General

Pronunciation:
byoo-proe-pee-on nal-trex-one

Trade Name(s)

• Contrave

Ther. Class.

weight control agents

Pharm. Class.

aminoketones

opioid antagonists

Indications

Adjunct to calorie-reduced diet and increased physical activity for chronic weight management in obese patients (BMI ≥30 kg/m² ) or overweight patients (BMI ≥27 kg/m² ) with at least one other comorbidity (hypertension, type 2 diabetes, or dyslipidemia).

Action

• Bupropion:  Antidepressant that acts as a weak inhibitor of neuronal reuptake of dopamine and norepinephrine.
• Naltrexone:  Acts as an opioid antagonist.
• In combination they affect two different brain areas involved in food intake: the hypothalamic appetite regulatory center and mesolimbic dopamine circuit reward system.

Therapeutic Effect(s):

Decreased appetite with associated weight loss.

Pharmacokinetics

Bupropion

Absorption: Well absorbed but rapidly metabolized by the liver. Absorption is enhanced by a high-fat meal.

Distribution: Unknown.

Metabolism and Excretion: Extensively metabolized; three metabolites are pharmacologically active. Excretion is mostly renal as metabolites; minimal renal excretion of unchanged drug.

Half-life: 21 hr (longer for some metabolites).

Naltrexone

Absorption: Well absorbed orally; undergoes extensive first-pass hepatic metabolism, resulting in 5–40% bioavailability. Absorption is enhanced by a high-fat meal.

Distribution: Parent drug and metabolites enter breast milk.

Metabolism and Excretion: Metabolized to 6-beta-naltrexol. Both parent drug and metabolite are pharmacologically active. Excretion is mostly renal as metabolite; less than 2% as unchanged drug.

Half-life: naltrexone:  5 hr;  6-beta-naltrexol:  13 hr.

TIME/ACTION PROFILE (weight loss)

Contraindication/Precautions

Contraindicated in:

• Known hypersensitivity to bupropion or naltrexone;
• Uncontrolled hypertension;
• End-stage renal disease;
• Severe hepatic impairment;
• Seizure disorders;
• Anorexia or bulimia;
• During withdrawal from or discontinuation of alcohol, benzodiazepines, barbiturates, or antiepileptics;
• Chronic opioid/opiate agonist or partial agonist use or acute opiate withdrawal;
• During/within 14 days of MAO inhibitors;
• Concurrent use of other bupropion-containing medications;
• OB:  Pregnancy;
• Pedi:  Not recommended for use in children.

Use Cautiously in:

• History of suicidal behavior/ideation;
• History of seizure risk (avoid administration with a high-fat meal, adhere to recommended dose);
• Cardiac/cerebrovascular disease;
• Angle-closure glaucoma;
• Diabetes mellitus (weight loss may result in hypoglycemia if treatment is not adjusted);
• Moderate or severe renal impairment (use lower dose);
• Moderate hepatic impairment (↓ dose);
• Lactation: Use while breastfeeding only if potential maternal benefit justifies potential risk to infant;
• Geri:  Older adults may have ↑ sensitivity to adverse CNS reactions.

Adverse Reactions/Side Effects

CV: hypertension, tachycardia

Derm: hot flush, sweating

EENT: angle-closure glaucoma (bupropion), tinnitus

GI: constipation, nausea, vomiting, abdominal pain, diarrhea, dry mouth, hepatotoxicity (naltrexone)

Neuro: headache, aggression, agitation, anxiety, delusions, depression, dizziness, dysgeusia, hallucinations, HOMICIDAL THOUGHTS/BEHAVIOR, hostility, insomnia, mania, panic, paranoia, psychosis, SEIZURES, SUICIDAL THOUGHTS/BEHAVIOR, tremor

Misc: HYPERSENSITIVITY REACTIONS (including anaphylaxis and anaphylactoid reactions)

* CAPITALS indicate life-threatening.
Underline indicate most frequent.

Interactions

Drug-Drug

• Concurrent use with  MAO inhibitors  may ↑ risk of hypertensive reactions; concurrent use contraindicated; at least 14 days should elapse between discontinuation of MAO inhibitor and initiation of bupropion (or vice versa).
• Concurrent use with  MAO-inhibitor-like drugs, such as  linezolid  or  methylene blue, may ↑ risk of hypertensive reactions; concurrent use contraindicated; do not start therapy in patients receiving  linezolid  or  methylene blue ; if  linezolid  or  methylene blue  need to be started in a patient receiving bupropion, immediately discontinue bupropion and monitor for 2 wk or until 24 hr after last dose of linezolid or methylene blue, whichever comes first (may resume bupropion therapy 24 hr after last dose of linezolid or methylene blue).
• May ↑ levels and risk of toxicity of  CYP2D6 substrates, including  SSRIs,  tricyclic antidepressants,  haloperidol,  risperidone,  thioridazine,  metoprolol,  flecainide, and  propafenone.
•  CYP2B6 inducers, including  carbamazepine,  efavirenz,  ritonavir,  lopinavir,  phenobarbital, and  phenytoin, may ↓ levels and effectiveness; avoid concurrent use.
•  CYP2B6 inhibitors, including  clopidogrel, may ↑ levels and risk of toxicity; do not exceed one tablet twice daily.
• Concurrent use of  drugs that ↓ seizure threshold  may ↑ risk of seizures.
•  Dopaminergic drugs, including  amantadine  and  levodopa, may ↑ risk of CNS toxicity.
• Concurrent ingestion of  alcohol  may ↑ risk of neuropsychiatric reactions (reduce or avoid consumption).
• May ↓ renal excretion of and ↑ levels/risk of toxicity from  amantadine,  amiloride,  cimetidine,  dopamine,  famotidine,  memantine,  metformin,  pindolol,  procainamide,  varenicline, and  oxaliplatin.
• May ↓ analgesic effects of  opioids.

