What are the potential interactions with Zepbound (eszetamine), particularly with central nervous system depressants, such as benzodiazepines, opioids, or alcohol, and other medications like fluoxetine (Prozac, a selective serotonin reuptake inhibitor (SSRI))?

Potential Interactions with Zepbound (Tirzepatide)

Zepbound (tirzepatide) should not be combined with benzodiazepines, opioids, or alcohol due to the significant risk of central nervous system depression and potentially fatal respiratory depression.

CNS Depressant Interactions

Benzodiazepines

• Concurrent use of benzodiazepines with other CNS depressants significantly increases the risk of potentially fatal overdose 1
• Epidemiologic evidence shows concurrent benzodiazepine use in a large proportion of opioid-related overdose deaths 1
• A case-cohort study found that concurrent benzodiazepine prescription with opioid prescription was associated with nearly quadrupling the risk for overdose death compared to opioid prescription alone 1
• Benzodiazepines cause central nervous system depression and can decrease respiratory drive, leading to potentially life-threatening respiratory depression when combined with other CNS depressants 1

Opioids

• Opioids combined with benzodiazepines or other CNS depressants significantly increase the risk of fatal and non-fatal overdose 2
• The American Geriatrics Society explicitly recommends avoiding concurrent use of opioids with benzodiazepines due to increased fall risk and CNS depression 1
• Patients with chronic pain who use opioid analgesics along with benzodiazepines have higher rates of adverse events, overdose, and death 2

Alcohol

• Alcohol potentiates the central nervous system depression associated with other CNS depressants 1
• Combining alcohol with benzodiazepines significantly increases toxicity - benzodiazepine overdose may be lethal when taken simultaneously with alcohol 3
• Patients should be explicitly warned about avoiding the combination of alcohol with any CNS depressant medication 1

SSRI Interactions (Fluoxetine/Prozac)

• SSRIs like fluoxetine have potential for drug-drug interactions through the cytochrome P450 system 1
• Fluoxetine may interact with drugs metabolized by CYP2D6 1
• When combining serotonergic medications (such as SSRIs like fluoxetine), there is risk of serotonin syndrome, which can cause:
  • Mental status changes (confusion, agitation, anxiety)
  • Neuromuscular hyperactivity (tremors, clonus, hyperreflexia, muscle rigidity)
  • Autonomic hyperactivity (hypertension, tachycardia, arrhythmias)
  • In severe cases: fever, seizures, unconsciousness, and death 1
• Caution should be exercised when combining two or more serotonergic drugs, with monitoring for symptoms especially in the first 24-48 hours after dosage changes 1

Management Recommendations

• Avoid concurrent prescribing of Zepbound with benzodiazepines, opioids, or alcohol whenever possible 1
• If concurrent therapy is absolutely necessary:
  • Use the lowest effective doses of each medication
  • Monitor patients closely for signs of excessive sedation or respiratory depression
  • Consider involving pharmacists and specialists as part of the management team 1
• If tapering is required to reduce risk:
  • It is generally safer to taper opioids before benzodiazepines due to greater risks of benzodiazepine withdrawal 1
  • Benzodiazepines should be tapered gradually (25% reduction every 1-2 weeks) to avoid withdrawal symptoms including rebound anxiety, hallucinations, seizures, and delirium tremens 1
• For patients requiring treatment of anxiety while on Zepbound:
  • Consider evidence-based psychotherapies (e.g., CBT)
  • Consider specific non-benzodiazepine medications approved for anxiety 1
• Regular urine drug testing is recommended for patients on chronic therapy with CNS depressants to confirm adherence to the treatment plan 2

Special Considerations

• Elderly patients are at particularly high risk for adverse effects from CNS depressant combinations and require dose reductions 1
• Patients with compromised respiratory function (e.g., asthma, COPD, sleep apnea) are at higher risk for respiratory depression with CNS depressants 1
• Patients with hepatic impairment may have reduced metabolism of many CNS depressants, increasing risk of toxicity 1