Utilization of fentanyl buccal tablets in England: Exploring off-label use reported in a cohort...

ORIGINAL ARTICLE

Utilization of fentanyl buccal tablets in England: Exploringoff-label use reported in a cohort studyV. Osborne1,2, D. Layton1,2, C. Fogg1,2, M. Al-Shukri1, S.A.W. Shakir1,2

1 Drug Safety Research Unit, Southampton, UK

2 School of Pharmacy and Biomedical Science, University of Portsmouth, UK

CorrespondenceVicki Osborne

E-mail: [email protected]

Funding sourcesThe Drug Safety Research Unit (DSRU) is an

independent charity (No. 327206) that works

in association with the University of

Portsmouth. It receives unconditional

donations from pharmaceutical companies.

The companies have no control on the

conduct or the publication of the studies

conducted by the DSRU. The unit has

received such funds from the manufacturer of

fentanyl buccal tablets (Cephalon). The DSRU

retained its academic independence with

respect to the conduct of the study and

external communications of the results of

the study.

Conflicts of interestSaad Shakir has received money for providing

training and advice in pharmacovigilance to

pharmaceutical companies. Deborah Layton

has received money for the development of

an educational module on ADR reporting for

the Royal Pharmaceutical Society and as a

guest lecturer to undergraduate pharmacy

students. Mohammad Al-Shukri is now an

employee of GlaxoSmithKline. Vicki Osborne

and Carole Fogg have no conflicts of interest

to declare.

Accepted for publication22 July 2013

doi:10.1002/j.1532-2149.2013.00389.x

Abstract

Background: Fentanyl citrate buccal tablets are indicated for thetreatment of breakthrough pain (BTP) in cancer, in adults who arereceiving maintenance opioid therapy for chronic cancer pain.Objective: One of the objectives of this study was to describe theutilization characteristics of patients prescribed fentanyl buccal and toassess how the product is being used in relation to the terms of licenseof marketing approval.Methods: An observational post-marketing cohort study was conducted.For the analysis of this study, exposure data were collected from dispensedprescriptions issued by general practitioners (GPs) between March 2009and June 2011. Outcome data (indication, event, patient demographic andselected clinical characteristics) were collected by sending questionnairesto GPs at least 6 months after the drug was first prescribed. Summarydescriptive statistics were calculated.Results: The cohort consisted of 551 patients, of which 54.8% (n = 302patients) were female. The median age for the cohort was 62 years(interquartile range: 50–72 years), with one patient (0.2%) aged less than18 years. A primary indication of BTP in cancer was reported for 61.9%(n = 341) patients. Regular opioid therapy was reported upon starting thetreatment for 383 patients (69.5% of cohort). In total, 69 patients (12.5%)had one or more contraindications for use. The most frequent initialtitration dose was 100 μg/day (n = 247).Conclusions: The final study results show that fentanyl buccal is largelybeing prescribed according to the terms of the license in general practice inEngland, but off-licence use and use in the presence of contraindicationsand warnings have been reported.

1. Introduction

Fentanyl citrate buccal tablets (Effentora™; Cephalon,Harlow, UK), an opioid analgesic, first marketed inJanuary 2009 in the United Kingdom, are indicated

for the management of breakthrough pain (BTP) inadult patients with cancer who are already receivingand who are tolerant to opioid therapy for theirunderlying persistent cancer pain (Cephalon, 2010).In the United Kingdom, this product is classified as a

© 2013 European Pain Federation - EFIC®506 Eur J Pain 18 (2014) 506–512

mailto:[email protected]

Class A drug according to the Misuse of Drugs Act1971 (based on the harmfulness attributable to a drugwhen misused) and subject to Schedule 2 require-ments regarding prescribing, supply and possessionaccording to the Misuse of Drugs Regulation 2001.

Fentanyl buccal tablets are available in the followingstrengths: 100, 200, 400, 600 and 800 μg. TheSummary of Product Characteristics (SmPC) states thatfentanyl buccal should be individually titrated to aneffective dose, and patients should be carefully moni-tored until an effective dose is reached. An effectivedose is defined as a dose that provides adequate anal-gesia and minimizes undesirable effects (Cephalon,2010).

