Suffolk PCT Drug & Therapeutics Committee New Medicine Report

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1 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 Prolonged release (PR) oxycodone & PR naloxone fixed dose oral tablet (Targactin, Napp) Document status Agreed at July 2009 Suffolk D&TC meeting Date of last revision 29 June 2009 Traffic light decision Blue Prescribers rating Prescribers rating: 7. Not acceptable - Product without evident benefit over others but with potential or real disadvantages Mechanism of action Medicine class Indication Dosage Oxycodone is an opioid analgesic which has an affinity for kappa, mu and delta opiate receptors in the brain, spinal cord and peripheral organs (e.g. intestine). Constipation is classed as a very common side effect with oxycodone, occurring in 1 in 10 people who take the medicine. Naloxone is a specific opioid antagonist that acts competitively at opioid receptors. In patients receiving long-term opioids, oral naloxone in a daily dose equivalent to 20 to 40% of the daily opioid dose has relieved opioid-induced constipation without compromising analgesic control by competitively antagonising local opioid receptors in the gut. Opioid analgesic + opioid antagonist (to counteract opioid induced constipation) This is the first PR agonist and antagonist combination licensed for pain management in the UK Severe pain which can be adequately managed only with opioid analgesics. The opioid antagonist naloxone is added to counteract opioid-induced constipation by blocking the action of oxycodone at opioid receptors locally in the gut. 20mg oxycodone + 10mg naloxone (20mg/10mg) 10mg oxycodone + 5mg naloxone (10mg/5mg). The PR oral tablet should be given every 12 hours. The usual starting dose for an opioid naïve patient is 10mg/5mg, patients already receiving opioids may be started on higher doses, depending on their previous opioid experience. The maximum daily dose is currently limited to 40mg/20mg (corresponding to twice daily administration of 20mg/10mg PR tablets). Patients requiring higher doses should be administered supplemental PR oxycodone at the same time intervals, taking into account the maximum daily dose of 400mg prolongedrelease oxycodone. In the case of supplemental oxycodone dosing, the beneficial effect of naloxone on bowel function may be reduced. Treatment alternatives Opioid agonist + laxative e.g. PR Morphine or PR oxycodone + bisacodyl, senna, ispaghula husk, lactulose or macrogol Place in therapy The Scottish Medicines Consortium (SMC) reviewed PR This is an NHS Suffolk document that has been adopted by the WSCCG.

2 Future alternatives Evidence for use oxycodone/pr naloxone in March The advice issued was that addition of naloxone to oxycodone did not impair analgesia and improved bowel function when patients were not receiving regular laxative therapy. However, the clinical benefit in patients receiving regular laxative therapy is uncertain and the economic analysis presented was not sufficiently robust to gain acceptance by the SMC. Oxycodone can be used in patients who require an opioid but cannot tolerate morphine. PR oxycodone/pr naloxone could therefore be used in patients who can not tolerate morphine due to opioid induced constipation. PR oxycodone/pr naloxone may be an option for patients who require a strong opioid and have experienced constipation while taking weak opioids (e.g. tramadol, codeine). Use of a PR oxycodone/pr naloxone fixed dose combination tablet may help to reduce polypharmacy in patients taking a large number of oral medications. None known Three phase III, randomised, double blind, parallel group, multicentre, 12 week trials in over 1,000 patients have assessed the analgesic efficacy, safety and effect on symptoms of constipation secondary to opioid treatment of PR oxycodone/pr naloxone against placebo and PR oxycodone. Each of these trials had 12 month extension phases, two of which have been completed but not yet published. Patients in the trials were mainly on long term opioids for back pain, osteoarthritic pain and neuropathic pain. Patients with cancer pain were excluded from the phase III trials. The trials showed that the addition of PR naloxone does not affect the analgesic efficacy of PR oxycodone. There was a clinically relevant improvement in bowel function with the PR oxycodone/pr naloxone combination compared to PR oxycodone monotherapy. This was based on the bowel function index (BFI) score which was the mean of the following items, which patients assessed at each visit (patients were asked to consider the last seven days when giving their assessments; for each of the measures, a lower score indicates better bowel function): Ease of defaecation (assessed using a numerical analogue scale, where 0 = easy/no difficulty and 100 = severe difficulty). Feeling of incomplete bowel evacuation (assessed using a numerical analogue scale, where 0 = not at all and 100 = very strong). Personal judgment of constipation (assessed using a numerical analogue scale, where 0 = not at all and 100 = very strong). Higher scores with the BFI indicate poor bowel function. A change in BFI score of >12 points is considered to be clinically relevant. The incidence of adverse effects was comparable between the different treatment groups. The addition of PR naloxone to PR oxycodone does not completely negate the need for laxatives, in a long term clinical

