New Medicines Committee Briefing November 2011 Abstral (sublingual fentanyl citrate tablet) for the management of breakthrough cancer pain

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1 New Medicines Committee Briefing November 2011 Abstral (sublingual fentanyl citrate tablet) for the management of breakthrough cancer pain Abstral is to be reviewed for use within: Primary Care Secondary Care Summary: Abstral is a sublingual fentanyl citrate tablet and is an immediate-release fentanyl product 1. Abstral is licensed for the management of breakthrough pain in adult patients using opioid therapy for chronic cancer pain (breakthrough pain is a transient exacerbation of.controlled chronic background pain) 1. Following an abbreviated submission the SMC accepted fentanyl sublingual tablets (Abstral ) for restricted use (ie when other short-acting opioids are unsuitable) in NHS Scotland for the licensed indication 2. SIGN recommends oral transmucosal fentanyl citrate for breakthrough pain 3. Significant improvements in pain intensity and significant increases in patient-reported satisfaction with pain medication have been shown with sublingual fentanyl 4,5,6. Abstral is a black triangle drug ( ) and is monitored intensively by the CHM and MHRA 1. Abstral is to be considered as a replacement for Effentora (buccal fentanyl citrate) on the North Staffordshire Joint Formulary. 1

2 Formulary application: Consultant submitting application: Clinical Director supporting application: Dr Selvaraj Giridharan (Consultant Clinical Oncologist) Dr Andrew Stewart Dr Giridharan has requested that Abstral be considered for inclusion in the North Staffordshire Joint Formulary for the management of breakthrough cancer pain in adult patients using opioid therapy for chronic cancer pain. In the formulary application Dr Giridharan lists the benefits of Abstral to be as follows: reduction in morbidity/improved quality of life, improved tolerability and convenient administration. Dr Giridharan proposes that Abstral would be used in patients receiving maintenance opioids prior to radiotherapy/physiotherapy and would replace Effentora (fentanyl buccal tablets) on the formulary which is currently being prescribed for this indication. In the application Dr Giridharan states that Abstral may be more convenient, provide better patient acceptability and be easier to use than Effentora for breakthrough cancer pain. Dr Giridharan suggests that Abstral would be for classified as a red drug on the formulary ie prescribed only within secondary care. Dr Giridharan has suggested that the prescribing of Abstral should be restricted in the same was as Effentora currently is on the formulary ie restricted for use in palliative, haematology and oncology only. Background: Breakthrough pain is a transient exacerbation of otherwise controlled chronic background pain. Background pain can, in most cases, be treated successfully with long-acting opioid formulations and adjuvant drugs eg gabapentin, amitriptylline 7. Breakthrough pain has been estimated to affect 50-90% of patients with cancer and can be predictable (related to movement or activity such as swallowing and coughing) or spontaneous. It is usually moderate to severe in intensity and the pathophysiology is often, but not always, the same as background pain ie it can be neuropathic, nociceptive or a combination of both. Breakthrough cancer pain (BTcP) episodes vary in duration, intensity and cause but the typical episode reaches peak intensity after 3-5 minutes and has an average duration of minutes and patients experience a median of 2-4 episodes per day. BTcP, if poorly controlled, can have a profound impact on quality of life and consequences can include- impairment of daily activities eg walking/working; anxiety and depression; difficulty sleeping; reduced social interaction; increased pain severity; dissatisfaction with pain management. Patients with BTcP have also been shown to be more likely to access health care resources, have more pain-related hospital admissions and emergency medical admissions 7,8. The aim of management of BTcP is to reduce the impact of pain episodes on the patient s quality of life. Immediate-release oral formulations of opioids such as morphine and oxycodone have historically been used to manage BTcP, however, these do not reach peak activity until