This study was conducted to fulfil the post-authorization commitment to the European MedicinesAgency. A Risk Minimization Plan (RMP) has beendeveloped for fentanyl buccal tablets by the manufac-turer. To add information to the RMP for fentanylbuccal tablets regarding minimization of abuse, theDrug Safety Research Unit (DSRU) has conducted apost-marketing surveillance study of fentanyl buccaltablets in primary care in England, using the non-interventional observational cohort technique ofModified Prescription-Event Monitoring (M-PEM)(Layton et al., 2011).

M-PEM systematically collects data on patients pre-scribed a drug in primary care clinical practice, includ-ing high-risk groups who may previously have beenexcluded from controlled clinical trials. Customizeddata-collection questionnaires are designed for thesestudies. Examples of the modifications may relateto establishing baseline characteristics of patients inrelation to pre-specified risks, identifying physicianprescribing and decision-making behaviour, and

evaluating risks of adverse events over various timeframes, including periods prior to starting or after dis-continuation of treatment.

This paper reports the results of an M-PEM post-marketing surveillance study undertaken to examinethe utilization of fentanyl buccal tablets as used inprimary care (general practice) in England.

2. Methods

2.1 Study design

An observational, retrospective, records-based, single-exposure cohort design. The general methodology has beenpublished in detail (Shakir, 2007; Layton et al., 2011). Studyspecific details are summarized below.

2.2 Identification of patients

Patients were identified by means of data from dispensedNational Health Service (NHS) prescriptions for fentanylbuccal tablets, written by general practitioners (GPs) inEngland between March 2009 and June 2011. These pre-scription data were supplied in confidence to the DSRU bythe NHS Business Services Authority.

At least 6 months after the first identified fentanyl buccaltablets prescription was issued for each patient, the prescrib-ing doctor was sent a questionnaire by post. All patients witha returned questionnaire, which confirmed that fentanylbuccal tablets had been prescribed, were included. Patientswere included in the study regardless of the dose or fre-quency of administration of fentanyl buccal tablets andirrespective of whether any medicines were concurrentlyadministered.

2.3 Data collection

The postal questionnaire sought information on how fenta-nyl citrate buccal was prescribed in daily medical practice.Prescribers were asked to summarize relevant informationthat has been recorded in the patient’s medical charts as partof routine clinical care. This included describing the indica-tion for prescribing fentanyl buccal tablets as either ‘Break-through pain in cancer’ or any ‘Other indication’ (GP invitedto further specify in free text format) on the questionnaire.The GP was also asked to indicate which practitioner initi-ated fentanyl buccal tablets. The questionnaire asked GPs toindicate in which setting fentanyl buccal tablets were initi-ated and which strength of tablet their patient was prescribedfor the initial titration dose, effective dose and dose to beused as part of the maintenance regimen. The date each dosewas reached was also requested, along with the frequencyper day for the maintenance regimen. GPs were also asked toreport if their patients had received any other medicationsfor pain control at the time of starting fentanyl buccal tablets,including other regular maintenance opioid therapy, pro re

What’s already known about this topic?• Off-label prescribing of opioids is a concern that

is specifically mentioned in the risk managementplans of new products due to the unknown riskof using a product outside the terms of thelicense.

What does this study add?• The amount of off-label prescribing of fentanyl

buccal tablets in primary care in England hasbeen quantified and a low level of off-label pre-scribing has been observed.

• However, fentanyl buccal is largely being pre-scribed for its licensed indication in general prac-tice in England.

V. Osborne et al. Utilization of fentanyl buccal tablets in England

© 2013 European Pain Federation - EFIC® Eur J Pain 18 (2014) 506–512 507

nata opioid use and other analgesic or adjuvant therapy.Information on prior and concomitant use of monoamineoxidase inhibitors (MAOI) and cytochrome P450 3A4(CYP3A4) inhibitors was requested, as use within 14 daysand concomitant use of MAOI inhibitors is contraindicated.In addition, concomitant use of CYP3A4 inhibitors is aspecial warning and precaution for use.

All data reported on questionnaires were coded onto theDSRU database (PEMbase).

2.4 Analysis

To examine the utilization of fentanyl buccal tablets, the datawere summarized quantitatively using descriptive statistics.All percentages were calculated using a denominator ofknown values for each data point, with the numbers ofpatients with known data expressed. We then assessed howthe product is being used in relation to the terms of license ofmarketing approval as defined in the SmPC at the time ofmarketing (Cephalon, 2010).

