Clinical Drug Investigation

, Volume 30, Issue 6, pp 365–373 | Cite as

Dose Proportionality of Fentanyl Buccal Tablet in Doses Ranging from 600 to 1300μg in Healthy Adult Subjects

A Randomized, Open-Label, Four-Period, Crossover, Single-Centre Study
  • Mona Darwish
  • Mary Kirby
  • Philmore RobertsonJr
  • William Tracewell
  • Fang Xie
Original Research Article


Background: Fentanyl buccal tablet (FBT) is indicated for the treatment of breakthrough pain in patients who are already receiving, and who are tolerant to, opioid therapy for underlying, persistent cancer pain. Breakthrough pain may be severe or excruciating, and some patients may require high doses of rapid-onset opioids to obtain adequate analgesia.

Objective: The objective of this study was to assess the dose proportionality of FBT over a range of 600–1300 μg in healthy subjects.

Methods: This was a randomized, open-label, four-period, crossover, single-centre study of FBT (Fentora®) conducted in healthy adult subjects who were not tolerant to opioids. The study included 120 men and women aged 18–45 years with a body mass index of 20–30 kg/m2 who had no clinically significant findings on medical and psychiatric histories, physical examination, ECG or standard clinical laboratory tests, and who had a negative urine screen for drugs and alcohol. Eligible subjects were randomized to one of four dose sequences: ABDC, BCAD, CDBA and DACB, where A, B, C and D were FBT doses from lowest to highest (600, 1000, 1200 and 1300 μg). Each dose of FBT was separated by a minimum of 7 days. Naltrexone 50 mg was administered to block the opioid receptor-mediated effects of fentanyl. Plasma fentanyl concentration was measured through 72 hours after placement of FBT. The main outcome measures, maximum plasma fentanyl concentration (Cmax) and area under the plasma drug concentration versus time curve from time zero to infinity (AUC∞), were analysed to determine dose proportionality. Other pharmacokinetic parameters were also evaluated. Dose proportionality was concluded if the two-sided 90% confidence intervals (CIs) for the slopes of the Cmax versus dose and AUC∞ versus dose curves were completely contained within the range of 0.711–1.289. The safety and tolerability of FBT were assessed throughout the study.

Results: The slope for Cmax versus dose was 0.8627 (90% CI 0.7730, 0.9525), and the slope for AUC∞ versus dose was 0.9330 (90% CI 0.8738, 0.9922). Given that the CIs for Cmax and AUC∞ were within the predefined range of 0.711–1.289, dose proportionality was concluded over the 600–1300 μg range. The mean dose-normalized plasma fentanyl concentration reached 80% of Cmax within 25 minutes; plasma fentanyl concentration was maintained at this level for 3 hours after dose. No unexpected safety or tolerability concerns were noted in the naltrexone-blocked healthy subjects. Seventy-four subjects (68%) experienced adverse events (AEs); all were mild (56 [51%]) or moderate (18 [17%]). The most common AEs were nausea, dizziness and headache. No serious AEs were reported.

Conclusion: The dose proportionality of FBT from 600–1300 μg was shown in healthy subjects. Based on the data, when FBT is titrated up to 1300 μg, a predictable and linear increase in systemic exposure can be expected. Currently, FBT is approved up to 800 μg. This study provides pharmacokinetic data to support a potential, expanded therapeutic dose range of FBT.


Fentanyl Naltrexone Breakthrough Pain Dose Proportionality Oral Transmucosal Fentanyl Citrate 



This study was sponsored by Cephalon, Inc. (Frazer, PA, USA). The authors acknowledge the medical review by Arvind Narayana, MD, MBA (Cephalon, Inc.). Writing support was provided by Peloton Advantage, LLC, funded by Cephalon, Inc. The authors are employees of Cephalon, Inc.


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Copyright information

© Adis Data Information BV 2010

Authors and Affiliations

  • Mona Darwish
    • 1
  • Mary Kirby
    • 1
  • Philmore RobertsonJr
    • 2
  • William Tracewell
    • 2
  • Fang Xie
    • 1
  1. 1.Clinical ResearchCephalon, Inc.FrazerUSA
  2. 2.Drug Safety & DispositionCephalon, Inc.FrazerUSA

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