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 Fentanyl-Piramal in spontaneously breathing patients may increase the risk of respiratory depression, profound sedation, coma, and death (see warnings and precautions).
Cytochrome P450 3A4 (CYP3A4) inhibitors
Fentanyl, a high clearance drug, is rapidly and extensively metabolised mainly by CYP3A4. When Fentanyl-Piramal is used, the concomitant use of a CYP3A4 inhibitor may result in a decrease in fentanyl clearance. With single-dose Fentanyl-Piramal administration, the period of risk for respiratory depression may be prolonged, which may require special patient care and longer observation. With multiple-dose Fentanyl- Piramal administration, the risk for acute and/or delayed respiratory depression may be increased, and a dose reduction of Fentanyl-Piramal may be required to avoid accumulation of fentanyl. Oral ritonavir (a potent CYP3A4 inhibitor) reduced the clearance of a single intravenous Fentanyl-Piramal 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-Piramal dose. Co- administration of other potent or less potent CYP3A4 inhibitors, such as voriconazole or fluconazole, and Fentanyl-Piramal 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 section 4.3 Contraindications).


Effect of fentanyl on other drugs
Following the administration of Fentanyl-Piramal, 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 warnings and precautions).
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.