Version May 2024
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.
Weight management, chronic (alternative agent):
Note: For use as an adjunct to diet and exercise in patients who cannot take preferred agents and who have a BMI ≥30 kg/m2 or patients with a BMI ≥27 kg/m2 and ≥1 weight-associated comorbidity (eg, dyslipidemia) (Ref). Avoid use in patients with uncontrolled hypertension, seizure disorder, eating disorder, use of other bupropion-containing products, chronic opioid use, or use within 14 days of monoamine oxidase inhibitors. Although may have benefit in patients with excess caloric intake from alcohol, avoid use in patients with risk of alcohol withdrawal due to bupropion component lowering seizure threshold (Ref).
Oral: Initial: One tablet (naltrexone 8 mg/bupropion 90 mg) once daily in the morning for 1 week; increase as tolerated in weekly intervals: 1 tablet twice daily for 1 week; then 2 tablets in the morning and 1 tablet in the evening for 1 week; and then 2 tablets twice daily (maximum dose: 4 tablets/day [naltrexone 32 mg/bupropion 360 mg per day]). Consider discontinuation if weight loss is <4% to 5% of baseline after 3 months (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Mild impairment: No dosage adjustment necessary.
Moderate or severe impairment: Maximum dose: One tablet (naltrexone 8 mg/bupropion 90 mg) twice daily
End-stage renal disease: Use is not recommended.
Mild impairment: No dosage adjustment necessary.
Moderate impairment: Maximum dose: 1 tablet (naltrexone 8 mg/bupropion 90 mg) twice daily.
Severe impairment: Use is not recommended.
Refer to adult dosing.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified. Also see individual agents.
>10%:
Gastrointestinal: Constipation (19%), nausea (33%), vomiting (11%)
Nervous system: Headache (18%), insomnia (9% to 11%), sleep disturbance (14%)
1% to 10%:
Cardiovascular: Acute myocardial infarction (<2%), hypertension (≤6%), increased blood pressure (≤6%), palpitations (2%), presyncope (<2%), tachycardia (<2%)
Dermatologic: Alopecia (<2%), hyperhidrosis (3%)
Endocrine: Dehydration (<2%), hot flash (4%), increased thirst (<2%), irregular menses (<2%)
Gastrointestinal: Abdominal pain (3%), cholecystitis (<2%), diarrhea (7%), dysgeusia (2%), eructation (<2%), hematochezia (<2%), hernia of abdominal cavity (<2%), lower abdominal pain (<2%), motion sickness (<2%), upper abdominal pain (4%), viral gastroenteritis (4%), xerostomia (8%)
Genitourinary: Erectile dysfunction (<2%), urinary tract infection (3%), urinary urgency (<2%), vaginal dryness (<2%), vaginal hemorrhage (<2%)
Hematologic & oncologic: Decreased hematocrit (<2%)
Hepatic: Increased liver enzymes (<2%)
Hypersensitivity: Swelling of lips (<2%)
Infection: Kidney infection (<2%), staphylococcal infection (<2%)
Nervous system: Abnormal dreams (<2%), agitation (<2%), altered mental status (<2%), amnesia (<2%), anxiety (4% to 6%), asthenia (<2%), balance impairment (<2%), depression (6% to 7%), derealization (<2%), disturbance in attention (≤3%), dizziness (10%), emotional lability (<2%), fatigue (4%), feeling hot (<2%), intention tremor (<2%), irritability (3%), jitteriness (<2%), lethargy (<2%), memory impairment (<2%), nervousness (<2%), tension (<2%), tremor (4%), vertigo (<2%)
Neuromuscular & skeletal: Herniated disc (<2%), jaw pain (<2%), muscle strain (2%)
Otic: Tinnitus (3%)
Renal: Increased serum creatinine (<2%)
Respiratory: Pneumonia (<2%)
<1%: Cardiovascular: Syncope
Postmarketing:
Cardiovascular: ECG abnormality (Brugada pattern/syndrome), increased heart rate (resting)
Nervous system: Loss of consciousness, malaise
Hypersensitivity to bupropion, naltrexone, or any other component of the formulation; concomitant use of other bupropion-containing products (eg, including [but not limited to] Wellbutrin, Wellbutrin SR, Wellbutrin XL, Aplenzin, Zyban); chronic opioid, opiate agonist (eg, methadone) or partial agonist (eg, buprenorphine) use; acute opioid withdrawal; uncontrolled hypertension; seizure disorder or a history of seizures; bulimia or anorexia nervosa; patients undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiseizure drugs; concomitant use of MAOIs (concurrently or within 14 days of discontinuing the MAOI or naltrexone/bupropion); initiation of naltrexone/bupropion in a patient receiving linezolid or IV methylene blue.