2.5 Ethical considerations

This study was conducted in accordance with the nationaland international guidelines (Royal College of Physicians ofLondon, 1996>; CIOMS-WHO, 2002; General MedicalCouncil, 2004; British Medical Association Board of Science,and British Medical Association Science & Education, 2006).In addition, under Section 251 of the NHS Act 2006, theDSRU have received support from the Ethics and Confiden-tiality Committee of the National Information GovernanceBoard to gain access to and process patient identifiable infor-mation without consent for the purposes of medical research(October 2009).

3. Results

3.1 Cohort characteristics

Of the 1277 M-PEM questionnaires posted to prescrib-ing GPs, 718 (56.2%) were returned. Of the 718returned forms, 162 (22.6%) provided no useable dataand were excluded from the evaluable cohort. Of the556 valid forms, five patients were further excludeddue to inability to confirm whether the patient hadbeen prescribed fentanyl buccal tablets (date of start-ing reported by the GP was prior to the drug launchdate in the United Kingdom), resulting in a finalevaluable cohort of 551 patients.

There were 302 (54.8%) women and 248 (45.0%)men. The median age of the cohort was 62 years, withan interquartile range (IQR) of 50–72 years [women,60 years (IQR 48–71 years); men, 63 years (IQR 54–72years)].

The median period of observation (time intervalbetween date of first prescription and date the M-PEMquestionnaire was returned) was 173 days (IQR 35and 393 days).

Cohort characteristics are presented in Table 1.

3.2 Paediatric use

There was one patient aged less than 18 years in thecohort, which is a contraindication for use (Cephalon,2010). The patient was a 14-year-old girl with aprimary indication of BTP in cancer. No events orsuspected adverse drug reactions (ADRs) werereported in this patient. This patient was not excludedfrom the cohort and is included in all subsequent drugutilization analyses.

3.3 Indication for prescribing

The most commonly reported indication was BTP incancer in 71.6% (341/476) of patients with an indica-

Table 1 Cohort characteristics.

Characteristics Total cohort n = 551

Age at start of treatment (years), n (%)

0–17 1 (0.2)

18–29 22 (4.0)

30–39 28 (5.1)

40–49 82 (14.9)

50–59 110 (20.0)

60–69 136 (24.7)

≥70 171 (31.0)

Median age (IQR) 62 (50–72)

Not known (% of total) 1 (0.2)

Sex, n (%)

Male 248 (45.0)

Female 302 (54.8)


Indication, n (%)

BTP 341 (61.9)

BTP and other 2 (0.4)

Other indications 133 (24.1)


Concomitant drugs for pain control, n (%)

Regular maintenance opioid 383 (69.5)

PRN opioid use 178 (32.3)

Analgesic/Adjuvant therapy 256 (46.5)

BMI, n (%)

<18.5 9 (1.6)

18.5–24.9 115 (20.9)

25–29.9 109 (19.8)

30–39.9 81 (14.7)

40+ 9 (1.6)


BMI, body mass index; BTP, breakthrough pain; IQR, interquartile range;

PRN, pro re nata.

Utilization of fentanyl buccal tablets in England V. Osborne et al.


tion specified. Some of the other indications reportedwere pain (n = 16), chronic pain (n = 9), multiple scle-rosis (n = 7) and osteoarthritis (n = 4).

For 484 patients, the practitioner initiating treat-ment most frequently was ‘Doctor-NHS primary care(GP)’ (n = 243, 50.2% where initiator specified). Thenext most frequently reported prescriber type was‘Doctor – NHS secondary care’ (n = 231, 47.7%).

For 402 patients, the setting most frequentlyreported to have been where treatment was initiatedwas ‘Other setting’ (n = 185, 46.0% where settingspecified). These reports were where treatment wasinitiated in the patient’s own home under medicalcare or where the setting of initiation differed from theoptions provided which were acute hospital ward, carehome, community hospital and specialist palliativecare hospital.

3.4 Dose

Where specified (n = 433), the most frequent initialtitration dose (n = 247) reflected the lowest strength offentanyl buccal (100 μg), which is in line with pre-scribing recommendations for treatment initiation.Where specified (n = 201), the most frequent effectivedose reported was 100 μg (n = 66), as was the dosereported on initiation of maintenance regimen offentanyl buccal tablets (n = 72 of 200 responses).There were four reports of doses in excess of 800 μgfor both the effective and the maintenance doses; onereport of 1000 μg, two reports of 1200 μg and one of3200 μg.

