Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and futher notice)

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1 Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and futher notice) This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Rasagiline (Azilect, Teva) Document status Reviewed at July 2009 Suffolk D&TC meeting Date of last revision 3 July 2009 Traffic light decision Jan 2006: GREEN = Hospital initiated, GP prescribed Prescribers rating Jan 2006: 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 Mechanism of action Medicine class Indication Dosage Treatment alternatives Place in therapy Potent, irreversible monoamine-oxidase-b inhibitor which may cause an increase in extracellular levels of dopamine in the striatum. The elevated dopamine level and subsequent increased dopaminergic activity are likely to mediate rasagiline's beneficial effects seen in models of dopaminergic motor dysfunction. BNF monoamine-oxidase-b inhibitor Rasagiline is the second drug in the class. Selegiline first line - used in conjunction with levodopa to reduce 'end-of-dose' deterioration in advanced Parkinson's disease. Early treatment with selegiline alone can delay the need for levodopa therapy. When combined with levodopa, selegiline should be avoided or used with great caution in postural hypotension. Treatment of idiopathic Parkinson's disease (PD) as monotherapy (without levodopa) or as adjunct therapy (with levodopa) in patients with end of dose fluctuations 1 mg once daily with or without levodopa Selegiline (10mg OM or 5mg BD) When the Suffolk DTC reviewed rasagiline in January 2006, the committee recommended that use should be restricted to patients selected for selegiline, who cannot tolerate selegiline because of side effects. The NICE clinical guideline on PD produced in June 2006 does not differentiate between rasagiline and selegiline. It states that MAO- B inhibitors may be used as a symptomatic treatment for people with early PD and MAO-B inhibitors may be used to reduce motor fluctuations in people with later PD. The guideline will be reviewed in June Further detail is given in the full guideline In early PD, the trial evidence supports the ability of MAO-B inhibitors in PD to improve motor symptoms, improve activities of daily living and delay the need for levodopa. The evidence on them delaying motor complications is unclear. This is at the expense of more dopaminergic adverse events and, as a result, more withdrawals from treatment. There was no conclusive evidence of any increase in mortality on selegiline. It is not possible from the evidence available to decide whether the lack of amphetamine metabolites

2 with rasagiline confers any clinical benefit compared with selegiline. Future alternatives Evidence for use In later PD the size and quality of the adjuvant selegiline trials was poor, so it is impossible to reach firm conclusions about its efficacy and safety in later PD. A more recent study with the buccal formulation of selegiline and two large oral rasagiline trials provide more convincing evidence for the efficacy and safety of MAO-B inhibitors in later PD. However, all studies were of short duration, so no comments on the long-term benefits and drawbacks of these agents can be made. Safinamide This report will look at evidence published since the original decision about rasagiline was taken in Jan A comprehensive review of rasagiline published in the journal Clinical Therapy in September 2007 [Chen JJ et al, vol 29 (9) p ] analysed data from 63 clinical and laboratory studies. Based on the results from the studies, the authors concluded that rasagiline 0.5 to 1 mg/day is effective and well tolerated and completely, selectively, and specifically inhibits MAO-B. Pharmacologically, rasagiline is < /= 10-fold more potent than selegiline and is not metabolized to amphetamine derivatives. Rasagiline is effective both as monotherapy in early PD and as adjunctive treatment in patients with advancing PD and motor fluctuations. As monotherapy, rasagiline provides modest yet clinically meaningful benefit. In patients with more advanced disease who receive treatment with dopaminergic agents, rasagiline and entacapone are associated with reductions of "off" time significantly greater than placebo. Rasagiline is well tolerated in younger (aged < 70 years) and older (aged >/=70 years) patients with early or advanced PD. Pharmacologically, rasagiline has the potential to augment the vasopressor effects of dietderived tyramine (ie, the "cheese reaction"). However, clinical challenge studies of tyramine have found this unlikely to occur even with ingestion of supraphysiologic amounts of tyramine. In experimental models, rasagiline has been found to have neuroprotective properties that may be independent of MAO-B inhibition. Whether rasagiline is associated with clinically significant neuroprotection (i.e. disease modification) in PD is the subject of ongoing clinical trials Information about the ADAGIO study was presented in August 2008 at the 12th Congress of European Federation of Neurological Societies (EFNS). The ADAGIO study is assessing the potential disease modifying effects of rasagiline by comparing the effects of treatment in patients who receive the medicine in early Parkinson s Disease to those who have therapy delayed. The rationale, design and baseline characteristics of the patients in the trial have already been published (Movement Disorders 2008; 23 (15): ). The results are detailed in appendix 1. The authors say that their findings support the potential for rasagiline to have an effect on disease progression, and that "the successful outcome of the study provides further rationale for the early use of rasagiline among PD patients."

