APC/DTC Briefing Document

Transcription

1 Page 1 London New Drugs Group APC/DTC Briefing Document FENTANYL BUCCAL TABLETS (EFFENTORA) Contents Summary 1 Points for consideration 2 Background 2 Fentanyl 3 Fentanyl buccal tablets 3 US FDA Safety warning 4 Pharmacokinetics 5 Special populations 5 Drug interactions 5 Adverse events 5 Clinical efficacy 5 Cost 10 References 11 Appendices Produced for the London New Drugs Group by: Alexandra Denby, Regional MI Manager (Projects & New Products) Contact: Alexandra Denby Regional MI Manager (Projects & New Products) London New Drugs Group Medicines Information Service Northwick Park Hospital Middlesex HA1 3UJ Tel: Med.info@nwlh.nhs.uk Further copies of this document are available from URL: Summary Fentanyl buccal tablets (Effentora) were approved for use in the EU in April 2008, for the treatment of breakthrough cancer pain in adults who are already receiving maintenance opioid therapy for chronic cancer pain. The tablets are available in five strengths: 100mcg, 200mcg, 400mcg, 600mcg and 800mcg, and the dose should be titrated to an effective dose that provides adequate analgesia with minimal side effects. Effentora tablets are not dose-equivalent to Actiq (fentanyl) lozenges (see Points for Consideration). Approximately 50% of the total dose of a fentanyl buccal tablet (FBT) administered is rapidly absorbed transmucosally and becomes systemically available. The rest of the dose is swallowed and is slowly absorbed from the GI tract. About 30% of the amount swallowed escapes hepatic and intestinal first-pass elimination and becomes systemically available. A pilot study showed that in patients with Grade 1 mucositis, the absorption of fentanyl was not affected. Caution is required in generalising these results to patients with higher grade (more severe) mucositis. Two placebo-controlled, randomised trials have evaluated the use of FBT for breakthrough cancer pain in adults. The trials started with an open-label phase during which the dose of FBT was titrated until 2 consecutive breakthrough pain episodes were adequately treated. The final dose was then used in the double-blind phase. The dose of FBT required was not found to be related to the regular dose of morphine (or equivalent), or the supplemental opioid dose used for breakthrough pain. Patients who did not respond to the highest dose of FBT (800mcg) did not continue with the double-blind phase of the trial. In both trials, FBT treated episodes of breakthrough pain faster and more effectively than placebo, as would be expected in a patient population already shown to be sensitive to the effects of fentanyl. Clinically significant improvements in pain intensity scores of 33% and 50% were seen earlier and to a greater extent with FBT compared with placebo. Supplemental medication use for breakthrough pain episodes was required less frequently in those episodes treated with FBT (11%-23% of episodes) compared with placebo (30%-50%). Analgesic effects of FBT lasted throughout the 2 hour observation period of one of the trials (and may continue for longer), which will be useful as the duration of breakthrough pain can last for up to 4 hours. The main adverse events associated with the use of FBT were those that would be expected with opioid medications: nausea, dizziness, headache, fatigue, vomiting and constipation. Administration site reactions occurred mainly during the titration phase of the studies. PRODUCED TO INFORM LOCAL DECISION-MAKING USING THE BEST AVAILABLE EVIDENCE AT THE TIME OF PUBLICATION.