The median time from test dose to effective dose was19.5 days (IQR 0–61 days), while the median timefrom effective dose to initiating maintenance regimenwas 0 days (IQR 0–7 days). Overall, the median timefrom test dose to initiating maintenance regimen was25 days (IQR 0–64 days).

3.5 Prior and concomitant medications

There were no reports of MAOI use within 14 daysprior to starting the treatment. There was 1 report ofMAOI use (0.2% of cohort) and 13 reports ofCYP3A4 inhibitor use (2.4% of cohort) during treat-ment with fentanyl buccal tablets. For one patient,both MAOI and CYP3A4 inhibitor use were reportedduring treatment with fentanyl buccal tablets. Nosuspected ADRs to fentanyl buccal tablets or seriousevents were reported in any of the patients concomi-tantly using either CYP3A4 or MAOI inhibitors in thecohort.

The most frequently reported other medication atthe start of treatment was regular opioid therapy(n = 383, 69.5% of cohort). Thirty-one patients (5.6%of total cohort) were specified as not using regularmaintenance opioid therapy.

3.6 Cessation of treatment

In total, 263 patients (58.4% where response to ques-tion on treatment cessation was provided; 47.7% ofthe total cohort) were reported to have discontinuedusing fentanyl buccal tablets. For 111 patients (20.1%of cohort), it was not known or unspecified if treat-ment had been discontinued.

In total, GPs reported 269 reasons for stoppingfentanyl buccal tablets (at any point after treatmentwas started) in 225 patients (40.8% of the totalcohort). The most frequently reported reason for stop-ping was ‘Not effective’ (n = 73, 27.1% of all reasonsfor stopping).

Using information on treatment cessation, 161patients (29.2% of cohort) were known to still be ontreatment by the beginning of month 4 and 100patients (18.1% of cohort) were known to still be ontreatment by the beginning of month 7. Assumingconstant regular use, the median duration of treat-ment (time interval between the date of first prescrip-tion and the date fentanyl buccal tablets were stopped)was 22 days (IQR 2 and 78 days).

3.7 Inappropriate use

A summary of the number of patients with contrain-dications and special warnings for use is given inTable 2.

The majority of patients in the cohort had no con-traindications for use (n = 482, 87.5% of the cohort),while 266 patients had no special warnings for use(48.3% of the cohort) of fentanyl buccal tablets.However, there were 69 (12.5% of the cohort)patients who had one or more contraindications foruse and 285 patients who had one or more specialwarnings for use (51.7% of the cohort).

The use of fentanyl buccal tablets is contraindicatedin patients who are opioid naïve or without regularmaintenance opioid therapy. There were 31 (5.6% ofthe total cohort) patients who were reported as nothaving regular maintenance opioid and also notreceiving any other opioid for BTP. There were also 35(6.4% of the total cohort) reports of chronic obstruc-tive pulmonary disease patients using fentanyl buccaltablets, which, being a severe obstructive lung condi-tion, is also a contraindication for use. The use of



fentanyl buccal tablets is also contraindicated inpatients with a history of respiratory depression; therewere three (0.5% of the total cohort) reports ofpatients with past history of respiratory failure andseven (1.3% of the cohort) reports of patients withpast history of respiratory depression upon startingtreatment (at baseline) with fentanyl buccal tablets.

Use in patients over 65 years of age is a specialwarning and precaution for use according to the rec-ommended terms of license. GPs reported 235 (42.6%of the total cohort) patients over the age of 65 yearsreceiving fentanyl buccal. Special warning/precautions also apply for patients with chronickidney disease (CKD) and liver disease (moderate/severe). GPs reported 43 (7.8% of the total cohort)patients with CKD, and 33 (6.0% of the total cohort)patients with past history of liver disease (moderate/severe) upon starting treatment (at baseline) withfentanyl buccal.

