Suffolk PCT Drug & Therapeutics Committee New Medicine Report This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Fentanyl citrate oral and intranasal preparations Abstral sublingual 100, 200, 300, 400, 600 & 800 mcg tablets, ProStraken Actiq 200, 400, 600, 800, 1200 & 1600 mcg compressed lozenge with integral oromucosal applicator, Flynn Pharma Effentora 100, 200, 400, 600 & 800 mcg buccal tablets, Cephalon Instanyl 50, 100 and 200 mcg/dose nasal spray, solution, Nycomed Document status Consultation / Draft for review at January 2010 Suffolk D&TC meeting Date of last revision 7 January 2010 Traffic light decision GREEN- Hospital initiated GP prescribed Prescribers rating Possibly helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances Mechanism of action Medicine class Indication (see refs 1-4) Fentanyl is a strong μ-opioid receptor agonist. It has a relatively low molecular weight and is lipophilic which makes it suitable for oral transmucosal administration. BNF 4.7.2 Opioid analgesics Abstral the management of breakthrough pain in adult patients using opioid therapy for chronic cancer pain. Actiq the management of breakthrough pain in patients already receiving maintenance opioid therapy for chronic cancer pain. Effentora - for the treatment of breakthrough pain in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain. Instanyl the management of breakthrough pain in adults already receiving maintenance opioid therapy for chronic cancer pain. Breakthrough pain is defined as a transient exacerbation of otherwise controlled chronic background pain. Patients receiving maintenance opioid therapy are those who are taking at least 60 mg of oral morphine daily, at least 25 micrograms of transdermal fentanyl per hour, at least 30 mg of oxycodone daily, at least 8 mg of oral hydromorphone daily or an equianalgesic dose of another opioid for a week or longer. Dosage (1-4) Abstral - the optimal dose of will be determined by upward titration, on an individual patient basis. Several doses are available for use during the dose titration phase. The initial dose of Abstral used should be 100 micrograms, titrating upwards as necessary through the range of available dosage strengths. Actiq the initial dose of Actiq used should be 200 micrograms, titrating upwards as necessary through the range of available dosage strengths (200, 400, 600, 800, 1200 and 1600 micrograms). Patients should be carefully monitored until a dose is reached that provides adequate analgesia with acceptable side effects using a single dosage unit per episode of breakthrough pain. This is defined as the successful dose. This is an NHS Suffolk document that has been adopted by the WSCCG.
Effentora the initial dose of Effentora should be 100 micrograms, titrating upwards as necessary through the range of available tablets strengths (100, 200, 400, 600, 800 micrograms). Instanyl - the initial strength should be one dose of 50 micrograms in one nostril, titrating upwards as necessary through the range of available strengths (50, 100, and 200 micrograms). If adequate analgesia is not obtained redosing of the same strength may be administered at the earliest after 10 minutes. Each titration step (dose strength) should be evaluated in several episodes. Pharmacokinetics (1-4) Abstral Actiq Effentora Instanyl Absorption Rapid absorption over about 30 minutes. 25% absorbed from the buccal muscosa; 75% swallowed & absorbed via the gastrointestinal tract (GIT). 50% of the dose absorbed transmucosally, 50% swallowed & absorbed slowly from the GIT. Absorbed rapidly through the nasal mucosa. Bioavailability Mean maximal plasma concentration ~70% 0.2-1.3ng/mL (after taking 100-800mcg) reached within 22.5-240 mins. ~50% 0.39-2.51ng/mL (after taking 200 to 1600mcg) around 20-40 minutes (range 20-480 minutes) post dose. 65% 0.6 to 1.44ng/nL are reached in 46.8 minutes (range 20-240). 89% 0.35-1.2ng/mL reached within 12-15 minutes from 50-200mcg doses. Time to pain relief post dose 15 minutes 15 minutes 10 minutes 10 minutes (range 7-11 minutes) Switching from one product to another must not be done at a 1:1 ratio due to differences in bioavailability and the absorption profiles: a new dose titration must be carried out. This may result in insufficient pain control during the titration phase. Treatment alternatives Place in therapy Morphine oral solution or immediate release tablets, oxycodone oral solution or immediate release capsules, hydromorphone capsules. (5) Various opioid preparations are available to manage breakthrough pain. Morphine oral solution or immediate release tablets have historically been the mainstay to manage breakthrough pain. A prospective survey of