Canadian labeling: Additional contraindications (not in US labeling): Concomitant use of thioridazine; severe hepatic impairment; end-stage renal failure
Major psychiatric warnings (use in treating psychiatric disorders):
• Suicidal thinking/behavior (use in treating psychiatric disorders): [US Boxed Warning]: Naltrexone/bupropion is not approved for use in the treatment of major depressive or psychiatric disorders; it contains bupropion the same active ingredient in some other antidepressant medications. Antidepressants increase the risk of suicidal thinking and behavior in children, adolescents, and young adults (18 to 24 years of age) with major depressive disorder (MDD) and other psychiatric disorders; consider risk prior to prescribing. Short-term studies of antidepressants did not show an increased risk in patients >24 years of age and showed a decreased risk in patients ≥65 years. Closely monitor patients for clinical worsening, suicidality, or unusual changes in behavior, particularly during the initial 1 to 2 months of therapy or during periods of dosage adjustments (increases or decreases); the patient's family or caregiver should be instructed to closely observe the patient and communicate condition with health care provider. A medication guide concerning the use of antidepressants should be dispensed with each prescription.
• The possibility of a suicide attempt is inherent in major depression and may persist until remission occurs. Worsening depression and severe abrupt suicidality that are not part of the presenting symptoms may require discontinuation or modification of drug therapy. Use caution in high-risk patients during initiation of therapy.
• Prescriptions should be written for the smallest quantity consistent with good patient care. The patient's family or caregiver should be alerted to monitor patients for the emergence of suicidality and associated behaviors such as anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia, hypomania, and mania; patients should be instructed to notify their health care provider if any of these symptoms or worsening depression or psychosis occur.
Concerns related to adverse effects:
• Accidental opioid overdose: Patients treated with naltrexone may respond to lower opioid doses than previously used. This could result in potentially life-threatening opioid intoxication. Warn patients that any attempt to overcome opioid blockade during naltrexone therapy is dangerous and could potentially lead to fatal opioid overdose; the opioid competitive receptor blockade produced by naltrexone is potentially surmountable in the presence of large amounts of opioids. If chronic opiate therapy is required, naltrexone/bupropion should be stopped; if intermittent opiate therapy is required, temporarily discontinue naltrexone/bupropion and lower doses of opioids may be needed.
• Acute opioid withdrawal: May precipitate symptoms of acute withdrawal in opioid-dependent patients. An opioid-free interval of a at least 7 to 10 days is recommended for patients previously dependent on short-acting opioids (including tramadol); consider an opioid-free interval of up to 2 weeks in patients transitioning from buprenorphine or methadone.
• Cardiovascular effects: May elevate heart rate, blood pressure and cause hypertension; use is contraindicated in patients with uncontrolled hypertension. Events have been observed in patients with or without evidence of preexisting hypertension. Risks may be greater during the initial 3 months of therapy. Assess heart rate and blood pressure before initiating treatment and monitor periodically.
• Hepatotoxicity: Cases of hepatitis, significant liver dysfunction, and transient, asymptomatic hepatic transaminase elevations have been observed with naltrexone use. Discontinue therapy if signs/symptoms of acute hepatitis develop. Clinicians should note that elevated transaminases may be a result of preexisting alcoholic liver disease, hepatitis B and/or C infection, or concomitant use of other hepatotoxic drugs; abrupt opioid withdrawal may also lead to acute liver injury.
• Hypersensitivity reactions: Anaphylactoid/anaphylactic reactions have occurred, including pruritus, urticaria, angioedema, and dyspnea. Serious reactions have been (rarely) reported with bupropion, including erythema multiforme, Stevens-Johnson syndrome, and anaphylactic shock. Arthralgia, myalgia, and fever with rash and other symptoms suggestive of delayed hypersensitivity resembling serum sickness have been reported with bupropion.