4. Discussion

4.1 General discussion

Post-marketing surveillance provides important infor-mation on the real-life use of products outside theclinical trial setting, including use in populations thatmay not have been previously studied (Martin et al.,2004; Shakir, 2007). This product was of interest due

to the specific therapeutic indication of BTP in cancerin patients using maintenance opioid therapy. Exam-ining the real-life utilization of a product is importantto establish whether a product is being prescribedaccording to the terms of the license and if anypatients could be at potential risk from using a productoutside the manufacturer’s recommendation. TheM-PEM study for fentanyl buccal tablets provides real-life data for the prescribing of this product in primarycare in England.

The final M-PEM cohort consisted of 551 patientsprescribed fentanyl buccal tablets in general practice inEngland. The majority of patients were prescribedfentanyl buccal tablets for the licensed primary indi-cation of BTP in cancer (n = 341, 71.6% of patientswhere the indication was known). Clinical trials forfentanyl buccal tablets have previously confirmed thatthey are efficacious and well tolerated in this patientpopulation (Cephalon Inc., 2006; Portenoy et al.,2006).

There is evidence that patients in this cohort wereprescribed fentanyl buccal tablets for other indicationsoutside the conditions of the licence and also whencontraindications may have existed. Other indicationssuch as pain and chronic pain were reported, althoughthe treatment of acute pain other than BTP is con-traindicated. However, it is possible that the painreported was related to cancer pain, although it wasnot specified as BTP. Two randomized trials have pre-viously examined the use of fentanyl buccal tablets innon-cancer-related chronic pain (Farrar et al., 2010;Ashburn et al., 2011). Fentanyl buccal tablets werefound to be more efficacious than placebo and oxyco-done in these studies and were generally well toler-ated by patients (Farrar et al., 2010; Ashburn et al.,2011). Another two randomized, double-blind,placebo-controlled studies examined the use of fenta-nyl buccal tablets in BTP with chronic low back painand chronic neuropathic pain (Portenoy et al., 2007;Simpson et al., 2007). Fentanyl buccal tablets werefound to be well tolerated and efficacious in both ofthese patient populations (Portenoy et al., 2007;Simpson et al., 2007).

There was one patient aged less than 18 years in thecohort. Fentanyl buccal tablets are not recommendedfor use in children and adolescents below 18 years dueto a lack of data on safety and efficacy (Cephalon,2010). There were no events or suspected ADRsreported in this patient; however, a conclusion onsafety and efficacy cannot be drawn from this limitedinformation.

Regular opioid therapy was reported upon startingtreatment for only 383 patients (69.5% of the cohort),

Table 2 Summary of indicators of contraindicated prescribing and

special warnings and precautions of use.

Patient

count

% of

cohort

Indicators of contraindicated use

Opioid naïve/Non-tolerant 31 5.6

Age < 18 years 1 0.2

Chronic obstructive pulmonary disease 35 6.4

Respiratory depression 7 1.3

Respiratory failure 3 0.5

Obliterative bronchiolitis 1 0.2

Breastfeeding 0 0.0

MAOI use <15 days of starting or concomitant 1 0.2

Indicator of special warning/Precautions for use

65+ years 235 42.6

Chronic kidney disease stage > = 3 43 7.8

Liver disease (moderate/severe) 33 6.0

Hypovolaemia 3 0.5

Hypotension 4 0.7

Bradyarrhythmia 0 0.0

Increased intracranial pressure 4 0.7

Pregnancy 0 0.0

Use of CYP3A4 moderate and strong inhibitors 13 2.4

MAOI, monoamine oxidase inhibitor.



although it is a requirement for use of fentanyl buccaltablets as mentioned in the SmPC (Cephalon, 2010).There were 31 patients (5.6% of the cohort) who wereconfirmed as opioid naïve or non-tolerant.

Some extreme doses (as defined by twice the upperlimit of the highest licensed dose) of fentanyl buccaltablets were reported to have been prescribed andthere were four maintenance doses reported thatexceeded the maximum daily dose licensed (800 μg/day) (Cephalon, 2010). Additionally, some of thedoses upon stopping treatment were reported to begreater than 800 μg/day, which suggests that somephysicians were prescribing fentanyl buccal higherthan the recommended doses before stopping treat-ment. However, the majority of patients in the cohortwere mostly being prescribed fentanyl buccal withinthe licensed dosage range. Prescribing of higher thanrecommended doses is not unexpected, as there is atendency in clinical practice to increase the dose of anopioid if it is not working effectively, although thisdoes not necessarily mean that it will be effective atthe higher dose (Ballantyne, 2011).

