Interactions : אינטראקציות

4.5   Interaction with other medicinal products and other forms of interaction

Effect of other drugs on fentanyl
Central Nervous System (CNS) depressants
The use of opioid premedication, barbiturates, benzodiazepines or related drugs, neuroleptics, general anaesthetics, gabapentinoids (gabapentin and pregabalin), and other non-selective CNS depressants (e.g. alcohol) may enhance or prolong the respiratory depression of fentanyl.
When patients have received other CNS-depressants, the dose of fentanyl required may be less than usual. Concomitant use with Fenta Injection in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma, and death (see section 4.4, Special warnings and precautions for use).


Cytochrome P450 3A4 (CYP3A4) inhibitors
Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4. When Fenta Injection is used, the concomitant use of a CYP3A4 inhibitor may result in a decrease in fentanyl clearance. With single-dose Fenta Injection administration, the period of risk for respiratory depression may be prolonged, which may require special patient care and longer observation. With multiple-dose Fenta Injection administration, the risk for acute and/or delayed respiratory depression may be increased, and a dose reduction of Fenta Injection may be required to avoid accumulation of fentanyl. Oral ritonavir (a potent CYP3A4 inhibitor) reduced the clearance of a single intravenous fentanyl injection 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 injection dose. Co- administration of other potent or less potent CYP3A4 inhibitors, such as voriconazole or fluconazole, and Fenta Injection may also result in an increased and/or prolonged exposure to fentanyl.
Bradycardia and possibly cardiac arrest can occur when fentanyl is combined with non- vagolytic muscle relaxants.
Serotonergic Drugs
Coadministration of fentanyl with a serotonergic agent, such as a Selective Serotonin Re-uptake Inhibitor (SSRI) or a Serotonin Norepinephrine Re-uptake Inhibitor (SNRI) or a Monoamine Oxidase Inhibitor (MAOI), may increase the risk of serotonin syndrome, a potentially life-threatening condition (see section4.3, Contraindications and section 4.4, Special warnings and precautions for use).
Effect of fentanyl on other drugs
Following the administration of Fenta Injection, 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 section 4.4, Special warnings and precautions for use).
Plasma concentrations of etomidate increased considerably (by a factor 2-3) when combined with fentanyl. 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.