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CONTRAVE is indicated 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 (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia)

The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of CONTRAVE in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

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FAQs

Frequently Asked Questions

Find answers to some of the frequently asked questions about CONTRAVE® below.

How much weight can my patients expect to lose on CONTRAVE?

Across three clinical trials, patients lost approximately 2 to 4 times more weight by adding CONTRAVE than with just diet and exercise alone. In these three trials, 46% of patients lost 5% or more of their body weight and kept it off with CONTRAVE versus 23% of patients on placebo.

Patients who completed the COR-BMOD (CONTRAVE + Intensive Behavioral Modification) study lost an average of 25 lb.*1,2 Patients who added CONTRAVE to a diet and exercise program (COR-I: Diet and Exercise Counseling) lost an average of 4 times more weight than the placebo group.

See the full results from clinical trials

*These data come from 2 studies. The co-primary endpoints for both studies were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight at Week 56.

COR-I, diet & exercise: Change from baseline body weight: –5.4% with CONTRAVE, –1.3% with placebo (ITT-LOCF analysis); patients achieving ≤5% weight loss: 42% with CONTRAVE, 17% with placebo (ITT-LOCF analysis). CONTRAVE: n=538; placebo: n=536.

  • 49% of patients in the CONTRAVE group and 50% of patients in the placebo group withdrew from the COR-I Trial prior to Week 56. The majority of these patients discontinued within the first 12 weeks of treatment1

COR-BMOD, intensive behavioral modification: Change from baseline body weight: –8.1% with CONTRAVE, –4.9% with placebo (ITT-LOCF analysis); patients achieving ≥5% weight loss: 57% with CONTRAVE, 43% with placebo (ITT-LOCF analysis). CONTRAVE: n=565; placebo: n=196.

  • 42% of patients in the CONTRAVE group and 42% of patients in the placebo group withdrew from the COR-BMOD Trial prior to Week 56. The majority of these CONTRAVE patients discontinued within the first 12 weeks of treatment1

In 3 clinical trials, there was significantly greater weight loss observed in patients using CONTRAVE compared to those on diet and exercise alone at the first time point assessed, which was 4 weeks after the initiation of therapy.

  • 2.7% weight loss was seen at 4 weeks with CONTRAVE + diet and exercise*1,2
  • 3% weight loss was seen at 4 weeks with CONTRAVE + Intensive Behavioral Modification.†1,2

*In the 56-week, multicenter, double-blind COR-I Trial, obese patients (BMI ≥30 kg/m2), or overweight patients (BMI ≥27 kg/m2) with at least 1 comorbidity (hypertension or dyslipidemia), were randomized to CONTRAVE 32 mg/360 mg per day or placebo. The co-primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight at Week 56.

In the 56-week, multicenter, double-blind COR-BMOD Trial, 793 obese patients (BMI ≥30 kg/m2), or overweight patients (BMI ≥27 kg/m2) with at least 1 comorbidity (hypertension or dyslipidemia), were randomized to CONTRAVE 32 mg/360 mg per day or placebo. The co-primary endpoints were percent change from baseline body weight and the proportion of patients achieving at least a 5% reduction in body weight at Week 56.

In the Phase 3 trials, peak weight loss, on average, was achieved after patients had been on CONTRAVE for 36 weeks. Patients on average then maintained this weight loss through 56 weeks. Longer-term studies were not performed as part of the Phase 3 clinical development program.*

See the full results from clinical trials

*Study 1 (COR-I): In this 56-week study, the CONTRAVE group lost 5.4% of their body weight (on average) compared with the placebo group who lost 1.3% (on average) with diet and exercise alone. Additionally, 42% of the CONTRAVE users lost at least 5% of their total body weight (while 17% of the placebo group lost at least 5% of their total body weight with diet and exercise). For participants who remained on CONTRAVE for the whole study, average weight loss was 8.1% or approximately 18 pounds, which was 4 times more weight than participants taking placebo.

 Study 2 (COR-BMOD): In this 56-week study, patients participated in an intensive diet and exercise program, including group visits. At 56 weeks, the CONTRAVE users lost 8.1% (on average) of their total body weight compared with a body weight loss of 4.9% (on average) for the placebo group. Additionally, 57% of those who took CONTRAVE lost at least 5% of their total body weight (while 43% of those on placebo lost at least 5% of their total body weight with diet and exercise alone). For participants who remained on CONTRAVE for the whole study, average weight loss was 11.5% or approximately 25 pounds.

