Cobicistat

Fentanyl

Generally avoid.

No pharmaceutical opinion available for this interaction.

Mechanism

Cobicistat can inhibit the metabolism (CYP 3A4) and increase the plasma concentration of Fentanyl.

Cobicistat

Pharmacodynamic effects

Recommendations

Alternative solution(s)

Fentanyl

Pharmacodynamic effects

Possible increase of adverse effects including potentially fatal respiratory depression.

Recommendations

Start with a low dosage if it is a new coadministration, or reduce significantly the dosage of fentanyl. A reduction of 50% of the intended dose may be necessary (to be adjusted according to the patient).

Then adjust the dose depending on effectiveness of treatment and tolerance. Requires special attention. See comments.

Or choose an alternative.

In patients already being treated with this combination and tolerating it, if deemed appropriate, keep actual treatment and exercise close monitoring of adverse effects.

Alternative solution(s)

Morphine and hydromorphone. As a precaution, start with 60 to 75% of the converted dose of oxycodone. Start analgesic substitution 8 hours after cessation of fentanyl.

Monitor

Signs and symptoms of opioid toxicity miosis, euphoria, dysphoria, drowsiness, confusion, excessive sedation, decreased alertness, hallucinations, dizziness, bradycardia, myoclonus, hypotension, prolonged or recurrent respiratory depression.

Tests

Pharmacokinetic parameters

Comment

Ref #1066 : In a study conducted with ritonavir, a potent CYP 3A4 inhibitor and fentanyl IV, a decrease of approximately 70% of fentanyl clearance and an increase in fentanyl half-life of 9.4 to 20.1 hours were observed.
Ref #2253 : Be cautious with any CYP 3A4 inhibitor. A case of death was reported with the use of Lopinavir/Ritonavir.
Ref #2590 : A case of delirium has been reported with the combination of fentanyl and diltiazem, a potent inhibitor of CYP3A4.
Ref #2591 : Cases of fentanyl poisoning have also been reported with antifungal agents such as itraconazole (a potent CYP3A4 inhibitor).

Recommandations : Requires special attention.

If the patient is already under fentanyl and antiretroviral therapy is started: remove the patch and start 8 hours later a decreased dose of fentanyl (suggested 50% of the dose) and then adjust according to efficacy and tolerability
or
Choose an alternative (morphine or hydromorphone). As a precaution use 60-75% of the dose converted. If possible stop the fentanyl patch 48 hours before starting the antiretrovirals and begin analgesia substitution 8 hours after discontinuation of fentanyl.
Monitor closely for signs and symptoms of toxicity narcotic.

If fentanyl is added to existing antiretroviral therapy : start with a small dose and gradually increase depending on the tolerance and efficacy or choose an alternative (morphine or hydromorphone).
Monitor closely for signs and symptoms of toxicity narcotic.

Reference
  • 2253
    Bulletin canadien des effets indésirables. Timbre de fentanyl et effets indésirables mortels. 2008: 18(3): 1-2.
  • 2590
    Levin TT, Bakr MH, Nikolova T. Case report: delirium due to a diltiazem-fentanyl CYP3A4 drug interaction. Gen Hosp Psychiatry. 2010; 32(6): 648.e9-648.e10.
  • 2591
    Mercadante S, Villari P AN Ferrera P. Itraconazole–Fentanyl Interaction in a Cancer Patient. Journal of Pain and Symptom Management. 2012; 24(3) : 284-286.
  • 3103
    Fentanyl (Duragesic MAT). Jansenn, Ontario, Canada, août 2014.
  • 2430
    Smith HS, Opioid Metabolism Mayo Clin Proc; 2009; 84(7):613-624.
  • 3104
    Maurer HH, Sauer C, Theobald DS. Toxicokinetics of drugs of abuse: current knowledge of the isoenzymes involved in the human metabolism of tetrahydrocannabinol, cocaine, heroin, morphine, and codeine. Ther Drug Monit. 2006 Jun; 28 (3): 447-453.
  • 1066
    Olkkola KT, Palkama VJ, and Neuvonen PJ. Ritonavir’s role in reducing fentanyl clearance and prolonging its half-life. Anesthesiol 1999;91:681-685.