There were 13 patients reported to be using CYP3A4inhibitors during treatment with fentanyl buccaltablets and one patient reported to be concomitantlyusing an MAOI inhibitor. The use of MAOI inhibitorsis contraindicated with fentanyl buccal tablets becausesevere and unpredictable potentiation has beenreported with opioid analgesics (Cephalon, 2010).Fentanyl is metabolized mainly via the humanCYP3A4 isoenzyme system; therefore, potential inter-actions may occur when fentanyl buccal tablets aregiven concurrently with agents that affect the CYP3A4activity (Cephalon, 2010). The concomitant use offentanyl buccal tablets with strong CYP3A4 inhibitorsor moderate CYP3A4 inhibitors may result inincreased fentanyl plasma concentrations, potentiallycausing serious ADRs, including fatal respiratorydepression (Cephalon, 2010).

Use in the presence of contraindications and specialwarnings for use were reported, although the fre-quency of use in the presence of contraindications waslow (12.5% of the cohort). A larger proportion of thecohort were prescribed fentanyl buccal tablets in thepresence of special warnings and precautions for use(51.7% of the cohort), but actual off-label use in thecohort appeared low overall.

4.2 Strengths and limitations

M-PEM is an observational cohort technique used forthe post-marketing surveillance of newly marketeddrugs. One of the major strengths of this study is that

it uses data from day-to-day clinical practice. Also, themethodology is non-interventional and does not influ-ence the prescribing practices of GPs. Additionally,there are no exclusion criteria applied to the identifi-cation of the eligible cohort, i.e., all patients prescribedand dispensed the study drug are eligible for inclusion.The overall evaluable M-PEM cohort comprisespatients whose GPs completed and returned anM-PEM questionnaire containing clinically usefulinformation.

Of particular note for this study is the potentialnon-response bias. It is unknown whether the GPswho returned the questionnaire are different fromthose GPs who did not return the questionnaire, as isthe potential selection bias in terms of representative-ness of patients included in this cohort. However, theresponse rate in this study (56.2%) is comparable tothe response rates reported elsewhere for GP postalsurveys (McAvoy and Kaner, 1996) and higher thanthe reported rates of suspected ADRs in the YellowCard scheme (Martin et al., 1998; Heeley et al., 2001).We have no reason to believe that the events reportedfor patients whose GPs did respond were any differentfrom those who did not respond. One explanation forpotential non-response is that GPs who were prescrib-ing off-licence or when contraindications and warn-ings existed may have been less likely to complete thequestionnaire. This would cause the level of inappro-priate prescribing of fentanyl buccal tablets to beunderestimated. Another explanation for potentialnon-response could be because of a delay in sendingthe questionnaires to GPs of patients who died in theintervening period.

Additionally, in this study, exposure is based ondispensed prescription data. These data are more accu-rate than exposure data based solely on writtenprescriptions. However, as with many observationalstudies, the degree of patient compliance in using theprescribed medication cannot be ascertained, particu-larly when a product may be used intermittently.

5. Conclusion

The final study results show that fentanyl buccal islargely being prescribed according to the terms of thelicense in general practice in England, but off-licenceuse and use in the presence of contraindications andwarnings have been reported.

Author contributions

V.O. assisted in designing the M-PEM study, monitoring datacollection for the study, interpreting the results of the study,



drafting and revising the paper. D.L. researched backgroundinformation, designed the M-PEM study, monitored datacollection for the study and wrote the statistical analysisplan. M.A.-S. and S.S. assisted in designing the M-PEMstudy, monitoring data collection for the study, interpretingthe results of the study and revising the paper. C.F. contrib-uted by performing data preparation and analysis for thestudy, interpreting the results of the study and revising thepaper. In addition, Mr Shayne Freemantle contributed byperforming data management and IT support for the study.

Acknowledgements

We would like to thank all the staff at the DSRU who con-tributed to this study. We would like to thank Mr ShayneFreemantle for data management and IT support. We thankthe GPs who have participated in this study, and withouttheir general support, PEM and M-PEM would not be pos-sible. We would also like to thank the NHS PrescriptionServices (NHSRxS) for their important participation.

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http://www.gmc-uk.org

Utilization of fentanyl buccal tablets in England: Exploring off-label use reported in a cohort...

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