 Study 3 (COR-DIABETES): For people with type 2 diabetes, CONTRAVE has the potential to provide sustainable weight loss and this weight loss may also lower A1C levels. In this study, the CONTRAVE group lost 3.7% of their body weight (on average) compared with the placebo group who lost 1.7% (on average) with diet and exercise alone after 56 weeks. Additionally, 36% of the CONTRAVE users lost at least 5% of their total body weight (while 18% of the placebo group lost at least 5% of their total body weight with diet and exercise). CONTRAVE users also had a reduction in HbA1c of 0.6% (compared with a reduction of 0.1% in the placebo group) at 56 weeks. (Keep in mind that CONTRAVE is not approved to treat diabetes.)

CONTRAVE is a combination of naltrexone HCl, an opioid antagonist, and bupropion HCl, a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. Although the exact neurochemical effects of CONTRAVE leading to weight loss are not fully understood, non-clinical studies suggest that these particular medications work together to affect 2 separate areas of the brain that impact appetite and reward system. The appetite center, or hypothalamus, which may help patients eat less, and the reward system, or mesolimbic dopamine circuit, which may help control cravings. Additionally, CONTRAVE is an unscheduled oral prescription treatment option for weight loss and the #1 prescribed weight-loss brand.*

The individual components of CONTRAVE are not approved for weight loss.

Watch the CONTRAVE mechanism of action video

*IMS NPA Branded Weight Loss Medicine Audit from March 2014 to March 2017.

The dose of CONTRAVE is slowly increased over time to help patients adjust to their medication.2 Refer to the table below for dosing instructions for most patients.1 Patients with hepatic or renal impairment, or those taking certain other medications, may need to take a different dose.

Not actual tablet size.

All patients should be evaluated after 16 weeks of therapy (12 weeks at the maintenance dose). If a patient has not lost at least 5% of baseline body weight, discontinue CONTRAVE.

See more dosing information

Most common adverse reactions reported (≥5%) include: nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%).1

Common GI-related adverse events were generally transient in nature and tended to resolve quickly.2

See additional safety information

Patients using the CONTRAVE Savings Card can save on their prescription with and without insurance coverage.

With the CONTRAVE Savings Card:

  • Most patients without CONTRAVE coverage, or paying cash, may pay approximately $3 a day for a monthly prescription
  • Patients with Medicare or TRICARE may pay approximately $3 a day for a monthly prescription
  • Most patients with commercial insurance covering CONTRAVE may pay approximately $1 a day for a monthly prescription

Help patients register for the CONTRAVE Savings Card

Must meet Eligibility Requirements. Some restrictions apply. For Eligibility Requirements and Terms and Conditions, please see the FAQ below.

Medicare Part D and TRICARE beneficiaries are eligible for the CONTRAVE Savings Card. However, to receive the CONTRAVE Savings Card benefits, the patient’s prescription will be processed with the assumption that they are a cash-paying customer. For Medicare Part D patients, the cash payments the patients make for CONTRAVE will not count towards their true out-of-pocket expenses. If Medicare or TRICARE coverage status for CONTRAVE changes in the future, the patient’s CONTRAVE Savings Card benefits may change too.

For patients with Medicare or TRICARE, the CONTRAVE Savings Card will cover any patient obligation amount over $99, up to a maximum benefit of $164 for a 30-day prescription, 120 tablets or fewer (i.e., a maximum benefit of $492 for a 90-day prescription, 360 tablets or fewer).

Must meet Eligibility Requirements. Some restrictions apply. For Eligibility Requirements and Terms and Conditions, please see the FAQ below.

Patient Eligibility Requirements:
The CONTRAVE Savings Card cannot be used if a patient is currently a Medicaid Beneficiary. Medicare Part D and TRICARE beneficiaries are eligible for the CONTRAVE Savings Card. However, to receive the CONTRAVE Savings Card benefits, the patient’s prescription will be processed with the assumption that they are a cash-paying customer. For Medicare Part D patients, the cash payments the patients make for CONTRAVE will not count towards their true out-of-pocket expenses. If Medicare or TRICARE coverage status for CONTRAVE changes in the future, the patient’s CONTRAVE Savings Card benefits may change too.