Route/Dosage

PO (Adults): Week 1:  One tablet in the morning;  Week 2:  One tablet in the morning and one tablet in the evening;  Week 3:  Two tablets in the morning and one tablet in the evening;  Week 4 and onward:  Two tablets in the morning and two tablets in the evening.   Concurrent use of CYP2B6 inhibitors:  Dose should not exceed one tablet twice daily.

Renal Impairment 
PO (Adults): Moderate or severe renal impairment:  Dose should not exceed one tablet in the morning and one tablet in the evening.

Hepatic Impairment 
PO (Adults): Moderate hepatic impairment:  Dose should not exceed one tablet in the morning and one tablet in the evening.

Availability

Extended-release tablets: 90 mg bupropion/8 mg naltrexone

Assessment

• Monitor for weight loss and adjust concurrent medications (antihypertensives, antidiabetics, lipid-lowering agents) as needed. Discontinue if ≥5% ↓ in baseline body weight is not achieved after 12 wk at maintenance dosage.
• Assess mental status and mood changes, especially during initial few months of therapy. Risk may be ↑ in children, adolescents, and adults ≤24 yr. Inform health care professional if patient demonstrates significant ↑ in signs of depression (depressed mood, loss of interest in usual activities, insomnia or hypersomnia, psychomotor agitation or retardation, ↑ fatigue, feelings of guilt or worthlessness, slowed thinking or impaired concentration, irritability, hostility, suicide or homicide attempt, suicidal ideation). Restrict amount of drug available to patient.
• Monitor for signs and symptoms of opioid withdrawal (tachycardia, diaphoresis, nausea, vomiting, anxiety, tremor, excessive yawning) in opioid-dependent patients.
• Monitor BP and HR at baseline and regularly for hypertension during therapy, especially during the initial 3 mo; ↑ risk in patients with concurrent use of other drugs that ↑ dopaminergic or noradrenergic activity.
• Monitor for signs and symptoms of seizure activity with higher doses, patient factors, clinical situations, and concurrent medications that lower the seizure threshold; ↑ dose gradually and discontinue use if a seizure occurs.
• Monitor for signs and symptoms of anaphylactic reactions (pruritus, urticaria, hives, angioedema, dyspnea). Discontinue therapy and treat symptomatically.

Lab Test Considerations:

Monitor blood glucose prior to and during therapy in patients with type 2 diabetes; may cause hypoglycemia.

• May cause false-positive urine test for amphetamines.

Implementation

• PO Administer in the morning and evening according to dose escalation schedule.  DNC: Swallow tablets whole; do not break, crush, or chew. 
  • Do not administer with a high-fat meal; may ↑ risk of seizures.
• Discontinue opioids prior to starting extended-release naltrexone/bupropion. Patients should be opioid-free for a minimum of 7–10 days in those receiving short-acting opioids and up to 14 days in those receiving buprenorphine or methadone.

Patient/Family Teaching

• Explain the purpose and side effects to patient. Instruct patient to take medication as directed, following the dose escalation schedule. If a dose is missed, omit and wait until next scheduled dose; do not double doses. Advise patient to read  Medication Guide  before starting therapy and with each Rx refill in case of changes.
• Instruct patient to adhere to a reduced-calorie diet and ↑ physical activity.
• Advise patient, family, and caregivers to look for suicidality, especially during early therapy. Notify health care professional immediately if thoughts about suicide, homicide, or dying; attempts to commit suicide; new or worse depression or anxiety, agitation, or restlessness; panic attacks; insomnia; new or worse irritability; aggression; hostility; acting on dangerous impulses; mania; or other changes in mood or behavior occur.
• Advise patient to notify health care professional if signs and symptoms of liver damage (stomach pain lasting more than a few days, dark urine, yellowing of skin and whites of eyes, tiredness) occurs.
• Advise patients they may be less sensitive to opioids during therapy. Advise patients to notify health care professional of bupropion/naltrexone therapy.
• Advise patient to notify health care professional of all Rx or OTC medications, vitamins, or herbal products being taken; to consult with health care professional before taking other medications; and to minimize or avoid alcohol during therapy.
• Rep:  Instruct women of reproductive potential to notify health care professional if pregnancy is planned or suspected and to avoid breastfeeding during therapy. Advise pregnant patients to discontinue medication, as appropriate weight gain based on prepregnancy weight is recommended for all pregnant patients, including those who are overweight or obese, due to the weight gain that occurs in maternal tissues during pregnancy.

Evaluation/Desired Outcomes

Decreased appetite with associated weight loss. Evaluate therapy after 12 wk at maintenance dose. If patient has not lost 5% of baseline body weight discontinue medication; clinically meaningful weight loss is unlikely.