Cilostazol and Fentanyl Transdermal Patch: Interaction Details

a) One fatal case of possible fentaNYL-fluconazole interaction was reported. The author judged that the patient died from fentaNYL intoxication. Furthermore, in a randomized crossover study with 12 healthy volunteers, it was shown that fluconazole delayed the elimination of fentaNYL significantly. Elevated fentaNYL concentration may lead to respiratory depression ⁶.

b) Twelve healthy volunteers received either placebo or ritonavir orally 3 times daily for 3 days, with a dose of fentaNYL 5 mcg/kg IV being administered after the second dose of ritonavir on the second day. To prevent the sedative and respiratory depressant effects of fentaNYL, naloxone was given before and with the fentaNYL dose. One subject discontinued the study before the administration of fentaNYL. In the 11 remaining participants, ritonavir decreased the plasma clearance of fentaNYL by 67% (from 15.6 to 5.2 mL/min/kg). The elimination half-life of fentaNYL increased from 9.4 hours to 20.1 hours after ritonavir, and the area under the concentration-time curve (AUC) increased by 174% (from 6.6 to 18.1 ng/mL/hr) when compared to placebo. It is considered probable that ritonavir would similarly affect the elimination of transdermally administered fentaNYL ⁵.

c) Coadministration of fluconazole with a single IV dose of fentaNYL decreased the mean plasma clearance of fentaNYL by 16% in an open, randomized, crossover study. Twelve healthy volunteers received a single IV dose of fentaNYL 5 mcg/kg either alone (control phase) or 1 hour following receipt of the final dose of fluconazole on day 2 (400 mg orally once daily on day 1, followed by 200 mg orally once daily on day 2). To prevent the sedative and respiratory depressant effects of fentaNYL, naloxone was given before and with the fentaNYL dose. All 12 subjects completed the study. During the fluconazole phase, the mean plasma clearance was decreased by 16% (range, -34% to 53%; p less than 0.05) compared with the control phase. Also, while a nonsignificant increase in the fentaNYL AUC was observed (fluconazole phase, 7.7 +/- 2.3 nanograms (ng) x hr/mL vs control phase 6.1 +/- 1.1 ng x hr/mL), a notable decrease in the inactive metabolite, norfentaNYL, occurred (fluconazole phase, 0.8 +/- 0.7 ng x hr/mL vs control phase, 1.8 +/- 1.1 ng x hr/mL) and the ratio of the norfentaNYL AUC to the fentaNYL AUC was significantly lower in the fluconazole phase compared with the control phase (AUC ratio, 0.1 +/- 0.1 vs 0.3 +/- 0.2). The mean elimination half-life of fentaNYL did not differ between the phases. The change in fentaNYL clearance appeared to be due to the inhibition of CYP3A4-mediated N-dealkylation of fentaNYL to norfentaNYL ⁷.

d) A 46-year-old man receiving transdermal fentaNYL died following concurrent treatment with fluconazole. The patient was experiencing oral pain caused by radiation therapy for tonsillar cancer was treated with fentaNYL 100 mcg/hr transdermal patch. Over the next 1.5 months, the fentaNYL dose was increased to 150 mcg/hr. Concomitant medications included morphine 10 mg orally once daily, diclofenac 50 mg orally 3 times daily, paracetamol 1000 mg orally 3 times daily, oxazepam 15 mg orally twice daily, zolpidem 5 mg orally nightly, nystatin (100,000 international units/mL) 4 times daily, metoclopramide 20 mg rectally 3 times daily, lidocaine oral spray, and lactulose. Two weeks after increasing the fentaNYL dose to 150 mcg/hr, the patient underwent a percutaneous gastrostomy because of worsening dysphagia. He developed an oral fungal infection 8 days later and was started on oral fluconazole 50 mg/day. Three days later, he died in his sleep. Forensic analysis revealed a toxic concentration of fentaNYL (0.017 mcg/g), high concentrations of fluconazole (2.4 mcg/g), lidocaine (1.6 mcg/g), and metoclopramide (0.15 mcg/g), along with a therapeutic concentration of zolpidem. The forensic analysis did not reveal any signs of ethanol or drugs of abuse. The only pathological findings noted from the autopsy were pulmonary congestion and brain edema. There was no sign of intentional overdosing, and the coroner concluded that respiratory depression and circulatory failure from fentaNYL intoxication was the cause of death ⁸.

e) Coadministration of voriconazole with a single IV dose of fentaNYL increased the mean AUC of fentaNYL by 1.4-fold and decreased the mean plasma clearance by 23% in an open, randomized, crossover study. Twelve healthy volunteers received a single IV dose of fentaNYL 5 mcg/kg either alone (control phase) or 1 hour following receipt of the final dose of voriconazole on day 2 (400 mg orally twice daily on day 1, followed by 200 mg orally twice daily on day 2). To prevent the sedative and respiratory depressant effects of fentaNYL, naloxone was given before and with the fentaNYL dose. All 12 subjects completed the study. During the voriconazole phase, the mean AUC (0 to infinity) of fentaNYL was increased by 1.4-fold (range, 0.81- to 2.04-fold) and the mean plasma clearance was decreased by 23% (range -22% to 48%) compared with the control phase. Notably, the mean fentaNYL plasma concentration at 12 hr during the voriconazole phase matched the level at 6 hr during the control phase. The mean elimination half-life of fentaNYL also did not differ between the phases. Nausea and vomiting were reported in 4 subjects during the voriconazole phase and in 2 subjects during the control phase. No further doses of naloxone were required and no other adverse events were reported ⁷.