3 minutes after administration and are therefore unable to match the timings of BTcP episodes. The ideal treatment for most episodes is a rescue dose of a strong opioid with pharmacokinetic properties that closely match the temporal characteristics of the BTcP; for most episodes the use of a short-acting opioid with quick onset and duration of action is the most appropriate treatment. Fentanyl is a lipophilic opioid that is rapidly absorbed across mucosal membranes with a rapid onset and shorter effect that closely matches the profile of ideal rescue treatment and administration via the buccal, sublingual or nasal routes provides more rapid absorption and onset of action compared with the oral route and with oral morphine 7,8,9. Abstral is a sublingual fentanyl citrate tablet and is an immediate-release fentanyl product. Other fentanyl products licensed for the treatment of breakthrough cancer pain include Effentora (a buccal fentanyl tablet), Actiq (buccal lozenges), Instanyl (nasal spray) and Pecfent (nasal spray) 9. Current formulary status: The North Staffordshire Joint Formulary currently lists the following agents: Opioid analgesics Codeine Diamorphine Dihydrocodeine Fentanyl Morphine Oxycodone Standard release preparations only Restriction: Patches only. See NMC/APC Advice Restriction: See NMC/APC Advice APC/NMC FF Article APC/NMC FF Article Buprenorphine 2 Tablets only NICE Restriction: Use in palliative care and substance NICE Methadone 2 misuse only CHM Pethidine 2 Fentanyl buccal tablet (Effentora ) Therapeutic class and mode of action: Restriction: For use in palliative, haematology and oncology only Abstral is a sublingual fentanyl citrate tablet and is an immediate-release fentanyl product; fentanyl is an opioid analgesic (Schedule 2 Controlled Drug) 1,9,10. Licensed indication: Management of breakthrough pain in adult patients using opioid therapy for chronic cancer pain (breakthrough pain is a transient exacerbation of otherwise controlled chronic background pain) 1. 3

4 Dosage and administration 1,10 : Abstral should only be administered to patients who are considered tolerant to their opioid therapy for persistent cancer pain; patients can be considered opioid tolerant if they take at least 60 mg oral morphine per day, 25 micrograms transdermal fentanyl per hour, or an equianalgesic dose of another opioid for a week or longer. Dose: Abstral should be individually titrated to identify an optimal maintenance dose for ongoing treatment of BTcP; this optimal dose should provide adequate analgesia with acceptable levels of adverse reactions. Dose titration Dose titration is required to identify an optimal maintenance dose as follows- All patients must start therapy with a single 100 microgram sublingual tablet; if adequate analgesia is not obtained within minutes a supplemental (second) 100 microgram sublingual tablet may be administered. If adequate analgesia is not obtained within minutes of the first dose, an increase in dose to the next highest tablet strength should be considered for the next episode of breakthrough pain (see figure below). Dose escalation should continue in a stepwise manner until adequate analgesia is achieved. The dose strength for the supplemental (second) sublingual tablet should be increased from 100 to 200 micrograms at doses of 400 micrograms and higher (see figure below). 4

5 Strength (micrograms) of first sublingual tablet per episode of breakthrough pain Strength (micrograms) of supplemental (second) sublingual tablet to be taken minutes after first tablet, if required If adequate analgesia is achieved at the higher dose, but undesirable effects are considered unacceptable, an intermediate dose (using the 100 microgram sublingual tablet where appropriate) may be administered. If patients are switched from another fentanyl-containing product a new dose titration is required ie switching from other fentanyl-containing products should not occur at a 1:1 ratio due to different absorption profiles. Patients should be monitored closely by health professionals during the titration process to minimise the risk of opioid related adverse reactions and to identify the appropriate dose. Maintenance therapy Once an appropriate dose has been established (which may be more than one tablet) patients should be maintained on this dose and should limit consumption to a maximum of 4 doses per day. 5