3 trial about 10% of patients still required regular additional laxatives. Currently there is very little long term data available. A 12 month open label extension to a phase III trial showed that patient scores for average pain over the last 24 hours, pain intensity, and interference of pain with sleep and activities remained low and stable. The mean daily dose of PR oxycodone/pr naloxone increased which possibly indicates a natural progression of the underlying chronic pain condition or increasing drug tolerance. Use of rescue medication was low. Patient assessment of the PR oxycodone/pr naloxone combination is that it is effective and well tolerated. NNT Cautions / side effects The safety and efficacy of the PR oxycodone/pr naloxone product has not been established in cancer patients and/or patients with liver metastasis in randomised clinical trials. There is data on use in cancer patients from an observational study. Not possible to calculate If abused parenterally, intranasally or orally by individuals dependent on opioid agonists such as heroin, methadone or morphine, abuse of the combination product is expected to produce marked withdrawal symptoms because of the opioid receptor antagonist characteristics of naloxone or it will intensify withdrawal symptoms already present. The major risk from opioids is respiratory depression. Caution must be exercised when administering PR oxycodone / PR naloxone to elderly or infirm patients, patients with opioidinduced paralytic ileus, patients presenting severely impaired pulmonary function, myxoedema, hypothyroidism, Addison s disease (adrenal cortical insufficiency), toxic psychosis, cholelithiasis, prostate hypertrophy, alcoholism, delirium tremens, pancreatitis, hypotension, hypertension, pre-existing cardiovascular diseases, head injury (due to the risk of increased intracranial pressure), epileptic disorder or predisposition to convulsions, or patients taking monoamine oxidase (MAO) inhibitors. During long-term administration, the patient may develop tolerance to the drug and require higher doses to maintain the desired analgesic effect. Chronic administration of PR oxycodone / with or without PR naloxone may lead to physical dependence. Withdrawal symptoms may occur upon the abrupt cessation of therapy. If therapy with PR oxycodone / PR naloxone is no longer required, it may be advisable to reduce the daily dose gradually. Common side effects of the combination tablet are - decreased appetite up to loss of appetite, anxiety, restlessness, headache, sedation, tremor, vertigo, decrease in blood pressure, rhinorrhoea, yawning, abdominal pain, diarrhoea, dry mouth, flatulence, vomiting, nausea, pruritis, skin reactions, hyperhidrosis, muscle spasms, muscle twitching, myalgia, drug withdrawal syndrome, feeling hot and cold, chills, asthenia. Is cost within PbR tariff? Included Cost for 28 days (prices from MIMS May 2009) 56 x 10mg/5mg: x 20mg/10mg: Comparative costs of Drug Dose Cost for 28 days

