

Patients should be advised that the excessive use or abrupt discontinuation of alcohol, benzodiazepines, antiepileptic drugs, or sedatives/hypnotics can increase the risk of seizure. Patients should be advised to minimize or avoid use of alcohol.

Patients should be advised that if they previously used opioids, they may be more sensitive to lower doses of opioids and at risk of accidental overdose should they use opioids after CONTRAVE treatment is discontinued or temporarily interrupted.

Patients should be advised that because naltrexone, a component of CONTRAVE, can block the effects of opioids, they will not perceive any effect if they attempt to self-administer any opioid drug in small doses while on CONTRAVE. Further advise patients that the attempt to administer large doses of any opioid or to bypass the blockade while on CONTRAVE may lead to serious injury, coma, or death.

Patients should be off all opioids for a minimum of 7 to 10 days before starting CONTRAVE in order to avoid precipitation of withdrawal. Advise patients they should not take CONTRAVE if they have any symptoms of opioid withdrawal.

Patients should be advised to call their healthcare provider if they experience increased blood pressure or heart rate.

Patients should be advised to notify their healthcare provider if they are taking, or plan to take, any prescription or over-the-counter drugs. Concern is warranted because CONTRAVE and other drugs may affect each other’s metabolism.

Patients should be advised to notify their healthcare provider if they become pregnant, intend to become pregnant, or are breastfeeding during therapy.

Patients with type 2 diabetes mellitus on antidiabetic therapy should be advised to monitor their blood glucose levels and report symptoms of hypoglycemia to their healthcare provider(s).

Patients should be advised to swallow CONTRAVE tablets whole so that the release rate is not altered. Do not chew, divide, or crush tablets.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Studies to evaluate carcinogenesis, mutagenesis, or impairment of fertility with the combined products in CONTRAVE have not been conducted. The following findings are from studies performed individually with naltrexone and bupropion. The potential carcinogenic, mutagenic and fertility effects of the metabolite 6-beta-naltrexol are unknown. Safety margins were estimated using body surface area exposure (mg/m²) based on a body weight of 100 kg.

In a two-year carcinogenicity study in rats with naltrexone, there were small increases in the numbers of testicular mesotheliomas in males and tumors of vascular origin in males and females. The incidence of mesothelioma in males given naltrexone at a dietary dose of 100 mg/kg/day (approximately 50 times the recommended therapeutic dose on a mg/m² basis for the naltrexone maintenance dose for CONTRAVE) was 6%, compared with a maximum historical incidence of 4%. The incidence of vascular tumors in males and females given dietary doses of 100 mg/kg/day was 4%, but only the incidence in females was increased compared with a maximum historical control incidence of 2%. There was no evidence of carcinogenicity in a two-year dietary study with naltrexone in male and female mice.

Lifetime carcinogenicity studies of bupropion were performed in rats and mice at doses up to 300 and 150 mg/kg/day, respectively. These doses are approximately 15 and 3 times the maximum recommended human dose (MRHD) of the bupropion component in CONTRAVE, respectively, on a mg/m² basis. In the rat study there was an increase in nodular proliferative lesions of the liver at doses of 100 to 300 mg/kg/day (approximately 5 to 15 times the MRHD of the bupropion component in CONTRAVE on a mg/m² basis); lower doses were not tested. The question of whether or not such lesions may be precursors of neoplasms of the liver is currently unresolved. Similar liver lesions were not seen in the mouse study, and no increase in malignant tumors of the liver and other organs was seen in either study.

There was limited evidence of a weak genotoxic effect of naltrexone in one gene mutation assay in a mammalian cell line, in the Drosophila recessive lethal assay, and in non-specific DNA repair tests with E. coli. However, no evidence of genotoxic potential was observed in a range of other in vitro tests, including assays for gene mutation in bacteria, yeast, or in a second mammalian cell line, a chromosomal aberration assay, and an assay for DNA damage in human cells. Naltrexone did not exhibit clastogenicity in an in vivo mouse micronucleus assay.

Bupropion produced a positive response (two to three times control mutation rate) in two of five strains in the Ames bacterial mutagenicity test and an increase in chromosomal aberrations in one of three in vivo rat bone marrow cytogenetic studies.

Naltrexone administered orally to rats caused a significant increase in pseudopregnancy and a decrease in pregnancy rates in rats at 100 mg/kg/day (approximately 50 times the MRHD of the naltrexone component in CONTRAVE on a mg/m² basis). There was no effect on male fertility at this dose level. The relevance of these observations to human fertility is not known.

A fertility study of bupropion in rats at doses up to 300 mg/kg/day (approximately 15 times the MRHD of the bupropion component in CONTRAVE on a mg/m² basis) revealed no evidence of impaired fertility.

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