2 Page 2 Points for consideration Ensure that the chronic pain is being managed appropriately, and consider whether there is a need for buccal drug administration. The randomised trials had limitations. The open-label dose-titration phase may have increased the possibility of unblinding the patients as they would become aware of the effects of fentanyl. There was patient selection bias: the patients who entered the double-blind phase had already demonstrated a favourable response to FBT (6%- 16% of those enrolled in the trials did not respond to even the highest dose of FBT during the open-label phase) and this would have resulted in bias in favour of fentanyl treatment. Care should be taken when extrapolating the results to the general population, not all of whom will respond to FBT. There are no direct active-comparator efficacy studies. FBT and oral transmucosal fentanyl lozenges (Actiq) have different pharmacokinetic profiles and are not doseequivalent: approximately half of the fentanyl is absorbed transmucosally from the FBT compared to 25% of the dose from an oral transmucosal fentanyl lozenge. Dose reductions are required when switching to the buccal tablets. FBT must not be substituted for Actiq lozenges on a microgram for microgram basis. The US Food and Drug Administration has issued strong guidance regarding the use of FBT (US trade name Fentora), following serious adverse events, including death, in patients treated with them: 1 Do not use fentanyl buccal tablets in patients who are opioid non-tolerant. Only use fentanyl buccal tablets for the licensed indications. Do not prescribe fentanyl buccal tablets for patients with acute pain, post-operative pain, headaches/ migraines or sports injuries. Fentanyl buccal tablets are not a generic version of Actiq lozenges. Do NOT substitute fentanyl buccal tablets for Actiq, or any other fentanyl-containing products. Follow the dosing instructions carefully: For unrelieved breakthrough pain, patients should not take more than two fentanyl buccal tablets per episode. Patients MUST wait at least four hours before treating another breakthrough pain episode with fentanyl buccal tablets. Fentora has been approved in the US with a comprehensive RiskMAP (Risk Minimisation Action Plan), to minimise risks whilst maintaining the products benefits. The US FDA advisory committee has voted not to recommend approval of a licence extension for Fentora in the management of breakthrough pain in opioid-tolerant patients with chronic pain conditions. 2 The panel expressed concerns about minimising risk potentially associated with an expanded indication of Fentora. BACKGROUND Fentanyl in an effervescent buccal tablet formulation, was approved for use in the EU in April 2008, for the treatment of breakthrough cancer pain in adult patients who are already receiving maintenance opioid therapy for chronic pain. 3 The fentanyl buccal tablets (FBT) are available in five strengths: 100mcg, 200mcg, 400mcg, 600mcg and 800mcg. 4 They can be used as required for breakthrough (episodic) pain (BTP), though administration should only be repeated once during a single pain episode after 30 minutes if the pain control is inadequate. 5 Breakthrough pain describes a transient exacerbation or recurrence of pain in someone who has mainly stable and/or adequately relieved background pain 6 and is experienced by 50%- 90% of patients referred to cancer pain clinics. 5;7 Patients with inadequately relieved background pain are excluded because this suggests overall poor pain relief that requires an increase in regular analgesia. The World Health Organisation (WHO) has a 3-step analgesic ladder for pain control: 6 Step 1: Non-opioid ± adjuvants Step 2: Weak opioid + non-opioid ± adjuvants Step 3: Strong opioid + non-opioid ± adjuvants Apart from the BTP that occurs with falling serum concentrations at the end of a dosing interval, there are two other types of BTP: 5;6 Predictable or incident pain: related to movement or activity Unpredictable or spontaneous pain: unpredictable, with no obvious precipitating factor. There are various ways to reduce the impact of BTP, such as treating precipitating factors, radiation therapy, positioning of the patient, re-

3 Page 3 laxation therapies, ensuring the background pain is adequately controlled, and prescribing a fast-acting, short-lasting opioid as rescue analgesia. 6 Appendix 1 details more information regarding analgesia. The onset of BTP is usually rapid and although most BTP episodes peak within 30 minutes, treatment of ambulatory patients usually relies on orally administered drugs, which have a time course of action that does not closely match the experience of the pain - the onset of analgesia may be after the peak of the target pain. 7 The rationale behind the development of the buccal fentanyl tablet was a faster onset of action, with studies showing that analgesia could be provided at 15 minutes. 7 Research was carried out to develop other nonparenteral opioid formulations with a faster onset of action. FENTANYL Fentanyl is a strong mu-opioid receptor agonist, like morphine, and acts at receptors located in the brain, spinal cord and smooth muscle. 6;8 Unlike morphine, it is lipophilic and is very rapidly absorbed through the oral mucosa but more slowly absorbed through the gastrointestinal tract. 6;8 This lipophilicity means that fentanyl is times more potent than morphine and can rapidly transfer across the blood-brain barrier. 5 Fentanyl distributes into body fat, including the white matter of the CNS (thalamus), so any effect in the dorsal horn (grey matter) is minimal. 6 This is reflected in the observation that patients with poor pain relief, despite using high doses of fentanyl, (e.g. 600mcg/hour transdermally) can obtain good relief with relatively smaller doses of morphine (e.g mg subcutaneously). 6 Fentanyl is available in transdermal patches (for severe, chronic pain) and as oromucosal lozenges (Actiq 8 ), which are indicated for BTP. 9 Actiq lozenges are available in doses ranging from 200mcg to 1600mcg, and contain both glucose and confectioners sugar: 8 one limitation of their use is potential dental decay. 5 Approximately 25% of the dose from an Actiq lozenge is absorbed transmucosally, whilst the rest is absorbed slowly through the gastrointestinal (GI) tract. Absolute bioavailability is about 50%. 8 FENTANYL BUCCAL TABLETS Fentanyl buccal tablets (Effentora) are effective in the treatment of BTP in cancer patients due to a rapid transmucosal absorption after buccal disintergration. 4 It is important that the long acting opioid used to treat the patients chronic pain has been stabilised before treatment with fentanyl buccal tablets begins. The tablets are available in five strengths: 100mcg, 200mcg, 400mcg, 600mcg and 800mcg. 10 Administration Fentanyl buccal tablets (FBT), once exposed to moisture, use an effervescent reaction to deliver fentanyl. The FBT should be placed in the upper portion of the buccal cavity above an upper rear molar between the cheek and gum. 10 The FBT should not be chewed or sucked or swallowed, as this will result in lower plasma concentrations than when taken as directed. If the FBT irritates the buccal mucosa, then placement in the mouth can be changed. 10 The FBT should be placed and retained in the buccal cavity for a period of time long enough to allow disintegration of the tablet (approximately minutes). If any remnants of the tablet remain after 30 minutes, they may be swallowed with a glass of water. 10 Dose titration 10 FBT should be individually titrated to an effective dose that gives adequate pain relief with minimal side effects. In clinical studies the effective dose was not predictable from the daily maintenance dose of opioids. Patients should be carefully monitored until an effective dose is reached. Dose titration in patients not switching from fentanyl-containing products The initial dose should be 100mcg, titrating upwards as necessary through the available dose ranges (200mcg, 400mcg, 600mcg and 800mcg). 10