6 Maximum 800 micrograms per episode of breakthrough pain Administration: Renal impairment: Hepatic impairment: Elderly patients: Administered directly under the tongue at the deepest part and allowed to completely dissolve in the sublingual cavity without chewing/sucking. Dose titration to be approached with particular care; observe for signs of fentanyl toxicity. Dose titration to be approached with particular care; observe for signs of fentanyl toxicity. Dose titration to be approached with particular care; observe for signs of fentanyl toxicity. Presentation 1 : 100 microgram, 200 microgram, 300 microgram, 400 microgram, 600 microgram, 800 microgram sublingual tablets in packs of 10 or 30. Guidance: NICE Guidance: NICE guidance published No Scottish Medicines Consortium (SMC) 2 : SMC recommended use within NHS Scotland: Yes Following an abbreviated submission the SMC accepted fentanyl sublingual tablets (Abstral ) for restricted use in NHS Scotland for the management of breakthrough pain in adult patients using opioid therapy for chronic cancer pain. Use of sublingual fentanyl tablets should be restricted to patients who are unsuitable for other short-acting opioids e.g. oral morphine. This product offers an alternative to buccal administration at a reduced cost per administration. Prescribers should be aware of the differing absorption and elimination characteristics of available oral fentanyl preparations; doses are not interchangeable. Cochrane Review 11 : Clinical trial evidence was sought to determine the effectiveness of opioids in relieving breakthrough pain and the incidence of side effects in these cancer patients. Four trials were identified and included 393 participants; the studies identified examined the use of oral 6

7 transmucosal fentanyl citrate (OTFC) in breakthrough pain in cancer patients taking regularly scheduled opioids. All four studies used similar outcome measures. Available data suggest that OTFC is safe and effective (compared to both placebo and morphine) in relieving breakthrough pain. The side effect profile of OTFC is similar to other opioids. Authors concluded that there is evidence that OTFC is an effective treatment in the management of breakthrough pain. The randomised trial literature for the management of breakthrough pain is small and no trials were found for other opioids. Given the importance of this subject, more trials need to be undertaken. NB Trials included in the review were for oral transmucosal fentanyl citrate ie Effentora Scottish Intercollegiate Guidelines Network (SIGN) 3 : SIGN guidelines published Yes Relevant guidelines 106- Control of pain in adults with cancer (November 2008) Sign recommends the following for breakthrough pain in cancer: Patients with moderate or severe breakthrough pain should receive breakthrough analgesia When using oral transmucosal fentanyl citrate for breakthrough pain the effective dose should be found by upward titration independent of the around the clock opioid dose MTRAC MTRAC reviewed No MTRAC have reviewed fentanyl lozenges (Actiq ) 12 and concluded that treatment with fentanyl lozenges for the management of breakthrough pain is appropriate for prescribing in primary care. Efficacy: Outcome measures used to assess efficacy of sublingual fentanyl: Pain Intensity Difference (PID)- a measure of the difference in pain intensity from immediately before treatment (at baseline) to after treatment and indicates the analgesic efficacy of the drug. Sum of pain intensity difference (SPID)- a measure of the overall performance of a study drug over 30 or 60 minutes and indicates the analgesic efficacy of the drug; calculated on a plot of PID against time. Patients global evaluation of medication (PGEM)- a measure of overall satisfaction with pain (patients responded to the question How satisfied are you with your current medication for pain? on a 5 point scale. 7