• Neuropsychiatric effect: Although naltrexone/bupropion is not approved for smoking cessation, serious neuropsychiatric events have occurred in patients taking bupropion for smoking cessation, including changes in mood (eg, depression, mania), psychosis, hallucinations, paranoia, delusions, homicidal ideation, hostility, agitation, aggression, anxiety, panic, suicidal ideation, suicide attempt, and completed suicide. The majority of these reactions occurred during bupropion treatment; however some occurred during treatment discontinuation. A causal relationship is uncertain as depressed mood may be a symptom of nicotine withdrawal. Some cases also occurred in patients taking bupropion who continued to smoke. Neuropsychiatric effects occurred in patients with and without preexisting psychiatric disease; some patients experienced a worsening of their psychiatric illnesses. Observe all patients taking bupropion for neuropsychiatric reactions. Instruct patients to stop taking naltrexone/bupropion and contact a health care provider if neuropsychiatric reactions occur. Depression, suicide, attempted suicide, and suicidal ideation have also been reported with naltrexone use for the treatment of opioid dependence; however, no causal relationship has been demonstrated.
• Ocular effects: Bupropion may cause mild pupillary dilation, which in susceptible individuals can lead to an episode of narrow-angle glaucoma. Consider evaluating patients who have not had an iridectomy for narrow-angle glaucoma risk factors.
• Seizures: Bupropion may cause a dose-related risk of seizures. Use is contraindicated in patients with a seizure disorder or a history of seizures, current or past diagnosis of bulimia or anorexia nervosa, or those undergoing abrupt discontinuation of alcohol, benzodiazepines, barbiturates, and antiseizure drugs. Use caution with concurrent use of antipsychotics, antidepressants, theophylline, systemic corticosteroids, or hypoglycemic agents, or with excessive use of ethanol, benzodiazepines, sedative/hypnotics, or opioids. Use with caution in seizure-potentiating metabolic disorders (hypoglycemia, hyponatremia, severe hepatic impairment, and hypoxia), in patients with a cocaine use disorder or stimulant use disorder, in patients withdrawing from sedatives, and in patients with a history of head trauma, severe stroke, arteriovenous malformation, or central nervous system tumor or infection. To minimize the risk of seizures, increase the dose gradually, administer the dose twice daily with no more than 2 tablets taken at a time, avoid administration with high-fat meals, skip missed doses, and limit the daily dose of bupropion to ≤360 mg. Use of multiple bupropion formulations is contraindicated. Permanently discontinue if seizure occurs during therapy.
Disease-related concerns:
• Cardiovascular disease: Use with caution in patients with cardiovascular disease; naltrexone/bupropion may cause an increase in blood pressure and heart rate.
• Diabetes mellitus: Weight loss may increase the risk of hypoglycemia in patients with type 2 diabetes mellitus treated with insulin and/or insulin secretagogues. Monitor blood glucose levels at baseline and periodically during treatment. Consider decreases in doses for concurrent antidiabetic medications which are non-glucose-dependent; adjust antidiabetic drug regimens if hypoglycemia develops during treatment.
• Hepatic impairment: Use with caution in patients with hepatic impairment and use extreme caution in patients with severe hepatic cirrhosis; plasma concentrations of bupropion are increased. Reduced doses are recommended. Use caution in patients with hepatic encephalopathy due to the risk of neurocognitive effects (Mauri 2014; Mullish 2014).
• Mania/hypomania: May precipitate a shift to mania or hypomania in patients with bipolar disorder. Monotherapy in patients with bipolar disorder should be avoided. Combination therapy with an antidepressant and a mood stabilizer should also be avoided in acute mania or mixed episodes, as well as maintenance treatment in bipolar disorder due to the mood-destabilizing effects of antidepressants (CANMAT [Yatham 2018]; WFSBP [Grunze 2018]). Patients presenting with depressive symptoms should be screened for bipolar disorder. Naltrexone/bupropion is not FDA approved for the treatment of bipolar depression.
• Renal impairment: Dosage reductions are necessary with moderate to severe impairment; avoid use in patients with end-stage renal disease.