By using the CONTRAVE Savings Card, patients agree to report their use of this offer to any Third Party that reimburses them or pays for any part of the prescription price. Use of this offer is confirmation that the patient is permitted, under the terms and conditions of the health benefit plan(s) covering their prescriptions, to take advantage of co-pay coverage programs. The patients additionally agree that they will not submit the cost of any portion of the product dispensed pursuant to this offer to a federal or state healthcare program for purposes of counting it toward their out-of-pocket expenses.

For patients with a co-pay obligation of $110 or less for a 30-day prescription, 120 tablets or fewer, ($330 or less for a 90-day supply, 360 tablets or fewer), the offer will cover any amount over $40 ($120 for a 90-day supply, 360 tablets or fewer).

For patients with a co-pay obligation greater than $110 for a 30-day prescription, 120 tablets or fewer, and for those without coverage, the offer will cover any patient obligation amount over $99, up to a maximum benefit of $164 (i.e., a maximum benefit of $492 for a 90-day prescription, 360 tablets or fewer). Retail CONTRAVE prices may vary.

Additionally, the CONTRAVE Savings Card cannot be used if the patient is purchasing their prescription through the Get CONTRAVE Now service.

Your patients can register for the CONTRAVE Savings Card at www.contrave.com/save. If they are having trouble signing up online, they can call 1-800-905-5576 for assistance.

Follow this process to submit a prior authorization (PA) for CONTRAVE.

Gather the key criteria needed for most PAs:

  • Patient’s current weight
  • Patient’s BMI
  • Presence of any weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)

A few health plans may require more information:

  • Different therapies they have tried
  • Medication list for any weight-related comorbidity (e.g., hypertension, type 2 diabetes mellitus, or dyslipidemia)
  • Patient’s baseline blood pressure, HbA1C and lipid panel (include date measured)
  • Patient’s weight before the diet and exercise plan was started (include date measured)
  • Dietician’s notes from the past 2 years
  • A copy of the patient’s current registration with a weight-loss program (such as “Weight Watchers®”)

Use this checklist to help collect the information most often needed to submit a PA for CONTRAVE.

Patients can have CONTRAVE delivered directly to their door through our partner, Ridgeway Mail Order Pharmacy. You can phone, fax, e-prescribe or mail your patient’s prescription directly to Ridgeway Mail Order Pharmacy. Make sure that the prescription is legible, includes the drug’s name, strength, the quantity to dispense, the exact daily dosage, and your patient’s name and phone number. Your patients will need to create an account at https://ridgeway.pharmacy to start the prescription order process.

For more information on how to get started, download the Home Delivery Instruction Sheet and share it with your patients

To learn more about the Home Delivery program, visit https://contrave.com/get-contrave-now/.

For immediate assistance, call Ridgeway Mail Order Pharmacy at 1-800-630-3124.

Yes, if your patients would prefer to mail their prescription to our partner, Ridgeway Mail Order Pharmacy, they can do so by completing this form.

To learn more about the Home Delivery program, visit https://contrave.com/get-contrave-now/.

For immediate assistance, call Ridgeway Mail Order Pharmacy at 1-800-630-3124.

Once you have submitted the prescription and patients have created an account at Ridgeway Mail Order Pharmacy, your patients will receive free, standard USPS first-class shipping, in approximately 2–4 business days.

To rush an order, patients can opt to pay for expedited delivery via UPS next day service.

Important Safety Information for CONTRAVE
(naltrexone HCl and bupropion HCl) extended-release tablets

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Suicidality and Antidepressant Drugs

CONTRAVE® is not approved for use in the treatment of major depressive disorder or other psychiatric disorders. CONTRAVE contains bupropion, the same active ingredient as some other antidepressant medications (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and APLENZIN). Antidepressants increased the risk of suicidal thoughts 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; there was a reduction in risk with antidepressant use in subjects aged 65 and older. In patients of all ages who are started on CONTRAVE, 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. CONTRAVE is not approved for use in pediatric patients.