4 Page 4 Titration in patients switching from other fentanyl-containing products Due to differences in absorption profiles, switching must not be done at a 1:1 ratio. If switching from another oral fentanyl citrate product, independent dose titration must be carried out with FBT as bioavailability between products differs significantly. 10 Method of titration 10 During titration, if adequate analgesia is not obtained within 30 minutes after the start of administration of a single tablet, a second tablet of the same strength can be used. If treatment of an episode of BTP needs more than one tablet, an increase in dose to the next higher available strength should be considered to treat the next BTP episode. During titration, multiple tablets may be used: up to four 100mcg or up to four 200mcg tablets may be used to treat a single episode of BTP during dose titration according to the following schedule: If the initial 100mcg tablet is not effective enough, the patient should be instructed to treat the next episode of BTP with two 100mcg tablets. One tablet should be placed in both sides of the mouth. If this dose is considered to be the most effective dose, successive episodes of BTP should be treated with a single 200mcg FBT. If a single 200mcg FBT is not considered to be efficacious, the patient can be instructed to use two 200mcg tablets (or four 100mcg tablets) to treat the next episode of BTP. The two tablets should be placed in each side of the mouth. If this dose is considered to be the most effective, treatment can be continued with a single 400mcg FBT. For titration up to 600mcg or 800mcg, tablets of 200mcg should be used. No more than two FBTs should be used to treat any individual BTP episode, unless titrating use up to four tablets. At least four hours must elapse before treating another BTP episode with FBT. Dose readjustment of the background opioid therapy and/or fentanyl buccal tablets is necessary if there are more than four BTP episodes in 24 hours. 10 This method of dose titration must be adhered to, and FBT must only be used for the licensed indication, i.e. treating breakthrough cancer pain in adults who are already receiving opioids. Safety information has been issued in the US and is described in the next section. US FDA Safety Warning In September 2007 the US FDA issued safety information for Fentora tablets, the US brand of Effentora. 1 The information was issued as a result of deaths occurring because of improper patient selection (e.g. opioid non-tolerant patients), improper dosing and/or improper product substitution. Key safety information regarding the use of Fentora was issued: 1 Do not use Fentora in patients who are opioid non-tolerant, i.e. in patients who are not on regular around the clock opioids. Patients are considered opioidtolerant if they are taking at least 60mg of oral morphine daily, at least 25 mcg transdermal fentanyl/hour, at least 30mg of oral oxycodone daily, at least 8mg oral hydromorphone daily, or an equivalent dose of another opioid for a week or longer. Only use Fentora for the licensed indications. Do not prescribe Fentora for patients with acute pain, post-operative pain, headaches/migraines or sports injuries, even if they are receiving other opioids on an asneeded basis. Fentora is not a generic version of Actiq lozenges: it is a distinct formulation of fentanyl. Do NOT substitute Fentora for Actiq, or any other fentanyl-containing products on a microgram per microgram basis. When switching a patient from Actiq to Fentora, physicians must follow the instructions in the prescribing information as Actiq and Fentora are not equivalent on a microgram to microgram basis. Follow the dosing instructions carefully: For unrelieved breakthrough pain, patients should not take more than two Fentora tablets per episode. Patients MUST wait at least four hours before treating another breakthrough pain episode with Fentora tablets. Fentora was approved with a comprehensive RiskMAP (Risk Minimisation Action Plan) 1;2 to reduce the risks associated with its use, whilst maintaining the product s benefits. RiskMAP