Special populations:
• Older adult: Use with caution in the elderly; may be at greater risk of drug accumulation during chronic dosing.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release 12 Hour, Oral:
Contrave: Naltrexone hydrochloride 8 mg and bupropion hydrochloride 90 mg [contains edetate (edta) disodium, fd&c blue #2 (indigo carm) aluminum lake]
No
Tablet, 12-hour (Contrave Oral)
8-90 mg (per each): $6.25
Disclaimer: A representative AWP (Average Wholesale Price) price or price range is provided as reference price only. A range is provided when more than one manufacturer's AWP price is available and uses the low and high price reported by the manufacturers to determine the range. The pricing data should be used for benchmarking purposes only, and as such should not be used alone to set or adjudicate any prices for reimbursement or purchasing functions or considered to be an exact price for a single product and/or manufacturer. Medi-Span expressly disclaims all warranties of any kind or nature, whether express or implied, and assumes no liability with respect to accuracy of price or price range data published in its solutions. In no event shall Medi-Span be liable for special, indirect, incidental, or consequential damages arising from use of price or price range data. Pricing data is updated monthly.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet Extended Release 12 Hour, Oral:
Contrave: Naltrexone hydrochloride 8 mg and bupropion hydrochloride 90 mg [contains edetate (edta) disodium, fd&c blue #2 (indigo carm) aluminum lake]
Administer twice daily doses in the morning and in the evening; do not administer with high-fat meals. Do not cut, chew, or crush tablets.
Bariatric surgery: Tablet, extended release: Some institutions may have specific protocols that conflict with these recommendations; refer to institutional protocols as appropriate. ER tablets should be swallowed whole. Do not cut, chew, or crush. No alternative formulations are available unless broken into individual components. If safety and efficacy can be effectively monitored, no change in formulation or administration is required after bariatric surgery; however, careful evaluation of GI status (gastric emptying and small bowel transit), nutritional intake, and behavioral habits is strongly advised before administering anorexiant agents after bariatric surgery.
An FDA-approved patient medication guide, which is available with the product information and as follows, must be dispensed with this medication:
Contrave: https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/200063s021lbl.pdf#page=40
Weight management, chronic: 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 ≥27 kg/m2 in the presence of at least one weight-related comorbid condition (eg, type 2 diabetes mellitus, dyslipidemia)
Limitations of use: The effect of naltrexone/bupropion on cardiovascular morbidity and mortality has not been established. The safety and effectiveness of naltrexone/bupropion in combination with other products intended for weight loss, including prescription drugs, over-the-counter drugs, and herbal preparations, have not been established.
Refer to individual components.
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Agents With Seizure Threshold Lowering Potential: BuPROPion may enhance the neuroexcitatory and/or seizure-potentiating effect of Agents With Seizure Threshold Lowering Potential. Risk C: Monitor therapy
Ajmaline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Ajmaline. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the adverse/toxic effect of BuPROPion. Specifically, seizure threshold may be lowered. BuPROPion may enhance the adverse/toxic effect of Alcohol (Ethyl). Specifically, alcohol tolerance may decrease during treatment. Management: Patients receiving bupropion should be advised to minimize or avoid alcohol consumption due to possible lower alcohol tolerance, and lower seizure threshold associated with heavy alcohol consumption/abrupt discontinuation of heavy consumption. Risk D: Consider therapy modification
Aldesleukin: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Amifampridine: Agents With Seizure Threshold Lowering Potential may enhance the neuroexcitatory and/or seizure-potentiating effect of Amifampridine. Risk C: Monitor therapy
Amisulpride (Oral): Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Amisulpride (Oral). Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Antihepaciviral Combination Products: May decrease the serum concentration of BuPROPion. Risk C: Monitor therapy
Anti-Parkinson Agents (Dopamine Agonist): May enhance the adverse/toxic effect of BuPROPion. Risk C: Monitor therapy
ARIPiprazole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of ARIPiprazole. Management: Aripiprazole dose reductions or avoidance are required for indications other than major depressive disorder. Dose adjustments vary based on formulation, initial starting dose, and the additional use of CYP3A4 inhibitors. See interact monograph for details Risk D: Consider therapy modification
ARIPiprazole Lauroxil: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of ARIPiprazole Lauroxil. Management: Decrease aripiprazole lauroxil dose to next lower strength if used with strong CYP2D6 inhibitors for over 14 days. No dose adjustment needed if using the lowest dose (441 mg) or if a CYP2D6 PM. Max dose is 441 mg if also taking strong CYP3A4 inhibitors. Risk D: Consider therapy modification
Asenapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Asenapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Atomoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Atomoxetine. Management: Initiate atomoxetine at a reduced dose (patients who weigh up to 70 kg: 0.5 mg/kg/day; adults or patients who weigh 70 kg or more: 40 mg/day) in patients receiving a strong CYP2D6 inhibitor. Increase to usual target dose after 4 weeks if needed. Risk D: Consider therapy modification
Benperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Benperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Blonanserin: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Blonanserin. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Bremelanotide: May decrease the serum concentration of Naltrexone. Risk X: Avoid combination
Brexanolone: BuPROPion may enhance the CNS depressant effect of Brexanolone. Risk C: Monitor therapy
Brexpiprazole: May enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase the serum concentration of Brexpiprazole. Management: Reduce brexpiprazole dose to 50% of usual dose with bupropion; reduce to 25% of usual if used with both bupropion and a strong or moderate CYP3A4 inhibitor. These recommendations do not apply if treating major depressive disorder. Monitor for seizures. Risk D: Consider therapy modification
Bromperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Bromperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Broom: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Broom. Specifically, the concentrations of sparteine, a constituent of broom, may be increased. Risk C: Monitor therapy
Cariprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Cariprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Carvedilol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Carvedilol. Risk C: Monitor therapy
Chlorpheniramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Chlorpheniramine. Risk C: Monitor therapy
ChlorproMAZINE: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of ChlorproMAZINE. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Citalopram: BuPROPion may enhance the adverse/toxic effect of Citalopram. BuPROPion may increase the serum concentration of Citalopram. Management: Initiate citalopram at the lower end of the normal dose range in patients receiving bupropion and consider limiting the maximum citalopram adult dose to 20 mg/day during concomitant bupropion treatment. Monitor for citalopram toxicities. Risk D: Consider therapy modification
Clothiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Clothiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
CloZAPine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of CloZAPine. Risk C: Monitor therapy
CloZAPine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
CYP2B6 Inducers (Moderate): May decrease the serum concentration of BuPROPion. Risk C: Monitor therapy
CYP2B6 Inducers (Weak): May decrease the serum concentration of BuPROPion. Risk C: Monitor therapy
CYP2B6 Inhibitors (Weak): May increase the serum concentration of BuPROPion. Risk C: Monitor therapy
Dapoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Dapoxetine. Risk C: Monitor therapy
Deutetrabenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Deutetrabenazine. Management: The total daily dose of deutetrabenazine should not exceed 36 mg with concurrent use of a strong CYP2D6 inhibitor. Risk D: Consider therapy modification
Dextromethorphan: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Dextromethorphan. Risk C: Monitor therapy
Digoxin: BuPROPion may decrease the serum concentration of Digoxin. Risk C: Monitor therapy
DOXOrubicin (Conventional): CYP2D6 Inhibitors (Strong) may increase the serum concentration of DOXOrubicin (Conventional). Risk X: Avoid combination
DroPERidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of DroPERidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
DULoxetine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of DULoxetine. Risk C: Monitor therapy
Eliglustat: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Eliglustat. Management: Eliglustat dose is 84 mg daily with CYP2D6 inhibitors. Use is contraindicated (COI) when also combined with strong CYP3A4 inhibitors. When also combined with a moderate CYP3A4 inhibitor, use is COI in CYP2D6 EMs or IMs and should be avoided in CYP2D6 PMs. Risk D: Consider therapy modification
Elranatamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Epcoritamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Escitalopram: BuPROPion may enhance the adverse/toxic effect of Escitalopram. Risk C: Monitor therapy
Fenfluramine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Fenfluramine. Management: Limit fenfluramine dose to 20 mg/day without concurrent stiripentol or to 17 mg/day with concomitant stiripentol and clobazam when used with a strong CYP2D6 inhibitor. Risk D: Consider therapy modification
Fesoterodine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Fesoterodine. Risk C: Monitor therapy
Fexinidazole: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Management: Avoid concomitant use of fexinidazole and CYP2B6 substrates when possible. If combined, monitor for reduced efficacy of the CYP2B6 substrate. Risk D: Consider therapy modification
Flecainide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Flecainide. Risk C: Monitor therapy
FLUoxetine: May enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of FLUoxetine. Risk C: Monitor therapy