4 other medicines (Drug Tariff, May 2009) Potential number of patients & usage in Suffolk PCT PR oxycodone 10mg BD - 20mg BD PR morphine 30mg BD depending on preparation used Fentanyl patch 12mcg/hr Bisacodyl 10mg/day 1.83 Senna 15-30mg ON Ispaghula husk 1 sachet (3.5g) in water, 1-3 times daily depending on preparation used Lactulose 15ml BD 4.87 Macrogol 1-3 sachet/day Large scale surveys done in Europe and Australia have shown that approximately 5-20% of the adult population has severe, persistent pain, which in many people is not related to cancer. The pain is not well controlled and seriously affects the quality of social and working lives. Applying these figures to the English adult population, suggests that persistent, severe, non-cancer pain affects up to 2-8 million people. Applying the above figures to the adult population of NHS Suffolk there could be approximately 23,250 92,995 people with persistent, severe, non-cancer pain. Up to 5% of patients with chronic non-malignant pain may take a strong opioid. A systematic review on prevalence of opioid adverse events in chronic non-malignant pain showed that 22% of patients withdrew because of adverse effects. Constipation occurred in 15% of patients. Applying the above estimates to Suffolk indicates there could be up to people who could be eligible for use of PR oxycodone / PR naloxone. In palliative care, if patients find morphine too constipating, one option is to switch the patient to an equivalent dose of fentanyl which is administered via a transdermal patch. A small dose of prophylactic laxative would still be prescribed. PR oxycodone / PR naloxone may displace use of fentanyl patches. Assumption Use of PR morphine + laxative in 5% of patients with chronic non-malignant pain Use of PR oxycodone / PR naloxone in 15% of above population due to constipation Use of fentanyl patches in 15% of the above population due to constipation Cost 160,261-1,445, , , , ,817 Points for consideration In line with the licensed indication, the combination product is recommended for the treatment of severe non-malignant pain. Safety and efficacy of the product are not established in cancer patients and/or patients with metastases. The analgesic efficacy of the PR oxycodone/pr naloxone combination is equivalent to PR oxycodone formulations. Use of PR oxycodone/pr naloxone leads to a clinically relevant improvement in bowel function compared to PR oxycodone monotherapy, although laxatives are still required on a regular basis by about 10% of patients in long

5 Decisions from other bodies Comments sought from term studies. Use of PR oxycodone/pr naloxone leads to a clinically relevant improvement in bowel function compared to PR oxycodone monotherapy, although laxatives are still required on a regular basis by about 10% of patients in long term studies. The trials showed that the addition of PR naloxone does not affect the analgesic efficacy of PR oxycodone. The incidence of adverse effects is comparable between the different treatment groups. PR oxycodone/pr naloxone has not yet been compared to other opioids or opioid + concomitant laxatives. To date there is no clinical experience to refer to for switching from other analgesics to the PR oxycodone/pr naloxone fixed dose combination. Cambridgeshire JPG not assessed yet Norfolk TAG not assessed yet SMC not accepted, clinical benefit in patients receiving regular laxative therapy is uncertain and the economic analysis presented was not sufficiently robust. (see above) AWMSG not assessed yet Decision review date July 2011 References 1. Smith K. Prolonged release (PR) oxycodone & naloxone (Targinact TM ) fixed combination oral tablets for severe chronic pain. London New Drugs Group APC/DTC Briefing Document, March Summary of Product Characteristics Targinact 20mg/10mg prolonged release tablets & Targinact 10mg/5mg prolonged release tablets. Napp Pharmaceuticals Ltd. Last revised 29 December Oxycodone/naloxone 10mg/5mg and 20mg/10mg prolonged releases tablets (Targinact). Scottish Medicines Consortium No. 541/09, March Based on Leyendecker P, Hopp M et al. Bowel function index a new validated questionnaire for assessing opioid induced constipation. Poster presented at IASP Congress on Pain, Glasgow, 2008, PH Vondrackova D, Leyendecker P et al. Analgesic efficacy and safety of oxycodone in combination with naloxone as prolonged release tablets in patients with moderate to severe chronic pain. The Journal of Pain 2008; 9 (12): Simpson K, Leyendecker P et al. Fixed-ratio combination oxycodone/naloxone compared with oxycodone alone for the relief of opioid-induced constipation in moderate-to-severe noncancer pain. Current Medical Research & Opinion 2008; 24 (12): Data on file. High-dose prolonged release oxycodone and naloxone in a fixed combination improves bowel function compared with prolonged release oxycodone in patients with moderate to severe non-malignant chronic pain a randomised controlled trial. [OXN3006] Napp Pharmaceuticals 8. Recommendations for the appropriate use of opioids for persistent non-cancer pain. A consensus statement prepared on behalf of the Pain Society, the Royal College of Anaesthetists, the Royal College of General Practitioners and the Royal College of Psychiatrists. March Moore RA & McQuay HJ. Prevalence of opioid adverse events in chronic non-malignant pain: systematic review of randomised trials of oral opioids. Arthritis Research & Therapy 2005; 7: R Breivik H, Collett B et al. Survey of chronic pain in Europe: prevalence, impact on daily life and treatment. European Journal of Pain 2006; 10: Twycross R & Wilcock A. (Ed, 2007) Palliative Care Formulary 3rd Edition. Palliativedrugs.com Ltd