5 Page 5 focuses on 3 primary objectives: Ensure that patients and healthcare professionals understand that Fentora should only be used by opioid tolerant patients with cancer. Minimise potential for misuse, abuse and diversion of Fentora. Minimise unintended or accidental exposure to Fentora. The manufacturer of Fentora, Cephalon Inc., has produced Dear Doctor and Dear Healthcare Professional letters which incorporate the safety information described above, and are issued in the US. The letter also advises that the full prescribing information should be reviewed and that the patients should be given the medicines guide to read. Pharmacokinetics Fentanyl is readily absorbed from the buccal tablets with an absolute bioavailability of 65%. 10 Approximately 50% of the total dose administered is rapidly absorbed transmucosally and becomes systemically available. The rest of the dose is swallowed and is slowly absorbed from the GI tract. About 30% of the amount swallowed escapes hepatic and intestinal first-pass elimination and becomes systemically available. 10 Special populations Patients over 65 years of age may require a lower dose than younger patients, and caution should be used when titrating the dose in elderly patients. Fentanyl buccal tablets are not licensed for use in children under the age of 18 years. They should be used with caution in patients with severe to moderate renal and hepatic impairment as the resulting increased bioavailability can lead to increased and prolonged opioid effects. Patients with xerostomia are advised to drink water to moisten the buccal cavity prior to administration; if this does not result in appropriate effervescence then a change of therapy may be advised. 10 Caution should be used when titrating FBT in patients who have non-severe chronic obstructive pulmonary disease (COPD), or other medical conditions that predispose them to respiratory depression. Even normally therapeutic doses of FBT can decrease respiratory drive to the point of respiratory failure. 10 Drug interactions Fentanyl is metabolised via the cytochrome P450 3A4 isoenzyme system (CYP3A4). Coadministration with CYP3A4 inhibitors (such as ritonavir, amprenavir, ketoconzole, fluconazole, clarithromycin, erythromycin, diltiazem, grapefruit juice) can result in increased fentanyl plasma concentrations and potentially cause serious adverse drug reactions include fatal respiratory depression. Co-administration with CYP3A4 inducers (such as rifampicin, carbamazepine, phenytoin, phenobarbitone, St Johns Wort) may reduce the efficacy of fentanyl. 10 Unpredictable potentiation of effects by MAO inhibitors has been reported with opioid analgesics. The concurrent use of partial opioid agonists/antagonists (such as nalbuphine and pentazocine) is not recommended as they may antagonise the analgesic effects of fentanyl. 10 Adverse events Adverse events that were most commonly reported in the Phase III trials were those associated with opioid use and were reported in up to two-thirds of patients: nausea, dizziness, headache, fatigue, vomiting, somnolence and constipation. 7;11 Administration-site reactions occurred infrequently, were of mild intensity but led to withdrawal from the study in two patients. 7 All of the 16 deaths that occurred during the studies were due to disease progression. 7;11 CLINICAL EFFICACY Phase I trials Oral mucositis is an acute and painful complication of cancer chemotherapy and radiotherapy. The oral mucosa becomes ulcerated and infected, and has a marked effect on the patients ability to eat and swallow and can impair their quality of life. 12 Mucositis-related pain affects 40% - 70% of patients receiving chemotherapy and is especially troublesome in patients with head and neck cancer. Darwish et al 12 assessed the absorption profile and tolerability of FBT in adults with cancer and with or without oral mucositis, in order to find out if there was any difference between the two populations. Those with mucositis were required to have grade 1-3 mucositis on clinical examination and

6 Page 6 grade 1 or 2 upon functional/symptomatic examination using the Common Terminology Criteria for Adverse Events grading system [see Appendix 2]. Topical treatment for mucositis was withheld for one hour before and eight hours after FBT administration. A single 200mcg FBT was administered and any tablet remaining after 30 minutes was swallowed with a glass of water. In patients with mucositis, the tablet was placed in the least affected buccal area. Blood samples were collected and oral mucosal examinations in eight areas of the mouth were carried out. Sixteen patients (eight with and eight without oral mucositis) completed the study. The clinical grade of mucositis was 1 and the functional grade was 1 for seven patients and 2 for one patient. FBT dissolved within 30 minutes in 14 patients. There was no difference in the time to or in the actual median maximal plasma concentrations between the two groups. The trend towards slightly higher overall systemic exposure in patients with mucositis should be considered in context of the small sample size. This was not associated with an increase in side effects. In this small pilot study, low grade mucositis did not significantly affect the absorption of active drug. As the patients affected in this study had clinical grade 1 mucositis, caution is required in extrapolating the results to patients with higher grades of oral mucositis. Phase III trials Two clinical trials have evaluated the efficacy of FBT in patients with breakthrough cancer pain. Both trials used placebo rather than active comparators. No active comparator studies were actually submitted to the European Medicines Evaluation Agency for efficacy and safety determination for licensing. The comparison with alternative treatments is largely confined to indirect assessment of pharmacokinetic profiles between FBT and Actiq lozenges rather efficacy studies. 13 Portenoy et al 7 and Slatkin et al 11 evaluated the efficacy, safety and tolerability of fentanyl buccal tablets in opioid-treated patients with breakthrough cancer pain. The following were common to both studies: 7;11 Patients were over the age of 18 years, with solid or haematological malignancies. They suffered from at least 1 to 4 BTP episodes a day despite oral morphine or equivalent (at least 60mg morphine/day) or transdermal fentanyl (at least 25mcg 11 to 50mcg 7 /hour), which were adequately controlled with supplemental opioids, were enrolled. An open-label, titration phase preceded the double-blind phase. During this phase, patients were started on a dose of 100mcg and titrated up to a dose which adequately controlled the breakthrough pain if 100mcg failed to provide relief. BTP episodes that could be treated with FBT had to occur at least 4 hours after administration of the study drug or supplemental medication. The purpose of the open-label phase was to find a suitable dose of FBT that could be used during the double blind phase. Patients discontinued the study if 800mcg was not adequately controlling the BTP episode. This led to a patient population in the double-blind phase who were known to be responsive to the effects of fentanyl up to a dose of 800mcg (the maximum licensed dose); this may not reflect the use of the product in the general population. In the double-blind, cross-over phase, patients were randomly allocated to one of 18 different dosing regimens, consisting of 10 tablets (7 FBT and 3 placebo). 7;11 Patients were instructed to take the tablets in the order that they were numbered and all 10 tablets had to be taken within 21 days. The patients continued to use their regular opioid regimen, and could use their supplemental drug if pain relief was not obtained within 30 minutes of taking the study drug. The cross-over design allowed the patients to act as their own controls. Usually the treatment periods in a cross-over trial are separated by a washout period which allows for any residual effects of the previous treatment to dissipate. Pain was measured using: 7;11 Pain intensity (PI) and PI differences (PID). PI was recorded on an 11-point numerical score (0=no pain, 10=worst pain). The pain intensity difference (PID) was the difference between each PI measurement after and before drug administration [greater PID indicates greater improvement in pain intensity]. Pain relief (PR) and total pain relief (TOTPAR) were measured at time points ranging from 5 to 120 minutes post-