Flupentixol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Flupentixol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
FluPHENAZine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of FluPHENAZine. Risk C: Monitor therapy
FluPHENAZine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of FluPHENAZine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
FluvoxaMINE: BuPROPion may enhance the adverse/toxic effect of FluvoxaMINE. Risk C: Monitor therapy
Galantamine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Galantamine. Risk C: Monitor therapy
Gefitinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Gefitinib. Risk C: Monitor therapy
Glofitamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Haloperidol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Haloperidol. Risk C: Monitor therapy
Haloperidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Haloperidol. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Iboga: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Iboga. Risk C: Monitor therapy
Iloperidone: May enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may decrease serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P95 may be decreased. BuPROPion may increase serum concentrations of the active metabolite(s) of Iloperidone. Specifically, concentrations of the metabolite P88 may be increased. BuPROPion may increase the serum concentration of Iloperidone. Management: Reduce iloperidone dose by half when administered with bupropion. Monitor for increased iloperidone toxicities, including QTc prolongation and arrhythmias. Additionally, monitor for increased risk of seizures when these agents are combined. Risk D: Consider therapy modification
Indoramin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Indoramin. Risk C: Monitor therapy
Iobenguane Radiopharmaceutical Products: BuPROPion may diminish the therapeutic effect of Iobenguane Radiopharmaceutical Products. Management: Discontinue all drugs that may inhibit or interfere with catecholamine transport or uptake for at least 5 biological half-lives before iobenguane administration. Do not administer bupropion until at least 7 days after each iobenguane dose. Risk X: Avoid combination
Ioflupane I 123: BuPROPion may diminish the diagnostic effect of Ioflupane I 123. Risk C: Monitor therapy
Iohexol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iohexol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iohexol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iomeprol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iomeprol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iomeprol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Iopamidol: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Iopamidol. Specifically, the risk for seizures may be increased. Management: Discontinue agents that may lower the seizure threshold 48 hours prior to intrathecal use of iopamidol. Wait at least 24 hours after the procedure to resume such agents. In nonelective procedures, consider use of prophylactic antiseizure drugs. Risk D: Consider therapy modification
Lofexidine: May decrease the serum concentration of Naltrexone. Risk C: Monitor therapy
Lorcaserin (Withdrawn From US Market): BuPROPion may enhance the serotonergic effect of Lorcaserin (Withdrawn From US Market). This could result in serotonin syndrome. Management: Seek alternatives to this combination when possible. Lorcaserin prescribing information advises “extreme caution” when combining lorcaserin with bupropion, due to a proposed increased risk of serotonin toxicity. Risk D: Consider therapy modification
Loxapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Loxapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lumacaftor and Ivacaftor: May decrease the serum concentration of CYP2B6 Substrates (High risk with Inducers). Risk C: Monitor therapy
Lumateperone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lumateperone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Lurasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Lurasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Maprotiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Maprotiline. Risk C: Monitor therapy
Mequitazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mequitazine. Risk X: Avoid combination
Methotrimeprazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Methotrimeprazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Methylnaltrexone: May enhance the adverse/toxic effect of Opioid Antagonists. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Metoclopramide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoclopramide. Management: For gastroparesis: reduce metoclopramide dose to 5mg 4 times/day and limit to 20mg/day; nasal spray not recommended. For GERD: reduce metoclopramide dose to 5mg 4 times/day or to 10mg 3 times/day and limit to 30mg/day. Monitor for toxicity when combined. Risk D: Consider therapy modification
Metoprolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Metoprolol. Risk C: Monitor therapy
Mexiletine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Mexiletine. Risk C: Monitor therapy
MiFEPRIStone: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Molindone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Molindone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Monoamine Oxidase Inhibitors: May enhance the hypertensive effect of BuPROPion. Risk X: Avoid combination