hospice admissions of patients with breakthrough pain compared patient assessments of various immediate release opioids. Fentanyl lozenges were rated more effective than morphine, oxycodone, methadone and hydromorphone. This may be because the fentanyl dose was ~36% of the total daily regular opioid whereas the other drugs were given at a dose of ~18% of the total daily regular dose. Methadone worked faster than morphine whilst fentanyl worked faster than all the other 4 medications. (6) Patients with a dry mouth are advised to moisten the buccal cavity before administration of Effentora, Actiq or Abstral; if this does not help then switching to another product is advised. Morphine sulphate oral solution would be a
suitable alternative. (2-4) 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 therefore extra caution is required during dose titration. Differences in exposure with Effentora have been shown in a clinical study in patients with grade 1 mucositis; the differences were not clinically significant. There is little information regarding the use of Actiq lozenges in patients with mucositis: results from a small pilot study of patients with grade 3/4 mucositis showed that the lozenges were well tolerated but could cause a mild burning sensation. If signs of excessive opioid effects appear before the whole lozenge is consumed, it should be removed and consideration given to decreasing future doses. (7) Fentanyl lozenges have been directly compared with morphine immediate release tablets. No other fentanyl preparation has been compared with morphine or any other immediate release opioid. A review of opioid analgesia in cancer by the Regional Drug & Therapeutics Centre in February 2009 stated that in the absence of active comparator studies, Effentora and Abstral were not recommended in preference to less costly alternatives. (5) Treatment with immediate release fentanyl should be initiated by and remain under the supervision of a physician experienced in the management of opioid therapy in cancer patients. Physicians should keep in mind the potential of abuse of fentanyl. (1-4) Future alternatives Evidence for use None known Breakthrough cancer pain is thought to occur in 50-90% of patients with cancer pain. There is a lack of evidence directly comparing fentanyl products for breakthrough cancer pain. No studies comparing the fentanyl products with each other have been identified. The majority of trials which included fentanyl products were placebo controlled. See appendix 1. One mixed treatment comparison study compared the evidence from placebocontrolled trials of three formulations of fentanyl: fentanyl buccal tablets, orotransmucosal fentanyl citrate (lozenge) and intranasal fentanyl spray, and a trial comparing orotransmucocal fentanyl lozenge in patients already using immediate release morphine sulphate. This has been published as a conference poster. The mixed treatment comparison is limited by the fact that randomisation and study design can differ across the trials. Patient characteristics were similar so bias may not be a problem. (8-12) In the trial comparing fentanyl with morphine, the morphine dose was not obtained in the same protocol-driven way in which the fentanyl dose was identified, and there was a time-lag between getting the morphine dose and identifying the fentanyl dose. If the patients were not satisfied with pain controlled achieved with morphine, the results may have been biased towards the fentanyl product. Morphine sulphate solution is absorbed faster than tablets, and would have been a more suitable comparator product to the orotransmucosal product. (9) All three fentanyl products were more effective than placebo in treating breakthrough cancer pain. Pain relief was attained within 10-15 minutes (the earliest time points that pain was assessed). Pain relief obtained with the morphine sulphate tablets was similar to that with placebo. The trials vary in design, hence the differences in assessment times.