3 NNT Cautions / side effects One of the issues highlighted in the NICE clinical guideline was that there was no long term data on use of rasagiline. In December 2008 a study was published where patients had taken rasagiline for an average of 3.6 ± 2.1 years TEMPO study extension. The purpose of this study to compare the long-term clinical outcome of early versus delayed rasagiline treatment in early PD. The results are detailed in appendix 1. The authors concluded that compared to delayed start, early initiation of rasagiline provided long-term clinical benefit, even in the face of treatment with other dopaminergic agents. This might reflect enduring benefits due to neuroprotection or effects on compensatory mechanisms in early PD. Not calculated Contraindicated in patients with severe hepatic insufficiency. Concomitant use of rasagiline and pethidine is contrainidicated. Rasagiline should not be administered along with other MAO inhibitors. Concomitant use of rasagiline and fluoxetine or fluvoxamine should be avoided. Concomitant use of rasagiline and dextromethorphan or sympathomimetics (ephedrine or pseudoephedrine) is not recommended. Concomitant antidepressants should be administered with caution. Monotherapy side effects Very common: headache Common: flu syndrome, malaise, neck pain, allergic reaction, fever, angina pectoris, dyspepsia, anorexia, leucopenia, arthralgia, arthritis, depression, vertigo, hallucinations Adjunct therapy side effects Very common: dyskinesia Common: abdominal pain, accidental injury (primarily falls), neck pain, postural hypotension, constipation, vomiting, anorexia, dry mouth, arthralgia, tenosynovitis, weight loss, dystonia, abnormal dreams, ataxia, rash, hallucinations Cost within PbR tariff? Cost (prices from June 2009 Drug Tariff) Comparative costs of other medicines (prices from June 2009 Drug Tariff) Potential number of patients & usage in Suffolk PCT Included 28 x 1mg tablets = Selegiline 10mg tablets x 30 = 7.91 Selegiline 5mg tablets x 60 = 4.55 PD is a common, chronic, progressive neurological condition, estimated to affect people per 100,000 of the population (between 6 and 11 people per 6000 of the general population in the UK) and has an annual incidence of 4 20 per 100,000. There is a rising prevalence with age and a higher prevalence and incidence of PD in males. Using the estimates above, there could be people with PD in Suffolk PCT. Rasagiline is unlikely to replace selegiline as a first line treatment.