7 Page 7 administration. PR was noted using a 5- point scale, where 0=none and 4=complete. Patient rating of global medication performance (GMP) was recorded at 30 and 60 minutes using a 5-point scale (0=poor and 4=excellent). Numerical rating scales are subjective and must be fully understood by patients. A rating of e.g. 2-3 (mild pain) or 7 (severe pain), is not clear in itself, and may mean different things to different patients. In these studies, the patients acted as their own controls and therefore how they rated FBT and placebo would be the same, but there may be interpatient variability. In the study by Portenoy et al 7 adults had an ECOG performance rating of 2 [see Appendix 2] and a life-expectancy of 3 months. Exclusion criteria included intrathecal opioids, mucositis/stomatitis of grade 2 or higher, sleep apnoea, active brain metastases with increased intracranial pressure, COPD or impaired liver or renal function. Once the patient had completed the titration phase, they entered the double-blind phase, (as already described), using the same dose from the titration phase throughout and with a maximum of 4 episodes treated per day. Patients recorded a baseline pain intensity (PI) score when a BTP episode began, study drug was then administered and pain intensity/relief were recorded at various time points. The patient s prior supplemental drug could be used to treat any BTP episode that did not respond to the study drug, or to treat any BTP episode in excess of 4 per day, or any that occurred <4 hours after rescue medication was administered. Adverse events were recorded after each dose and at clinical visits. Approximately 63 patients were required to provide a 95% power to detect a treatment difference of 1.4 between FBT and placebo in the primary efficacy measure, which was the summed pain intensity difference (SPID 30 ) at 30 minutes. Secondary efficacy variables included PR, PID and total PR (TOTPAR) at each time point, and GMP assessment. In addition, the proportion of episodes in which there was 33% or 50% improvement in PI scores at each time point was analysed. The efficacy-evaluable (per-protocol) population was defined as all patients who received at least one FBT and one placebo treatment, and had pre-treatment PI scores for each BTP episode. The intention-to-treat population (i.e. all randomised patients) was not analysed. A total of 123 patients enrolled in the titration phase: 20 (16%) withdrew from the study due to lack of efficacy at the highest fentanyl dose, 80 (65%) identified an effective FBT dose and 77 (63%) were randomised to double-blind treatment. At baseline, in the efficacyevaluable population (n=72), the mean daily dose of oral opioid was ± morphine-equivalent mg, and the mean daily dose of supplemental medication was 21.0 ± 23.4 morphine-equivalent mg. No relationship was seen between the FBT dose and the baseline or supplemental opioid dose.. For the efficacy-evaluable population, a total of 493 BTP episodes were treated with FBT and 208 with placebo. The mean PI score at baseline was 6.9 ± 0.19, which decreased by 2.3 (FBT) and 1.4 (placebo) points at 30 minutes. PID and PR scores at each time point were significantly higher with FBT than placebo, as were the mean SPID and TOTPAR scores. See Table 1 for results. The difference in the primary endpoint, SPID 30, was 1.2, which was less than the study was powered for, but was statistically significant (p<0.0001). Clinically significant improvements in pain scores occurred in more of the FBTtreated episodes compared with the placebotreated episodes, at all time points, with more than a 33% improvement in pain intensity seen as early as 15 minutes after administration. Greater satisfaction with FBT treatment compared with placebo was seen, (as indicated by GMP ratings). Not surprisingly, patients were more likely to require supplemental medication during a BTP episode treated with placebo compared with those treated with FBT. Patients with predominantly neuropathic or mixed (neuropathic and nociceptive) pain showed slightly better efficacy, as determined by the mean SPID 60, compared with patients with nociceptive pain (5.3 vs. 3.1). The FBT provided rapid-onset, effective analgesia when compared with placebo. The dose required was not related to either the background or supplemental opioid dose required by the patient; it is therefore essential that the dose is titrated in order to establish an effective FBT dose for individual patients.