8 Brief pain inventory (BPI)- records patients experience of pain, pain relief and the effects of pain on physical functioning using scales for pain and pain relief Depression, anxiety positive outlook scale (DAPOS)- a measure of changes in physiological factors associated with pain (comprises statements that patients are asked to indicate their agreement with on a scale among the 3 domains depression, anxiety and well-being. Pain intensity- patients rated the maximum pain intensity experienced during BTcP episodes. Efficacy: Analgesic efficacy of fentanyl is well-established 8. Summary: First detectable levels of plasma fentanyl observed as early as 8-11 minutes after administration 13. Lennernas et al 13 conducted a phase I double-blind, cross-over trial in opioid-tolerant patients with cancer and reported that detectable levels of plasma fentanyl were observed as early as 8-11 minutes after sublingual fentanyl administration and the pharmacokinetics demonstrated dose proportionality. Summary: Sublingual fentanyl tablets provided significant improvements in pain intensity compared to placebo from 10 minutes post-administration and throughout the 60-minute assessment period 4. Rauck et al 4 conducted a phase III, randomised, placebo-controlled, multi-centre trial in opioidtolerant patients with BTcP. Following a 2-week open-label titration phase to determine the effective dose, patients entered a 2-week, double-blind, placebo-controlled efficacy phase in which patients received sublingual fentanyl citrated orally disintegrating tablets (sublingual fentanyl ODT) or placebo, in a random order. The primary efficacy end-point was the sum of pain intensity difference (SPID) over 30 minutes post-administration; secondary efficacy measures included pain intensity difference (PID) through-out the 60 minute assessment period. Sublingual fentanyl ODT provided significant improvements in SPID relative to placebo at 30 minutes (49.5 v 36.6; p=0.0004) and at the improvement was maintained at 60 minutes postdose (140.3 vs 104.5; p=0.0002; sublingual fentanyl ODT provided significant improvements in PID compared to placebo from 10 minutes post dose (p=0.0055). Summary: significant increases in patient-reported satisfaction with pain medication were recorded during treatment with sublingual fentanyl 5. Nalamachu et al 5 conducted a non-randomised, open-label, multi-centre study in opioid-tolerant patients with BTcP comprising a 2-week open-label titration phase to determine the effective dose followed by a 12-month open-label maintenance phase. Effectiveness was asses using patients global evaluation of medication (PGEM), the brief pain inventory (BPI) and the depression, anxiety positive outlook scale (DAPOS). Reported satisfaction with pain medication (using PGEM) at the 6-month and end-of-study visits was significantly increased when compared to screening (p 0.01); BPI scores showed significant improvements in pain scores at 6-months and end-of-study compared to screening (p 0.05); DAPOS scores showed numerical trends towards improvements in all 3 domains at the end of the study compared to screening (statistically significant improvement in depression scores at month 6 (p=0.011). 8

9 Summary: patients experienced significant improvements in pain intensity for BTcP episodes treated with sublingual fentanyl compared to baseline 6. Uberall and Muller-Schwefe 6 carried out a prospective-multi-centre phase IV study in which opioid-tolerant patients with BTcP received sublingual fentanyl ODT in the course of routine clinical practice and completed questionnaires relating to their health and treatment over a 28- day observation period. The study recorded a significant improvement in pain intensity compared to baseline (2.6 vs 7.8; p<0.0001) and patients reported experiencing the first effects of the study drug within 10 minutes of administration in 82.8% of episodes and a time to maximum effect of 30 minutes in 63.2% of episodes. Comparison to other immediate-release opioid preparations: There are no studies comparing Abstral to other fentanyl preparations for breakthrough cancer pain. Experience with palliative care patients has found that Effentora takes longer to dissolve than Abstral, feels uncomfortable and can leave a prolonged taste. Patients tend to prefer Abstral and Actiq (fentanyl buccal lozenges) to Effentora (fentanyl buccal tablets) 8. There are no studies directly comparing Abstral to morphine and oxycodone immediaterelease preparations. Safety and adverse effects 1 : Contraindications: Adverse effects: Hypersensitivity to active ingredient/excipients; Opioid-naïve patients (risk of respiratory depression); severe respiratory depression or severe obstructive lung conditions. As for fentanyl ie serious potential adverse effects associated with opioid analgesia- respiratory depression, hypotension, circulatory shock; commonly reported ADRs-nausea, vomiting, headache, constipation, somnolence/fatigue, dizziness. NB The use of Abstral has not been studied in patients with mucositis or mouth wounds; there may be a risk of increased systemic drug exposure and extra caution is therefore advised during dose titration. For more information refer to the Summary of Product Characteristics 1. Drug Interactions 1 : As for fentanyl- refer to the Summary of Product Characteristics 1. 9