Contraindications

CONTRAVE is contraindicated in: uncontrolled hypertension; seizure disorder or a history of seizures; use of other bupropion-containing products; bulimia or anorexia nervosa, which increase the risk for seizure; chronic opioid or opiate agonist (eg, methadone) or partial agonist (eg, buprenorphine) use, or acute opiate withdrawal; patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs; use during/within 14 days following treatment with monoamine oxidase inhibitors (MAOIs), as there is an increased risk of hypertensive reactions when CONTRAVE is used concomitantly with MAOIs, including reversible MAOIs such as linezolid or intravenous methylene blue; known allergy to any component of CONTRAVE, as anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported; and pregnancy.

WARNINGS AND PRECAUTIONS

Suicidal Behavior and Ideation

All patients being treated with antidepressants for any indication should be monitored and observed 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.

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 suicidality, anxiety, agitation, irritability, unusual changes in behavior, and other symptoms, and to report such symptoms immediately to healthcare providers.

Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment

CONTRAVE is not approved for smoking cessation. 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

The risk of seizure is dose-related. Discontinue treatment and do not restart CONTRAVE in patients who experience a seizure. Use caution when prescribing CONTRAVE to patients with an elevated risk of seizure, including: history of head trauma or prior seizure, severe stroke, arteriovenous malformation, central nervous system tumor or infection, or metabolic disorders (eg, 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.

Clinical experience with bupropion suggests that the risk of seizure may be minimized by adhering to the recommended dosing recommendations, including the avoidance of high-fat meals while taking CONTRAVE.

Patients Receiving Opioid Analgesics

CONTRAVE should not be administered to patients receiving chronic opioids. 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 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 (BP) and Heart Rate (HR)

CONTRAVE can cause an increase in systolic BP, diastolic BP, and/or resting HR. These events were observed in both patients with and without evidence of preexisting hypertension. In clinical practice with other bupropion-containing products, hypertension, in some cases severe and requiring acute treatment, has been reported. Blood pressure and pulse should be monitored at regular intervals.

Allergic Reactions

Anaphylactoid/anaphylactic reactions and symptoms suggestive of delayed hypersensitivity have been reported with bupropion, as well as rare spontaneous reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock. Instruct patients to discontinue CONTRAVE and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction.

Hepatotoxicity

Cases of hepatitis, clinically significant liver dysfunction, and transient asymptomatic hepatic transaminase elevations have been observed with naltrexone exposure. Warn patients of the risk of hepatic injury and advise them to discontinue CONTRAVE if they experience symptoms of acute hepatitis.

Activation of Mania

CONTRAVE 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 history of bipolar disorder and the presence of risk factors for bipolar disorder (eg, family history of bipolar disorder, suicide, or depression). CONTRAVE is not approved for use in treating bipolar depression.

Angle-Closure Glaucoma

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

Hypoglycemia with Use of Antidiabetic Medications

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (eg, 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 that are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia.

Adverse Reactions

Most common adverse reactions (≥5%) include: nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%).

Drug Interactions

Use caution when prescribing CONTRAVE concomitantly with dopaminergic drugs (levodopa and amantadine), drugs metabolized by CYP2D6, or drugs that lower the seizure threshold. Avoid concomitant use with MAOIs and CYP2B6 inducers. Reduce CONTRAVE dose when taken with CYP2B6 inhibitors. CONTRAVE can cause false positive urine test results for amphetamines.

Indication

CONTRAVE is indicated 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 (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia)

Limitations of Use

The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of CONTRAVE in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

Please see accompanying Full Prescribing Information for complete Boxed Warning and Medication Guide for CONTRAVE.

References

  1. CONTRAVE (naltrexone HCl and bupropion HCl) Prescribing Information, Orexigen Therapeutics.
  2. Data on file, Orexigen Therapeutics.

Important Safety Information, including Boxed Warning

WARNING: SUICIDAL THOUGHTS AND BEHAVIORS

Suicidality and Antidepressant Drugs

CONTRAVE® is not approved for use in the treatment of major depressive disorder or other psychiatric disorders. CONTRAVE contains bupropion, the same active ingredient as some other antidepressant medications (including, but not limited to, WELLBUTRIN, WELLBUTRIN SR, WELLBUTRIN XL, and APLENZIN). Antidepressants increased the risk of suicidal thoughts 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; there was a reduction in risk with antidepressant use in subjects aged 65 and older. In patients of all ages who are started on CONTRAVE, 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. CONTRAVE is not approved for use in pediatric patients.