4 Points consideration for Decisions from other bodies The NICE clinical guideline on PD produced in June 2006 does not differentiate between rasagiline and selegiline, the guideline will be reviewed in June A review of data from 63 clinical and laboratory studies concluded that rasagiline 0.5 to 1 mg/day is effective and well tolerated and completely, selectively, and specifically inhibits MAO-B. Ongoing studies have indicated that early use of rasagiline in Parkinson s disease patients provides long term clinical benefit. Cambridgeshire Joint Prescribing Group Sept 2005: Double Red, not funded for prescribing in primary or secondary care due to lack of supporting evidence and no long-term outcomes for irreversible MAO-B inhibition Comments from sought Norfolk Therapeutic Advisory Group March 2006: Green (GP prescribable at the request of consultant/specialist); for third line use only as adjunctive therapy for motor fluctuations where entacapone not tolerated Scottish Medicines Consortium Nov 2006: not recommended for the treatment of idiopathic PD as adjunct therapy (with levodopa) in patients with end of dose fluctuations. Rasagiline reduces offtime in patients with PD and end of dose fluctuations on levodopa, similar to reductions shown with the less effective of two currently marketed catechol-o-methyl transferase inhibitors. The economic case has not been demonstrated. Rasagiline is not recommended for the treatment of idiopathic PD as monotherapy (without levodopa). Rasagiline provides modest symptomatic improvement for patients with early PD. The economic case has not been demonstrated. Midlands Therapeutic Review Advisory Committee Jan 2006: PD should be diagnosed and managed in secondary care. Rasagiline is suitable for prescribing in primary care with the guidance of an Effective Shared Care Agreement (ESCA), upon the advice of a specialist, which could include a specialist Nurse in a Neurology clinic or a GP with a special interest in neurology. Decision review date July 2011 References 1. BNF 57 th Ed, March Summary of Product Characteristics - Azilect 1 mg Tablets. Teva Pharmaceuticals Ltd, last revised 02/04/07 3. NICE Clinical Guideline. Parkinson s Disease: diagnosis and management in primary and secondary care. June Parkinson s Disease National clinical guideline for diagnosis and management in primary and secondary care. The National Collaborating Centre for Chronic Conditions, Pocock N. Conference report: Earlier use of rasagiline associated with more improvement in Parkinson s disease? National electronic Library for Medicines 27/08/2008

5 6. Hauser RA, Lew MF et al. Long-term outcome of early versus delayed rasagiline treatment in early Parkinson s disease. Movement Disorders 2008; 24 (4): Parkinson Study Group. A Controlled, Randomized, Delayed-Start Study of Rasagiline in Early Parkinson Disease. Archives of Neurology 2004; 61:

6 Appendix 1 Summary of clinical trials Ref No 5 Prospective, randomised, controlled, double blind, multi-centre Phase III study (ADAGIO) Trial Design Trial Population Treatment Primary Outcomes 6 Open label extension to the TEMPO study 1,176 patients with very early PD 7 TEMPO study: Multicentre, 52-week, parallel-group, randomized, doubleblind, placebo-controlled clinical trial, in 404 early Parkinson s Disease patients with rasagiline 1mg or 2mg/day for 1 year or placebo for 6 months followed by rasagiline 2mg/day for 6 months. Rasagiline 1 or 2 mg/day for 72 weeks (early start) or placebo for 36 weeks followed by rasagiline 1 or 2 mg/day for 36 weeks (delayed start). N=306 Rasagiline + other Parkinson s Disease medications as needed Change in total UPDRS (Unified Parkinson's Disease Rating Scale) including slope superiority of rasagiline over placebo in the placebocontrolled phase, change from baseline to week 72, and non-inferiority of early-start vs. delayed-start slopes during weeks of the active phase. The 1mg dose met all three primary endpoints: A) superiority of slopes in weeks (-0.05; p=0.013, 95%CI to ) B) change from baseline to week 72 (-1.7 units; p=0.025, 95%CI to ) C) non-inferiority of slopes in weeks (0.0; 90%CI to 0.04). 177 subjects received rasagiline for 5.0 years. Over the entire 6.5-year follow-up period, the adjusted mean difference in change from baseline in total UPDRS scores was 2.5 units (SE 1.1; P = 0.021) or 16% (SE 5.7; P = 0.006) in favour of the early-start versus delayed-start rasagiline group. Significantly less worsening (percent change) in total UPDRS scores was observed in the early-start group at the time points 0.5, 1.5, 2.0, 3.0, 4.5, 5.0, and 5.5 years (P < 0.05).

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 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 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.

9 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) To Decide Where A Medication Is To Be Used In Suffolk Skills of the prescriber Criterion Red Amber Green D Green Experience Of The Condition Specific Specific Specific General Diagnosis Specific Specific Specific General Monitoring Progress Of Treatment Difficult Specific General General 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