Absorption of Fentanyl from Fentanyl Buccal Tablet in Cancer Patients

Abstract and Introduction

Abstract

Background and objectives: Patients with cancer, particularly those undergoing chemotherapy or radiotherapy, may develop oral mucositis. This is the first study to investigate the absorption profile of fentanyl buccal tablet (FBT) -- an effervescent formulation of fentanyl indicated for the management of breakthrough pain in opioid-tolerant cancer patients -- in patients with or without oral mucositis.
Methods: In this open-label study, patients with or without oral mucositis self-administered a single 200µg dose of FBT by placing the tablet between the upper gum and cheek above a molar tooth. Venous blood samples for measurement of plasma fentanyl concentrations were collected at regular intervals up to 8 hours following FBT administration. Parameters of interest included maximum plasma concentration (C_max), time to reach C_max (t_max), area under the plasma concentration-time curve from time zero to 8 hours (AUC₈), and AUC from time zero to the median t_max (AUC_tmax'). Adverse events were monitored throughout the study. Oral mucosal examinations and measurements of vital signs were performed at intervals up to 8 hours following FBT administration.
Results: Sixteen patients, 8 with and 8 without oral mucositis, received FBT and completed the study. The severity of oral mucositis was mild in the patients exhibiting this condition. Median C_max values were comparable: 1.14 ng/mL (range 0.26-2.69 ng/mL) in patients with mucositis, and 1.21 ng/mL (range 0.21-2.34 ng/mL) in patients without mucositis. The t_max was not significantly different in the two groups: median t_max was 25.0 min (range 15-45 min) in patients with mucositis and 22.5 min (range 10-121 min) in patients without mucositis. Median AUC_tmax' values were 0.17ng · h/mL (range 0.04-0.52 ng · h/mL) in patients with mucositis, and 0.20 ng · h/mL (range 0.00-0.65 ng · h/mL) in patients without mucositis. The corresponding AUC₈ values were 2.05 ng · h/mL (range 1.16-3.83 ng · h/mL) and 1.55 ng · h/mL (range 0.74-3.07 ng · h/mL), respectively. FBT was generally well tolerated in this small group. No application site adverse events or changes in oral mucosal assessments were reported.
Conclusion: The absorption profile of a single dose of FBT 200µg was similar in patients with or without mild oral mucositis. The compound was generally well tolerated.

Introduction

Pain is a prevalent symptom in cancer patients, affecting up to 50% of patients undergoing active cancer treatment and up to 90% of those with advanced disease.^[1] In these cancer populations, over half (50-90%) of those with chronic pain despite opioid therapy will experience breakthrough pain, defined as a transient exacerbation of pain that occurs with otherwise stable, controlled, persistent pain.^[2,3]

Oral mucositis is an acute, painful and distressing complication of cancer chemotherapy and radiotherapy.^[4] The resulting ulceration and infection of the oral mucosa has a marked impact on patients´ ability to eat and swallow;^[5] it impairs their quality of life, including social and daily functioning.^[4] Mucositis-related pain affects between 40% and 70% of patients receiving chemotherapy^[6] and is particularly troublesome in patients with head and neck cancer.^[7] Oral mucositis may develop as a result of multiple mechanisms, including direct and indirect cytotoxicity, local tissue cytokine and immune activity, and bacterial colonisation of oral lesions^[8] set against a background of precipitating factors such as age, oral hygiene level, nutritional status and xerostomia.^[9,10]

Fentanyl buccal tablet (FBT) [FENTORA^®, Cephalon, Inc., Frazer, PA, USA)¹ is a novel formulation of fentanyl that facilitates rapid absorption of the active compound through the oral mucosa using an enhanced effervescent absorption technology (OraVescent^®; CIMA Labs, Inc., Eden Prairie, MN, USA). FBT has been shown to provide rapid-onset analgesia and to be well tolerated in the treatment of cancer-related breakthrough pain,^[11] and is indicated for the management of breakthrough pain in patients with cancer who are already receiving and who are tolerant to opioid therapy for their underlying persistent pain. Transmucosal delivery of FBT is achieved by placing the tablet buccally between the upper gum and the mucosal surface of the cheek above a molar tooth. Absorption of fentanyl from FBT is optimised by the effervescent reaction that produces shifts in pH within the microenvironment between a dissolving FBT and the buccal mucosa.^[12]

It was hypothesised that the tolerability and absorption of FBT may be different in opioid-tolerant patients with cancer and oral mucositis compared with those without oral mucositis. This study assessed the absorption profile and tolerability of FBT in these two populations.

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