Contraindications

CONTRAVE is contraindicated in: uncontrolled hypertension; seizure disorder or a history of seizures; use of other bupropion-containing products; bulimia or anorexia nervosa, which increase the risk for seizure; chronic opioid or opiate agonist (eg, methadone) or partial agonist (eg, buprenorphine) use, or acute opiate withdrawal; patients undergoing an abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiepileptic drugs; use during/within 14 days following treatment with monoamine oxidase inhibitors (MAOIs), as there is an increased risk of hypertensive reactions when CONTRAVE is used concomitantly with MAOIs, including reversible MAOIs such as linezolid or intravenous methylene blue; known allergy to any component of CONTRAVE, as anaphylactoid/anaphylactic reactions and Stevens-Johnson syndrome have been reported; and pregnancy.

WARNINGS AND PRECAUTIONS

Suicidal Behavior and Ideation

All patients being treated with antidepressants for any indication should be monitored and observed 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.

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 suicidality, anxiety, agitation, irritability, unusual changes in behavior, and other symptoms, and to report such symptoms immediately to healthcare providers.

Neuropsychiatric Adverse Events and Suicide Risk in Smoking Cessation Treatment

CONTRAVE is not approved for smoking cessation. 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

The risk of seizure is dose-related. Discontinue treatment and do not restart CONTRAVE in patients who experience a seizure. Use caution when prescribing CONTRAVE to patients with an elevated risk of seizure, including: history of head trauma or prior seizure, severe stroke, arteriovenous malformation, central nervous system tumor or infection, or metabolic disorders (eg, 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.

Clinical experience with bupropion suggests that the risk of seizure may be minimized by adhering to the recommended dosing recommendations, including the avoidance of high-fat meals while taking CONTRAVE.

Patients Receiving Opioid Analgesics

CONTRAVE should not be administered to patients receiving chronic opioids. 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 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 (BP) and Heart Rate (HR)

CONTRAVE can cause an increase in systolic BP, diastolic BP, and/or resting HR. These events were observed in both patients with and without evidence of preexisting hypertension. In clinical practice with other bupropion-containing products, hypertension, in some cases severe and requiring acute treatment, has been reported. Blood pressure and pulse should be monitored at regular intervals.

Allergic Reactions

Anaphylactoid/anaphylactic reactions and symptoms suggestive of delayed hypersensitivity have been reported with bupropion, as well as rare spontaneous reports of erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock. Instruct patients to discontinue CONTRAVE and consult a healthcare provider if they develop an allergic or anaphylactoid/anaphylactic reaction.

Hepatotoxicity

Cases of hepatitis, clinically significant liver dysfunction, and transient asymptomatic hepatic transaminase elevations have been observed with naltrexone exposure. Warn patients of the risk of hepatic injury and advise them to discontinue CONTRAVE if they experience symptoms of acute hepatitis.

Activation of Mania

CONTRAVE 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 history of bipolar disorder and the presence of risk factors for bipolar disorder (eg, family history of bipolar disorder, suicide, or depression). CONTRAVE is not approved for use in treating bipolar depression.

Angle-Closure Glaucoma

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

Hypoglycemia with Use of Antidiabetic Medications

Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues (eg, 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 that are non-glucose-dependent should be considered to mitigate the risk of hypoglycemia.

Adverse Reactions

Most common adverse reactions (≥5%) include: nausea (32.5%), constipation (19.2%), headache (17.6%), vomiting (10.7%), dizziness (9.9%), insomnia (9.2%), dry mouth (8.1%), and diarrhea (7.1%).

Drug Interactions

Use caution when prescribing CONTRAVE concomitantly with dopaminergic drugs (levodopa and amantadine), drugs metabolized by CYP2D6, or drugs that lower the seizure threshold. Avoid concomitant use with MAOIs and CYP2B6 inducers. Reduce CONTRAVE dose when taken with CYP2B6 inhibitors. CONTRAVE can cause false positive urine test results for amphetamines.

Indication

CONTRAVE is indicated 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 (eg, hypertension, type 2 diabetes mellitus, or dyslipidemia)

Limitations of Use

The effect of CONTRAVE on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of CONTRAVE in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.

Please see accompanying Full Prescribing Information for complete Boxed Warning and Medication Guide for CONTRAVE.