10 Cost analysis Costs of in primary and secondary care: Strength Pack size Primary Care (exc. VAT) (BNF price 9 ) Secondary Care (inc. VAT) Per pack Per dose Per pack Per dose 100 micrograms micrograms micrograms micrograms micrograms micrograms 400 micrograms micrograms micrograms 800 micrograms Estimated cost: Dr Giridharan estimates that 1-2 patients per month will be prescribed Abstral an average of 5 doses with a final dose range of between 200 and 300 micrograms. Estimated cost per patient: = per dose= The estimated annual cost is therefore between and Comparison with other therapy: Comparative expenditure for Abstral (sublingual fentanyl tablets) and Effentora (buccal fentanyl tablets) in primary and secondary care for a 6-month period (January- June 2011): Fentanyl tablet UHNS Stoke-on-Trent PCT North Staffordshire PCT Abstral Nil Effentora 5, ,

11 Comparative price per dose: Cost per dose Primary Care (exc. VAT) (BNF price 9 ) Abstral Effentora Actiq (all strengths) (all strengths) (all strengths) Secondary Care (inc. VAT) NB Each fentanyl product should be titrated to the most effective dose that provides adequate analgesia and minimises side effects. Switching from one product to another must not be done at a 1:1 ratio due to differences in bioavailability and absorption profiles: a new dose titration must be carried out 11

12 References 1. Abstral sublingual tablets. Summary of Product Characteristics. ProStraken. Last updated 3/6/2010. Accessed 5/10/ Scottish Medicines Consortium (SMC). fentanyl 100, 200, 300, 400, 600 and 800 microgram sublingual tablets (Abstral) (No: 534/09). Abstr al_/fentanyl_sublingual Abstral_ 3. SIGN. SIGN 106: Control of pain in adults with cancer (November 2008). Accessed via 4. Rauck R, Tark M et al. Efficacy and long-term tolerability of sublingual fentanyl orally disintegrating tablet in the treatment of breakthrough cancer pain. Curr Med Res Opin 2009; 25: Nalamachu S, Hassman D et al. Long-term effectiveness and tolerability of sublingual fentanyl orally disintegrating tablet for the treatment of breakthrough cancer pain. Curr Med Res Opin 2011; 27: Uberall M and Muller-Schwefe. Sublingual fentanyl orally disintegrating tablet in daily practice: efficacy, safety and tolerability in patients with breakthrough cancer pain. Curr Med Res Opin 2011; 27: Dickman A. Basics of managing breakthrough cancer pain. The Pharmaceutical Journal : 283; UKMi. London New Drugs Group APC/DTC Briefing Document: Fentanyl preparations for breakthrough cancer pain (August 2009). 9. British National Formulary No 62 (September 2011). BMJ and Pharmaceutical Press: London. 10. Abstral Product Monograph (May 2011). ProStraken. 11. Zeppetella G and Ribeiro M Stowe R et al. Opioids for the management of breakthrough (episodic) pain in cancer patients. Cochrane Database of Systematic Reviews 2006, Issue 1. Art. No.: CD Midlands Therapeutics Review Advisory Committee (MTRAC). Verdict: - Oral Transmucosal Fentanyl Citrate (Actiq ), July Lenneras B et al. Pharmacokinetics and tolerability of different doses of fentanyl following sublingual administration of a rapidly dissolving tablet to cancer patients: a new approach to treatment of incident pain. Br J Pharmacol 2004; 59 (2): Produced by Julie Shenton Primary / Secondary Care Interface Pharmacist University Hospital of North Staffordshire Telephone: julie.shenton@uhns.nhs.uk Produced for use within the NHS. Not to be reproduced for commercial purposes 12