Mosunetuzumab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Naldemedine: Opioid Antagonists may enhance the adverse/toxic effect of Naldemedine. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Naloxegol: Opioid Antagonists may enhance the adverse/toxic effect of Naloxegol. Specifically, the risk for opioid withdrawal may be increased. Risk X: Avoid combination
Nebivolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Nebivolol. Risk C: Monitor therapy
Nicergoline: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MMDL metabolite may be increased. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Nicergoline. Specifically, concentrations of the MDL metabolite may be decreased. Risk C: Monitor therapy
Nirmatrelvir and Ritonavir: May decrease the serum concentration of BuPROPion. Risk C: Monitor therapy
OLANZapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of OLANZapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Olmutinib: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Olmutinib. Risk C: Monitor therapy
Opioid Agonists: Naltrexone may diminish the therapeutic effect of Opioid Agonists. Management: Seek therapeutic alternatives to opioids. See full drug interaction monograph for detailed recommendations. Risk X: Avoid combination
Ozanimod: May enhance the hypertensive effect of BuPROPion. Risk C: Monitor therapy
Paliperidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Paliperidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
PARoxetine: BuPROPion may enhance the adverse/toxic effect of PARoxetine. Risk C: Monitor therapy
Perhexiline: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perhexiline. Risk C: Monitor therapy
Periciazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Periciazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Perphenazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Perphenazine. Risk C: Monitor therapy
Perphenazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Perphenazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Pimozide: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pimozide. Risk X: Avoid combination
Pipamperone [INT]: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Pipamperone [INT]. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Pitolisant: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Pitolisant. Management: Reduce the pitolisant dose by 50% if a strong CYP2D6 inhibitor is initiated. For patients receiving strong CYP2D6 inhibitors, initiate pitolisant at 8.9 mg once daily and increase after 7 days to a maximum of 17.8 mg once daily. Risk D: Consider therapy modification
Polyethylene Glycol-Electrolyte Solution: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Polyethylene Glycol-Electrolyte Solution. Specifically, the risk of seizure may be increased. Risk C: Monitor therapy
Primaquine: CYP2D6 Inhibitors (Strong) may diminish the therapeutic effect of Primaquine. CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Primaquine. Risk C: Monitor therapy
Prochlorperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Prochlorperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Promazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Promazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Propafenone: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propafenone. Risk C: Monitor therapy
Propranolol: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Propranolol. Risk C: Monitor therapy
QUEtiapine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of QUEtiapine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
RisperiDONE: CYP2D6 Inhibitors (Strong) may increase the serum concentration of RisperiDONE. Management: Careful monitoring for risperidone toxicities and possible dose adjustment are recommended when combined with strong CYP2D6 inhibitors. See full interaction monograph for details. Risk D: Consider therapy modification
Sertindole: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Sertindole. Management: Consider alternatives to this combination when possible. If combined, consider using lower doses of sertindole and monitor the ECG closely for evidence of QTc interval prolongation. Risk D: Consider therapy modification
Sertraline: BuPROPion may enhance the adverse/toxic effect of Sertraline. Risk C: Monitor therapy
Sibutramine: May enhance the adverse/toxic effect of Centrally Acting Weight Loss Agents. Risk X: Avoid combination
Sodium Phosphates: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sodium Phosphates. Specifically, the risk of seizure or loss of consciousness may be increased in patients with significant sodium phosphate-induced fluid or electrolyte abnormalities. Risk C: Monitor therapy
Sulpiride: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Sulpiride. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Talquetamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Tamoxifen: CYP2D6 Inhibitors (Strong) may decrease serum concentrations of the active metabolite(s) of Tamoxifen. Specifically, strong CYP2D6 inhibitors may decrease the metabolic formation of highly potent active metabolites. Management: Avoid concurrent use of strong CYP2D6 inhibitors with tamoxifen when possible, as the combination may be associated with a reduced clinical effectiveness of tamoxifen. Risk D: Consider therapy modification
Tamsulosin: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tamsulosin. Risk C: Monitor therapy
Taurursodiol: May increase the serum concentration of CYP2B6 Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk X: Avoid combination
Teclistamab: May increase the serum concentration of CYP Substrates (Narrow Therapeutic Index/Sensitive with Inhibitors). Risk C: Monitor therapy
Tetrabenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Tetrabenazine. Specifically, concentrations of the active alpha- and beta-dihydrotetrabenazine metabolites may be increased. Management: Limit the tetrabenazine dose to 50 mg per day (25 mg per single dose) in patients taking strong CYP2D6 inhibitors. Risk D: Consider therapy modification
Thioridazine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Thioridazine. Risk X: Avoid combination
Thiotepa: May increase the serum concentration of CYP2B6 Substrates (High risk with Inhibitors). Risk C: Monitor therapy
Thiothixene: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Thiothixene. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Timolol (Ophthalmic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Ophthalmic). Risk C: Monitor therapy
Timolol (Systemic): CYP2D6 Inhibitors (Strong) may increase the serum concentration of Timolol (Systemic). Risk C: Monitor therapy
Tolterodine: CYP2D6 Inhibitors (Strong) may increase the serum concentration of Tolterodine. Risk C: Monitor therapy
Tricyclic Antidepressants: May enhance the neuroexcitatory and/or seizure-potentiating effect of BuPROPion. BuPROPion may increase the serum concentration of Tricyclic Antidepressants. Risk C: Monitor therapy
Trifluoperazine: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Trifluoperazine. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Valbenazine: CYP2D6 Inhibitors (Strong) may increase serum concentrations of the active metabolite(s) of Valbenazine. Management: Reduce valbenazine dose to 40 mg once daily when combined with a strong CYP2D6 inhibitor. Monitor for increased valbenazine effects/toxicities. Risk D: Consider therapy modification
Vilazodone: BuPROPion may enhance the adverse/toxic effect of Vilazodone. Risk C: Monitor therapy
Vortioxetine: BuPROPion may enhance the adverse/toxic effect of Vortioxetine. BuPROPion may increase the serum concentration of Vortioxetine. Management: The vortioxetine dose should be reduced by 50% when used together with bupropion. Following cessation of bupropion, the vortioxetine dose should be returned to the normal level. Risk D: Consider therapy modification
Ziprasidone: Agents With Seizure Threshold Lowering Potential may enhance the adverse/toxic effect of Ziprasidone. Specifically, the risk of seizures may be increased. Risk C: Monitor therapy
Zuclopenthixol: May enhance the adverse/toxic effect of BuPROPion. Specifically, the risk for seizures may be increased. BuPROPion may increase the serum concentration of Zuclopenthixol. Risk C: Monitor therapy
Obesity increases the risk of infertility. Optimal weight control prior to conception improves pregnancy outcomes. However, medications for weight loss are not recommended prior to pregnancy due to safety issues and adverse events. Weight loss medications should be discontinued prior to conception (ACOG 2021; Wharton 2020).
Information related to the use of this combination in pregnancy is limited.
An increased risk of adverse maternal and fetal events is associated with obesity. However, moderate gestational weight gain based on pre-pregnancy BMI is required for positive fetal outcomes in all pregnancies, including patients with overweight or obesity. Therefore, medications for weight loss therapy are not recommended during pregnancy (ACOG 2021; Wharton 2020). Due to the lack of clinical benefit and potential for fetal harm associated with weight loss in pregnancy, naltrexone/bupropion should be discontinued once pregnancy is detected.
Also refer to individual monographs for additional information.
Naltrexone, bupropion, and their metabolites are present in breast milk.
According to the manufacturer, the decision to breastfeed during therapy should consider the risk of infant exposure, the benefits of breastfeeding to the infant, and the benefits of treatment to the mother. Due to safety concerns, medications for weight loss therapy are not recommended for patients who are breastfeeding (Wharton 2020).
Also refer to individual monographs for additional information.
Do not administer with high-fat meals; may result in a significant increase in bupropion and naltrexone systemic exposure.
Blood pressure and heart rate (baseline and periodic); blood glucose (baseline and periodic); weight; BMI; renal and liver function (base and periodic); mental status for depression, suicidal ideation (especially at the beginning of therapy or when doses are increased or decreased), anxiety, social functioning, mania, and panic attacks.
Adult classification of weight by BMI (kg/m2):
Underweight: <18.5
Normal: 18.5 to 24.9
Overweight: 25 to 29.9
Obesity, class I: 30 to 34.9
Obesity, class II: 35 to 39.9
Obesity, class III: ≥40
Waist circumference: In adults with a BMI of 25 to 34.9 kg/m2, high-risk waist circumference for adiposity-related disease is defined as (AACE/ACE [Garvey 2016]):
Males >102 cm (>40 in).
Females >88 cm (>35 in).
Naltrexone is a pure opioid antagonist, and bupropion is a relatively weak inhibitor of the neuronal reuptake of dopamine and norepinephrine. The exact neurochemical effects of naltrexone/bupropion leading to weight loss are not fully understood. Effects may result from action on areas of the brain involved in the regulation of food intake: the hypothalamus (appetite regulatory center) and the mesolimbic dopamine circuit (reward system).
See individual agents.
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