Effect of other drugs on FENTANYL: Central Nervous System (CNS) depressants: Drugs such as barbiturates, benzodiazepines or related drugs, neuroleptics, general anesthetics, and other, non-selective CNS depressants (e.g., alcohol) may potentiate the respiratory depression of opioids. When patients have received such CNS depressant drugs, the dose of FENTANYL required may be less than usual. Concomitant use with FENTANYL in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma, and death (see Precautions).
Cytochrome P450 3A4 (CYP3A4) inhibitors: Fentanyl, a high clearance drug, is rapidly and extensively metabolized mainly by CYP3A4. When FENTANYL is used, the concomitant use of a CYP3A4 inhibitor may result in a decrease in fentanyl clearance. With single-dose FENTANYL administration, the period of risk for respiratory depression may be prolonged, which may require special patient care and longer observation. With multiple-dose FENTANYL administration, the risk for acute and/or delayed respiratory depression may be increased, and a dose reduction of FENTANYL may be required to avoid accumulation of fentanyl. Oral ritonavir (a potent CYP3A4 inhibitor) reduced the clearance of a single intravenous FENTANYL dose by two thirds, although peak plasma concentrations of fentanyl were not affected. However, itraconazole (another potent CYP3A4 inhibitor) at 200 mg/day given orally for 4 days had no significant effect on the pharmacokinetics of a single intravenous FENTANYL dose. Co-administration of other potent or less potent CYP3A4 inhibitors, such as voriconazole or fluconazole, and FENTANYL may also result in an increased and/or prolonged exposure to fentanyl.
Monoamine Oxidase Inhibitors (MAOI): It is usually recommended to discontinue MAOIs 2 weeks prior to any surgical or anesthetic procedure. However, several reports describe the uneventful use of FENTANYL during surgical or anesthetic procedures in patients on MAOIs.
Serotonergic drugs: Coadministration of fentanyl with a serotonergic agent, such as a SSRI, SNRI, or MAOI, may increase the risk of serotonin syndrome, a potentially life-threatening condition.
Effect of FENTANYL on other drugs: Following the administration of FENTANYL, the dose of other CNS-depressant drugs should be reduced. This is particularly important after surgery, because profound analgesia is accompanied by marked respiratory depression, which can persist or recur in the postoperative period. Administration of a CNS depressant, such as a benzodiazepine or related drugs, during this period may disproportionally increase the risk for respiratory depression (see Precautions).
The total plasma clearance and volume of distribution of etomidate is decreased by a factor of 2 to 3 without a change in half-life when administered with fentanyl. Simultaneous administration of FENTANYL and intravenous midazolam results in an increase in the terminal plasma half-life and a reduction in the plasma clearance of midazolam. When these drugs are co-administered with FENTANYL, their dose may need to be reduced.