8 Page 8 Table 1: Results from the study by Portenoy et al 7 Fentanyl Placebo Mean PI at baseline 6.9 ± ± 0.19 No. of BTP episodes treated Reduction in PI at 30 mins 2.3 ± ± 0.2 Primary endpoint: 3.0 ± 0.12 SPID 30 p< (95% CI 0.83 to 1.62) 1.8 ± 0.18 Supplemental 23%; relative risk ratio 0.47, 95% medication % of CI 0.37 to 0.60 episodes 50% Time point 15 mins 30 mins 45 mins 60 mins Number (%) with 33% improvement in pain intensity score FBT (n=493) 69 (13)* 240 (48) 352 (71) 373 (75) Placebo (n=208) 20 (9) 61 (29) 93 (44) 100 (48) Number (%) 50% improvement in pain intensity score FBT (n=493) 44 (8) 122 (24)* 253 (51) 319 (64) Placebo (n=208) 13 (6) 34 (16) 52 (25) 74 (35) Global Medication Performance ratings FBT (n=493) Placebo (n=208) FBT: fentanyl buccal tablets * p<0.05 p< PI: Pain intensity; PID: Pain intensity difference; SPID: summed PID In the study by Slatkin et al 11 a protocol amendment allowed patients with mucositis and stomatitis to enrol, as these are common occurrences in patients with cancer. Other enrolment criteria have been described previously. Patients were aged years with a life expectancy of at least 2 months. Exclusion criteria were similar to those used by Portenoy et al. 7 A dose-titration phase preceded the doubleblind phase (both described previously). The primary efficacy measure was the sum of pain intensity differences from 5 minutes to 60 minutes (SPID 60 ); a difference 3.00 was considered clinically relevant. A sample size of 70 evaluable patients was required to give statistical power of 90%. PI was rated just prior to study drug administration and at set intervals from 5 to 120 minutes after treatment. Secondary measures included individual PIDs and PR at each time point; the percentage of BTP episodes with an improvement in PI scores from baseline of 33% and 50% following study drug administration, TOTPAR at 60, 90 and 120 minutes, GMP at 30 and 60 minutes and the proportion of BTP episodes that required supplemental medication. Efficacy analyses were performed on the full data set: all patients who treated at least one BTP episode with FBT and one with placebo, and had pre-treatment PI scores for those episodes. A total of 75 patients (58%) of the 129 enrolled in the dose-titration phase completed the double-blind phase and 78 were evaluable for efficacy. Eight patients (6%) withdrew due to lack of efficacy. The mean daily dose of morphine equivalent was ± mg, with a supplemental dose of 24.7 ± morphine equivalent mg. The mean pain intensity at

9 Page 9 baseline was the same for both FBT (6.4 ± 1.8) and placebo (6.4 ± 1.7). There was no relationship between the FBT dose and the dose of either regular medication or supplemental medication. During the double-blind phase, a total of 493 BTP episodes were treated with FBT and 223 treated with placebo. SPID 60 was significantly greater for episodes treated with FBT compared with placebo (difference 4.8, p<0.0001), and a significantly greater improvement in pain control with FBT was seen as early as 10 minutes (p<0.0001). The difference in PID between FBT and placebo increased at subsequent time points up to 90 minutes, and was then maintained through to 2 hours (p< for each time point). Pain relief was significantly better with FBT than with placebo as early as 10 minutes (0.815 vs , p<0.0001); the differential increased over time up to 90 minutes and was maintained for 2 hours (p< for each time point). TOTPAR was significantly better at all time points (p<0.0001) with FBT than placebo. Supplemental medicine was required for more placebo-treated episodes than FBTtreated episodes. These are lower percentages compared to the study by Portenoy 7 ; the reason for this is unclear. A clinically significant improvement in PI scores of 33% and 50% occurred in a larger proportion of BTP episodes treated with FBT compared with placebo (see table 3). The differential increased through to 60 minutes and was maintained through to 2 hours for 33% (p<0.0001), whilst it continued to increase for 50% improvement (p<0.0001). Overall, 53% of patients preferred FBT to their prior breakthrough medication, with good to excellent ratings given to onset of action (by 79% of patients), ease of administration (73%) and convenience of use (79%). Table 2: Results from the study by Slatkin et al. 11 Fentanyl Placebo Mean PI at baseline 6.4 ± ± 1.7 No. of BTP episodes treated Primary endpoint: SPID ± ± 0.50, p< Supplemental medication % of episodes 11% (n=53) 30% (n=67) Time point 10 mins 15 mins 30 mins Number (%) with 33% improvement in pain intensity score FBT (n=493) 16%* 29% 51% Placebo (n=223) 10% 14% 26% Number (%) 50% improvement in pain intensity score FBT (n=493) 7 18% 38% Placebo (n=223) 4% 8% 15% GMP 60 mins 120 mins FBT (n=493) Placebo (n=223) FBT: fentanyl buccal tablets GMP: Global Medication Performance ratings * p=0.007 p< p=0.033 PI: Pain intensity; PID: Pain intensity difference; SPID: summed PID