Intranasal fentanyl provided a greater reduction in pain intensity than the buccal and orotransmucosal lozenge products at each time point assessed (10, 20 and 30 minutes for the intranasal formulation and 15, 30 and 45 minutes for the buccal and orotransmucosal lozenge formulations). Orotransmucosal fentanyl (lozenge) produced significantly lower pain intensity scores than morphine sulphate at all time points, as well as greater pain relief. All immediate release fentanyl products give pain relief within 10-15 minutes of administration. Maximum plasma concentrations are reached faster with fentanyl nasal spray than with the oral/buccal formulations. (8-12) NNT Contraindications / Cautions (1-4) Not calculated Contraindications Hypersensitivity to the active substance or to any of the excipients. Use in opioid-naïve patients. Severe respiratory depression or severe obstructive lung conditions. Previous facial radiotherapy. (Instanyl only) Recurrent episodes of epistaxis. (Instanyl only) Simultaneous use of MAOI or within 2 weeks of stopping use of MAOI. (Actiq only) Cautions Respiratory depression Chronic pulmonary disease Impaired renal or hepatic function Increased intracranial pressure Cardiac disease Abuse potential and dependence Withdrawal symptoms Diabetes patients (Actiq only) Hereditary problems with fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltose insufficiency (Actiq only) Patients on a sodium controlled diet (Effentora only) Use in patients with mouth wounds/mucositis (Abstral only) Common cold (Instanyl only) Nasal conditions (Instanyl only) Concurrent use with other nasally administered medicines (Instanyl only) Side effects (1-4) Side effects typical of opioids would be expected with all of the preparations. Side effects tend to decrease in intensity with continued use. The most serious potential adverse effects are respiratory depression, hypotension and shock. Other very commonly reported adverse reactions include nausea, vomiting, constipation, headache, somnolence/fatigue and dizziness. Abstral, Effentora and Instanyl are black triangle drugs and any adverse reaction should be reported to the CHM/MHRA. Cost within PbR tariff Cost (prices from MIMS Dec 2009) In tariff Abstral Tablets (sublingual) 10 x100mcg, 200mcg, 300mcg, or 400mcg = 49.99; (1 tablet = 4.99) 30 x100mcg, 200mcg, 300mcg, 400mcg, 600mcg or 800mcg = 149.70. (1 tablet = 4.99) Actiq Lozenge with oromucosal applicator: 3 x 200mcg, 400mcg, 600mcg, 800mcg, 1200mcg or 1600mcg = 17.86; (1 lozenge = 5.95) 30 x 2000mcg, 400mcg, 600mcg, 800mcg, 1200mcg or 1600mcg = 178.55 (1
lozenge = 5.95) Effentora buccal tablets: 4 x100mcg, 200mcg, 400mcg, 600mcg or 800mcg= 20.56 (1 tablet = 5.14) Instanyl 10 doses of 50mcg/dose, 100mcg/dose and 200mcg/dose = 59.50 (1 dose = 5.95) 20 doses of 50mcg/dose, 100mcg/dose and 200mcg/dose = 119 (1 dose = 5.95) Comparative costs of other medicines Oramorph (morphine oral solution) 10mg/5mL (2mg/mL): 100mL = 1.87; 300mL = 5.21; 500mL = 7.86. (10mg = 16-19p) Sevredol (morphine sulphate immediate release tablets) 56x10mg = 5.61 (1 tablet = 10p) 56x20mg = 11.21 (1 tablet = 20p) 56x50mg = 28.02 (1 tablet = 50p) Potential number of patients & usage in Suffolk PCT The 2008/09 national QOF prevalence rates for cancer and palliative care are 1.3% and 0.1% respectively. Applying these figures to NHS Suffolk with a population of approximately 610,000, the number of patients affected are 7,930 and 610. If 50% of these patients require medication for breakthrough pain, 4270 may need an immediate release opioid analgesic. Points for consideration If all 4,270 were to use a dose of 15-60 mg immediate release morphine four times a day for a week, the cost would be ~ 16,000-71,700 If 10% of patients were to use 50-1600mcg of four times a day for a week instead, costs would be ~ 59,660-71,140 No more than 4 episodes of breakthrough pain a day should be treated with an immediate-release fentanyl preparation. The fixed dose of strong opioid to control the cancer-related pain should be reviewed and adjusted frequently to ensure that breakthrough pain episodes and the use of immediate-release products are kept to a minimum. All of the immediate release fentanyl preparations provide adequate pain relief within 10-15 minutes, when compared to placebo, albeit to varying degrees. Intranasal fentanyl reaches maximal plasma concentrations faster than the other preparations and the mean pain intensity difference from baseline compared to placebo, is greater than that achieved with the other products. The wide range of fentanyl products can lead to errors in dosing due to differences in pharmacokinetic/dynamic profiles. The products are not interchangeable. There is potential for prescribing and dispensing errors if more than one formulation is available locally or prescribed in the community, as the strengths are similar. In order to prevent such errors, ensure that the brand name of the correct product is on the prescription. 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 to Effentora. Re-dosing with any of the immediate-release products should not be done within at least 4 hours of the previous dose. There are no specific guidelines on how to change from one product to another, but based on how often a dose can be taken, it could be assumed that a different preparation should not be used within 4 hours of the original one.