6 Appendix 1 Summary of clinical trials Ref No 5 Randomised, double blind, placebo and active controlled, double dummy, parallel group, phase III study + 12 month extension phase Trial Design Trial Population Treatment Primary Outcomes 6 Randomised, double-blind, double dummy, parallel-group, multicentre, 12 week, phase III study + 52 week extension phase 7 Randomised, double blind, double dummy, parallel group, multicentre trial + 52 week extension phase Adults over 18 yrs old with a history of severe chronic non-malignant lower back pain currently managed by an opioid analgesic Adults over 18 years old taking continuous opioid therapy (oxycodone equivalent of 20mg/day and 50mg/day) for moderate to severe non-cancer pain with constipation caused or aggravated by an opioid As above, except with oxycodone equivalent of 60mg/day and 80mg/day PR oxycodone/pr naloxone (10/5mg or 20/10mg); N=154 PR oxycodone (10mg or 20mg); N=151 Placebo; N=158 All patients were allowed to use immediate release oxycodone every 4-6 hours as required as rescue medication at a quarter of the dose of their total daily opioid intake PR oxycodone; N=160 PR oxycodone/pr naloxone; N=162 PR oxycodone; N=135 PR oxycodone/pr naloxone; N=130 Demonstrate the analgesic superiority of PR oxycodone and PR naloxone over placebo measured as the time from the initial dose of study medication to recurrent pain events (defined as inadequate analgesia) Mean time to first pain event Placebo: 19.3 days PR oxycodone: 33.7 days PR oxycodone/naloxone: 32.2 days P< vs. placebo Whether PR oxycodone/pr naloxone lead to improvements in constipation, as measured by the Bowel Function Index (BFI)* score vs. patients taking PR oxycodone alone after 4 weeks of treatment Change in BFI score after 4 weeks PR oxycodone: 61.0 to 51.6 (9.4 point decrease) PR oxycodone/pr naloxone: 61.8 to 34.9 (26.9 point decrease clinically relevant change) As above Change in BFI score after 4 weeks PR oxycodone: 10.4 point decrease PR oxycodone/pr naloxone: 26.4 point decrease clinically relevant change

7 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

8 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 Magnitude of effect inferred from trials reviewed Low Medium High Are trial end-points surrogate markers or clinical outcomes? Clinical usefulness of trial end-points 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 High Medium Low Comparison Of Effectiveness With Other Medicines In Use For The Poor Medium Good Same Condition Severity of Condition to be Treated Trivial Medium 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) Prescriber s Rating Definitions 1. Bravo! -The drug is a major therapeutic advance in an area where previously no treatment was available. 2. A real advance - The product is an important therapeutic innovation but has certain limitations. 3. Offers an advantage - The product has some value but does not fundamentally change present therapeutic practice. 4. Possibly Helpful - The product has minimal additional value, and should not change prescribing habits except in rare circumstances. 5. Judgement reserved - The Committee postpones its judgement until better data and a more thorough evaluation of the drug are available. 6. 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. 7. Not acceptable - Product without evident benefit over others but with potential or real disadvantages. (With acknowledgement to Prescrire)

9 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: Suffolk Drug & Therapeutics Committee Responsibility for prescribing, Hospital Trust or GP Attached as Appendix 1 & Appendix 2