10 Page 10 The authors of the study state that this is the first study to demonstrate a decrease in pain intensity with FBT compared with placebo as early as 10 minutes in the treatment of breakthrough pain in this patient population. The study by Portenoy et al 7 did not score pain intensity/pain relief until 15 minutes post-dose, but still showed a greater decrease with FBT at this time. The analgesic effects were sustained for the 2 hour observation period, which may be of clinical benefit as the duration of an episode of BTP can range from 1 to 240 minutes. There are limitations to the two studies. The open-label dose-titration phase may have increased the possibility of unblinding the patients as they would become aware of the effects of fentanyl. The numerical rating scale is subjective and there may be interpatient variability. The patients who entered the double-blind phase had already demonstrated a favourable response to FBT up to a dose of 800mcg, so care should be taken when extrapolating the results to the general population. Once the patients had been titrated to the optimum dose of FBT in the open label study, further dose titration in the double-blind phase was not allowed. Up to 23% of episodes treated with FBT also required supplementary medication; the investigators do not state what dose of fentanyl these were treated with, and therefore whether a dose titration was necessary or possible. The trials were placebo-controlled so no conclusions can be drawn regarding the effects of FBT in comparison to other medication used for breakthrough cancer pain. Cost Fentanyl buccal tablets have not been compared directly to other medications, but it is likely that it will be a direct competitor to fentanyl lozenges (Actiq). The costs of fentanyl buccal tablets are not yet known. Fentanyl lozenges cost for 3 or for 30, regardless of the strength (200mcg, 400mcg, 600mcg, 800mcg, 1.2mg and 1.6mg). 9 Reference List (1) Important safety information for FEN- TORA. U.S.Food and Drugs Administration. drug/infopage/fentanyl_buccal/ default.htm Date accessed: 07/05/08 (2) Cephalon recieves negative opinion from US advisory committee for expanded label for Fentora. NewDrug- File Daily News Review. Daily News Alert 7 May 2008 (3) EC approves buccal fentanyl tablet (Effentora) for the treatment of breakthrough cancer pain. NeLM News & Updates Viewing/vR.aspx?id= Accessed: (4) Committee for Medicinal Products for Human Use. Summary of Positive Opinion for Effentora. Committee for Medicinal Products for Human Use (CHMP) opinion/opinion.htm (5) Blick SKA, Wagstaff AJ. Fentanyl buccal tablet in breakthrough pain in opioid-tolerant patients with cancer. Drugs 2006; 66(18): (6) Analgesics. In: Twycross R, Wilcock A, editors. PCF3. Palliative Care Formulary. Nottingham: Palliativedrugs.com Ltd, 2007: (7) Portenoy RK, Taylor D, Messina J et al. A randomized, placebo-controlled study of fentanyl buccal tablet for breakthrough pain in opioid-treated patients with cancer. Clin J Pain 2006; 22(9): (8) Actiq. Summary of Product Characteristics. Cephalon Limited. emc.medicines.org.uk/emc/assets/c/ html/displaydocprinterfriendly.asp? documentid=11145 Date of accessed: 18/04/08. Date of revision of the text: January (9) British National Formulary, 55th edition. March BMJ Group and RPS Publishing (10) Effentora 100 microgram buccal tablets. Summary of Product Characteristics. Cephalon Europe. Humans/EPAR/effentora/ effentora.htm Date published on 04/04/08 Date accessed: 28/04/08

11 Page 11 (11) Slatkin NE, Xie F, Messina J et al. Fentanyl buccal tablet for relief of breakthrough pain in opioid-tolerant patients with cancer-related chronic pain. Journal of Supportive Oncology 2007; 5(7): (12) Darwish M, Kirby M, Robertson P et al. Absorption of fentanyl from fentanyl buccal tablet in cancer patients with or without oral mucositis. A pilot study. Clin Drug Invest 2007; 27 (9): (13) Effentora. Public assessment record. EMEA humandocs/humans/epar/effentora/ effentora.htm Date published: 23/04/08 Date accessed: 28/04/08 (14) ECOG Performance Status Eastern Cooperative Oncology Group ecog.dfci.harvard.edu/general/ perf_stat.html Date accessed: 30/04/2008 (15) Darwish M, Kirby M, Robertson P et al. Absolute and relative bioavailability of fentanyl buccal tablet and oral transmucosal fentanyl citrate. J Clin Pharmacol 2007; 47: This document was written by the London New Drugs Group. The LNDG would like to Dr Andrew Wilcock, Macmillan Reader in Palliative Medicine and Medical Oncology, University of Nottingham and Steve Wanklyn, Senior Pharmacist in Palliative Medicine, Guys and St Thomas Foundation Trust, for their comments on the review. Cephalon UK Ltd had no comments to make on this review.