Decisions from other bodies Cambridgeshire JPG not assessed Norfolk TAG not assessed AWMSG not assessed SMC Feb 2009: Abstral sublingual tablets were accepted for restricted use within NHS Scotland for the management of breakthrough pain in adult patients using opioid therapy for chronic cancer pain. The 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. Feb 2009: Effentora were accepted for restricted use within NHS Scotland for the treatment of breakthrough pain in adults with cancer who are already receiving maintenance opioid therapy for chronic cancer pain. The use of fentanyl buccal tablets should be restricted to patients who are unsuitable for other short-acting opioids e.g. oral morphine. Furthermore, prescribers should be aware of the differing absorption and elimination characteristics of available buccal fentanyl preparations i.e. doses are not interchangeable. Nov 2009: Instanyl accepted for restricted use within NHSScotland for the management of breakthrough pain in adults already receiving maintenance opioid therapy for chronic cancer pain. Use should be restricted to patients who are unsuitable for other short-acting oral opioids (e.g. oral morphine) as an alternative to other buccal and sublingual fentanyl preparations. Comments sought from Decision review date Jan 2012 References 1. Summary of Product Characteristics. Abstral sublingual tablets, last revised 19/09/08. 2. Summary of Product Characteristics. Actiq. Flynn Pharma Ltd, last revised 08/10/05. 3. Summary of Product Characteristics. Effentora 100, 200, 400, 600 and 800 micrograms buccal tablets. Cephalon UK Ltd, last revised 04/04/08. 4. Summary of Product Characteristics. Instanyl 50, 100 and 200mcg/dose nasal spray. Nycomed UK Ltd, last revised 20/07/09. 5. Opioid analgesia in cancer. Drug Update. Feb 2009 http://www.nyrdtc.nhs.uk/docs/dud/du_63_opioid.pdf 6. Zeppetella G. Opioids for cancer breakthrough pain: a pilot study reporting patient assessment of time to meaningful pain relief. J Pain Symptom Manage 2008; 35(5):563-567. 7. Denby A. Fentanyl preparations for breakthrough cancer pain. London New Drugs Group APC/DTC Briefing Document. August 2009 http://www.nelm.nhs.uk/en/ 8. Stam WB, Lenre M, Nolte T et al. Efficacy of intranasal fentanyl spray versus oral transmucosal fentanyl citrate, fentanyl buccal tablet and oral morphine for breakthrough pain in cancer: a metaanalysis of randomised controlled trials. Poster presentation. Presented at ISPOR 11th Annual European Congress. Athens, Greece. 8-11 November: 2008 9. Coluzzi PH, Schwartzberg L, Conroy JD et al. Breakthrough cancer pain: a randomized trial comparing oral transmucosal fentanyl citrate (OTFC) and morphine sulfate immediate release (MSIR). Pain 2001; 91:123-130. 10. 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):805-811. 11. Farrar JT, Cleary J, Rauck R et al. Oral transmucosal fentanyl citrate: randomized, double-blinded, placebo-controlled trial for treatment of breakthrough pain in cancer patients. J Natl Cancer Inst 1998; 90(8):611-616. 12. Slatkin NE, Xie F, Messina J et al. Fentanyl buccal tablet for relief of breakthrough pain in opioidtolerant patients with cancer-related chronic pain. Journal of Supportive Oncology 2007; 5(7):327-334. Appendix 1: Individual trial details (no published details for the intranasal trial)
Patients Regular pain medication Breakthrough episodes a day Type of cancer Life expectancy Titration phase (open label) Treatment Buccal tablets (10) Buccal tablets (12) Lozenge (11) 18 years of age (n=77) Oral morphine 60-1000mg/day, or equivalent, or 50-300mcg/hour transdermal fentanyl for at least 1 week 18-80 years of age (n=87) At least 60mg/day oral morphine or 25mcg/hr transdermal fentanyl, or equivalent for at least 1 week. 18 years of age (n=93) At least 60mg/day oral morphine or 50mcg/hr transdermal fentanyl or equivalent. 1-4 1-4 At least 1 1-4 Solid or haematologic malignancy and an Eastern Cooperative Oncology Group (ECOG) performance status rating of 2. Solid or haematologic malignancy. All types and stages. Morphine sulphate immediate release (MSIR) (9) Adults (n=89) Oral morphine 60-1000mg/day, or equivalent, or 50-300mcg/hour transdermal fentanyl, plus successful dose of MSIR (15-60mg). All types and stages. 3 months At least 2 months Not stated Not stated. Yes, to effective dose. Yes, to effective dose. Yes, to effective dose. Random assignment to 1 of 18 pre-specified dose sequences of 10 tablets (7 active and 3 placebo), all of which had to be taken within a 21-day period, with a maximum of 4 episodes treated each day). Prestudy supplemental medicines could be taken if adequate pain relief not achieved within 30 mins. Random assignment to 1 of 18 pre-specified dose sequences of 10 tablets (7 active and 3 placebo), all of which had to be taken within a 21-day period, with a maximum of 4 episodes treated each day. Prestudy supplemental medicines could be taken if adequate pain relief not achieved within 30 mins. 10 period crossover: 10 sequentially numbered units (7 active and 3 placebo) to be taken in the designated order. Second dose could be taken after 30 mins if first not effective enough. Yes, to effective OTFC dose. 10 prenumbered sets of OTFC/placebo MSIR and placebo OTFC/MSIR, to be taken by a randomised order. No additional medications allowed for 1 hour poststudy medication. New episodes could be treated after 2 hours had elapsed. Mean MSIR dose: 31±13.5mg Mean OTFC dose: 811±452mcg. Pain intensity measured at 15, 30, 45 and 60 mins post dose. 5, 10, 15, 30. 