Table 8: Fentanyl Drug-Drug Interactions
| Interacting Drug | Interaction | Recommendation | Clinical Significance Level# |
|---|---|---|---|
| amiodarone | concurrent use may result in cardiac toxicity (e.g., bradycardia, low cardiac output) and increased risk of fentanyl toxicity (e.g., respiratory and CNS depression) as amiodarone inhibits CYP3A4 | if combination utilized, monitor patients closely for enhanced pharmacologic/toxic effects | major (DrugReax) 3-moderate (CP) |
| CNS depressants (e.g., skeletal muscle relaxants, haloperidol, other opioids) | potential for additive CNS effects, including respiratory depression, excessive sedation or coma | use cautiously together; modify fentanyl doses as necessary and observe patients for enhanced CNS adverse effects | major (DrugReax) 2-major (CP) |
| CYP3A4 inducers (e.g., rifampin, barbiturates, carbamazepine, phenytoin, aprepitant, efavirenz) | may increase fentanyl clearance and reduce fentanyl systemic concentrations leading to decrease effectiveness as fentanyl is a CYP3A4 substrate | monitor fentanyl efficacy in patients prescribed CYP3A4 inducers concurrently; adjust doses as necessary when CYP3A4 inducer added, deleted, or changed to therapeutic regimen | moderate (DrugReax) 2-major, 3-moderate (CP) |
| CYP3A4 inhibitors (e.g., aprepitant, protease inhibitors, macrolides, azole antifungals, efavirenz) | may decrease fentanyl clearance and increase fentanyl systemic concentrations leading to potential for enhanced pharmacologic/toxic effects as fentanyl is a CYP3A4 substrate | monitor for enhanced fentanyl pharmacologic/toxic effects and adjust doses as necessary | strong inhibitors - contraindicated, inhibitors - major (DrugReax) 2-major, 3-moderate (CP) |
| MAOIs (e.g., phenelzine, procarbazine, linezolid) | concurrent administration may potentiate severe, unpredictable opioid effects including CNS depression and hypotension | fentanyl should not be prescribed during or within 14 days of MAOI administration | major (DrugReax) 2-major (CP) |
| mifepristone | adjunctive administration may result in increased fentanyl serum levels and the potential for enhanced pharmacologic/ serious adverse effects as fentanyl is a CYP3A4 substrate and mifepristone is a CYP3A4 inhibitor | avoid concurrent administration | contraindicated (DrugReax) 1-severe (CP) |
| nasal decongestants (e.g., oxymetazoline) and intranasal fentanyl | combined administration of intranasal fentanyl with vasoconstrictive nasal decongestants results in reduced fentanyl absorption through the nasal mucosa, reduced Cmax and delayed Tmax, and the potential for reduced effectiveness in pain management | use combination cautiously; avoid intranasal fentanyl dose titration in patients using vasoconstrictive decongestants as inappropriate maintenance dose may be calculated; interaction does not occur with other fentanyl dosage forms | 2-major (CP) |
| opioid antagonists (e.g., naloxone, naltrexone) | may precipitate withdrawal symptoms and/or decrease fentanyl effectiveness | use with caution only when necessary and monitor for signs of fentanyl withdrawal/loss of efficacy | naltrexone: contraindicated (DrugReax) 2-major (CP) |
| serotonergic agents (e.g., selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors) | concurrent use increases risk for serotonin syndrome or neuroleptic malignant syndrome-like reactions as both agents have serotonergic properties | administer cautiously together; observe for signs/symptoms of serotonin syndrome (e.g., agitation, confusion, hyperthermia, shivering) | major (DrugReax) 2-major (CP) |
Legend:
- #CP = Clinical Pharmacology
- CNS = central nervous system
- Cmax = maximum serum concentration
- CYP = cytochrome P450
- MAOIs = monoamine oxidase inhibitors
- Tmax = time when maximum serum concentration is reached