12 Page 12 Appendix 1: Analgesia There a three categories of drugs which are used alone or in combination according to the type of pain the patient has: 6 Non-opioids Opioids Adjuvants Paracetamol NSAIDs Nefopam Ziconotide Codeine ( weak ) Morphine ( strong ) Corticosteroids Antidepressants Anti-epileptics NMDA-receptor channel blockers Muscle relaxants bisphosphonates Management of BTP can be approached in a number of ways: 6 Correct the correctable Non-drug measures Drug Anticancer treatment, e.g. radiotherapy, chemotherapy, hormone therapy Treatment of precipitating factors, such as cough, constipation Positioning Modification to way of life and environment Relaxation therapies Surgery, e.g. internal fixation of a long bone Relieve background pain using WHO guidelines, nonopioid, opioid and adjuvant analgesics Prescribe rescue analgesia e.g. a fast-acting, shortlasting opioid, titrated against efficacy and tolerability Nerve blockade Spinal analgesia

13 Page 13 Appendix 2: Rating scales Common Terminology Criteria for Adverse Events grading system 12 Grade Clinical examination Functional/symptomatic examination 1 Erythema of the mucosa Minimal symptoms, normal diet, minimal respiratory symptoms but not interfering with function Patchy ulcerations or pseudomembranes Confluent ulcerations or pseudomembranes; bleeding with minor trauma Tissue necrosis, significant spontaneous bleeding, lifethreatening consequences Symptomatic but can eat and swallow modified diet; respiratory symptoms interfering with function but not interfering with activities or daily living. Symptomatic and unable to adequately eat or drink orally; respiratory symptoms interfering with activities of daily living. Symptoms associated with life-threatening consequences. 5 Death Death ECOG performance status: 14 The Eastern Cooperative Oncology Group scales and criteria assess how a patient s disease is progressing, how it affects their daily living abilities and determines appropriate treatment and prognosis. Grade ECOG 0 Fully active, able to carry on all pre-disease performance without restriction Restricted in physical strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, e.g. light house work, office work. Ambulatory and capable of all self care, but unable to carry out any work activities. Up and about more than 50% of working hours. Capable of only limited self care, confined to bed or chair more than 50% of waking hours. Completely disable. Cannot carry on any self care. Totally confined to bed or chair. 5 Dead.

14 Page 14 Appendix 3: Bioavailability studies A phase I study was carried out to determine the absolute and relative bioavailability of fentanyl delivered by the FBT compared with oral transmucosal fentanyl citrate (OTFC, Actiq lozenge) and intravenous fentanyl. 13;15 The study design was an open-label, four-period, cross-over study in 32 healthy adults. The subjects received FBT 400mcg transmucosally, fentanyl 400mcg intravenously, FBT 800mcg orally and Actiq lozenge 800mcg transmucosally, with a minimum washout of 7 days between each dosing period. The 400mcg dose was chosen as it would provide measurable plasma concentrations throughout the blood sampling period (immediately before to 72 hours after dosing), and the Actiq lozenge dose of 800mcg was chosen to achieve comparable systemic exposure to the FBT 400mcg dose. If the subjects thought that a portion of the FBT still remained after 10 minutes, they could massage their cheek in the area of the tablet for 5 minutes. This might have had an effect on the results of the study. Twenty six subjects completed the study and composed the pharmacokinetic analysis set. Pharmacokinetic parameters are shown in table 1. The absolute bioavailability was higher with FBT 400mcg compared with Actiq lozenges, due to more being absorbed across the oral mucosa: approximately half of the FBT dose was absorbed across the oral mucosa and became systemically available, whilst the rest was swallowed and slowly absorbed through the gastrointestinal (GI) tract. A smaller amount of the Actiq lozenge dose was absorbed through the oral mucosa, with approximately 80% of the dose swallowed and absorbed through the GI tract. A higher early systemic exposure to fentanyl was seen with FBT administered transmucosally than with Actiq, as measured by C max and AUC 0-tmax. A greater systemic exposure to fentanyl from FBT was seen compared to that from Actiq lozenges. On the basis of the comparisons conducted, the authors suggest that an approximately 30% smaller dose of FBT would achieve systemic exposures comparable to those following administration of Actiq lozenges. In practice, a much smaller dose may be required. Thus, the differences in the bioavailability between FBT and Actiq lozenges must be taken into account when switching between dosing formulations and they must not be substituted dose for dose as a much smaller dose of FBT will suffice. Failure to do this has led to deaths and serious adverse events, sufficient to warrant warning letters sent from the FDA and Cephalon to US physicians. Table 1: Pharmacokinetic parameters by fentanyl study drug Parameter FBT 400mcg FBT 800mcg Actiq 800mcg IV 400mcg C max, ng/ml 1.02 ± ± ± ± 1.11 t max mins 46.8 (20-240) 90.1 ( ) 90.8 ( ) NA t 1/2 hour AUC 0-tmax ng hr/ml Absolute bioavailability 14.4 ( ) 15.4 ( ) 18.3 ( ) 17.6 ( ) 0.40 ± ± ± ± ± 0.20 [95% CI 0.51 to 0.70] 0.31 ± 0.13 [95% CI 0.24 to 0.33] 0.47 ± 0.11 [95% CI 0.40 to 0.54] C max maximum plasma concentration of fentanyl, mean value t max time of observed C max, median value t 1/2 - half life, median AUC 0-tmax area under the curve from time 0 to time of median tmax, mean value