45, 60, 90, 120 mins post dose. 15, 30, 45 and 60 mins post dose. 15, 30, 45 and 60 mins post dose. Pain intensity difference (active placebo)* Pain intensity difference (active placebo) ITT population* 30 mins: 1.2 Not stated 10 mins: 0.4 60 mins: 4.8 Not stated 15 mins: 0.60 30 mins: 0.90 45 mins: 0.97 60 mins: 1.06 15 mins: 0.58 30 mins: 0.87 45 mins: 0.63 60 mins: 0.66 At each time point mean PID favoured OTFC over MSIR (p<0.008). Pain relief was significantly greater with OTFC than MSIR at all time points (p 0.009). Note that no numerical data were presented and therefore PIDs cannot be compared. >33% change in PID seen in 42.3% of episodes treated with OTFC and 31.8% of episodes treated with MSIR (p 0.009). * published in clinical trial; 11 point scale (0=no pain, 10=worst pain)
Grids used to assist the NHS Suffolk PCT Drug & Therapeutics Committee in reaching a decision about new medications For many years scientists have recognised two types of research: Primary: original studies, based on observation or experimentation on subjects. Secondary: reviews of published research, drawing together the findings of two or more primary studies. In biomedical science there is general agreement over a hierarchy: the higher up a methodology is ranked, the more robust and closer to objective truth it is assumed to be. The orthodox hierarchy looks something like this- Rank: Methodology Description 1 Systematic reviews and meta-analyses Systematic review: review of a body of data that uses explicit methods to locate primary studies, and explicit criteria to assess their quality. Meta-analysis: A statistical analysis that combines or integrates the results of several independent clinical trials considered by the analyst to be "combinable" usually to the level of re-analysing the original data, also sometimes called: pooling, quantitative synthesis. Both are sometimes called "overviews." 2 Randomised controlled trials (finer distinctions may be drawn within this group based on statistical parameters like the confidence intervals) Individuals are randomly allocated to a control group and a group who receive a specific intervention. Otherwise the two groups are identical for any significant variables. They are followed up for specific end points. 3 Cohort studies Groups of people are selected on the basis of their exposure to a particular agent and followed up for specific outcomes. 4 Case-control studies "Cases" with the condition are matched with "controls" without, and a retrospective analysis used to look for differences between the two groups. 5 Cross sectional surveys Survey or interview of a sample of the population of interest at one point in time 6 Case reports. A report based on a single patient or subject; sometimes collected together into a short series 7 Expert opinion A consensus of experience from the good and the great. 8 Anecdotal Something a bloke told you after a meeting or in the bar. Adapted from Systematic reviews, What are they and why are they useful? ScHARR 2008
To Decide if a Medication Is To Be Used In Suffolk Criterion to be measured Tends to poor 2 Medium 4 Tends to good Quality of evidence in the papers reviewed 7-8 5-6 3 4 2 1 Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Clinical outcomes Clinical usefulness of trial end-points x Known Side Effect Profile High Medium Low Known Interactions High Medium Low Concern re Possible Side Effects Not Yet Uncovered High Medium Low Balance of Benefit To Harm (side effects toxicity interactions etc) Poor Medium Good NNT not possible to calculate High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Same Condition Poor x Medium Good Severity of Condition to be Treated Trivial Medium x Severe Novel drug or member of existing class Uptake (estimated proportion of people with this condition likely to be prescribed the medication under consideration maximum and minimum uptake) Existing class 10% Prescriber s Rating Definitions Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. A real advance - The product is an important therapeutic innovation but has certain limitations. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. Nothing New - The product may be a new substance but is superfluous because it does not add to the clinical possibilities offered by previous products available. In most cases these are me-too products. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire)
To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green Blue Experience Of The Condition Specific Specific Specific Genera Diagnosis Specific Specific Specific Genera Monitoring Progress Of Treatment Difficult Specific General Genera Therapy Patient Selection Difficult Specific Specific Easy Initiation Of Treatment Difficult Difficult Easy Easy Dose Titration Difficult Specific Easy Easy Monitoring Of Side Effects Complex Easy Easy Easy Method Of Administration Complex Normal Normal Normal Discontinuation Of Treatment Complex Complex Easy Easy References Jonsen A. Bentham in a box: Technology assessment and health care allocation. Law Med. Health Care. 1986;14:172-174 1 Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2