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

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1 Suffolk PCT Drug & Therapeutics Committee New Medicine Report (Adopted by the CCG until review and further notice) This drug has been reviewed because it is a product that may be prescribed in primary care. Medicine Indication Paliperidone palmitate long acting injection (Xeplion, Janssen-Cilag) Maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone. In selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, paliperidone long acting injection (LAI) may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed. [1] Document status Reviewed at July 2011 Suffolk D&TC meeting Date of last revision 7 July 2011 Traffic light decision Red- Hospital only Prescribers rating TBC Mechanism of action Medicine class Dosage Paliperidone is the major active metabolite of risperidone. [3] Paliperidone is a selective blocking agent of monoamine effects, whose pharmacological properties are different from that of traditional neuroleptics. Paliperidone binds strongly to serotonergic 5-HT2- and dopaminergic D2-receptors. Paliperidone also blocks alpha 1-adrenergic receptors and slightly less, H1-histaminergic and alpha 2- adrenergic receptors. The pharmacological activity of the (+)- and (-)-paliperidone enantiomers are qualitatively and quantitatively similar. Paliperidone is not bound to cholinergic receptors. Even though paliperidone is a strong D2-antagonist, which is believed to relieve the positive symptoms of schizophrenia, it causes less catalepsy and decreases motor functions less than traditional neuroleptics. Dominating central serotonin antagonism may reduce the tendency of paliperidone to cause extrapyramidal side effects. [1] BNF Antipsychotic depot injections Recommended initiation of paliperidone LAI is with a dose of 150 mg on treatment day 1 and 100 mg one week later (day 8), both administered in the deltoid muscle in order to attain therapeutic concentrations rapidly. The recommended monthly maintenance dose is 75 mg; some patients may benefit from lower or higher doses within the recommended range of 25 to 150 mg based on individual patient tolerability and/or efficacy. Patients who are overweight or obese may require doses in the upper

2 range. Following the second dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. [1] Treatment alternatives Place in therapy Flupenthixol decanoate, fluphenazine decanoate, haloperidol decanoate, olanzapine embonate, pipotiazine palmitate, zuclopenthixol decanoate. [2] Not clear effectiveness and safety compared to first and second generation oral and long acting injectable antipsychotics are lacking. Future alternatives Evidence for use Paliperidone LAI may have a number of practical advantages over some currently available depots/lais. Compared to risperidone LAI, paliperidone LAI does not need refrigerating or initial oral supplementation and is given monthly, rather than fortnightly. Unlike risperidone and olanzapine LAIs, paliperidone LAI does not need reconstituting. Approximately 2% of patients treated with olanzapine LAI during pre-marketing clinical studies presented with 'post-injection syndrome' which is consistent with the signs and symptoms of olanzapine overdose. Therefore, appropriately qualified staff must observe patients for at least three hours after each injection. Paliperidone LAI may be given into the gluteal or deltoid muscle, whereas olanzapine and first-generation antipsychotic depots can only be given into the gluteal muscle (or lateral thigh in the case of flupentixol or zuclopenthixol). These practical advantages would need to be balanced against any increase in cost from using the newer agent. [3] Depots/LAIs can play a useful role in reducing the risk of relapse by reducing covert non-adherence. Although paliperidone LAI has been shown to reduce the risk of relapse compared with, it is not known if paliperidone LAI offers any advantage over existing antipsychotics in this regard. [3] None known The efficacy of paliperidone LAI in the acute treatment of schizophrenia was established in four short-term (one 9- week and three 13-week) double-blind, randomised, -controlled, fixed-dose studies of acutely relapsed adult patients who met DSM-IV criteria for schizophrenia. The fixed doses of paliperidone LAI in these studies were given on days 1, 8, and 36 in the 9-week study, and additionally on day 64 of the 13-week studies. No additional oral antipsychotic supplementation was needed during the acute treatment of schizophrenia with paliperidone LAI. The primary efficacy endpoint was defined as a decrease in Positive and Negative Syndrome Scale (PANSS) total scores. The PANSS is a validated multi-item inventory composed of five factors to evaluate positive symptoms, negative symptoms, disorganised

3 thoughts, uncontrolled hostility/excitement and anxiety/depression. Functioning was evaluated as a secondary endpoint using the Personal and Social Performance (PSP) scale. The PSP is a validated clinician rated scale that measures personal and social functioning in four domains: socially useful activities (work and study), personal and social relationships, self-care and disturbing and aggressive behaviours. Approximately 50% of the patients prematurely discontinued the studies either due to lack of efficacy, patient choice or adverse events. [1, 4-7] All the trials are summarised in appendix 1. The efficacy of paliperidone LAI in maintaining symptomatic control and delaying relapse in schizophrenia was established in a longer-term, randomised, doubleblind, -controlled, flexible-dose study involving 849 patients with schizophrenia. [8] A total of 410 stabilised patients were randomised to either paliperidone LAI or to until they experienced a relapse of schizophrenia symptoms in the variable length double-blind phase of the study. Most patients assigned to paliperidone LAI received the 100mg dose (~70%). The trial was stopped early for efficacy reasons as a significantly longer time to relapse (p < ) was seen in patients treated with paliperidone LAI compared to. The interim analysis results show that during the double-blind phase of the study, fewer patients treated with paliperidone LAI experienced a relapse (10% [n=15/156]) compared with those in the group (34% [n=53/156]). The final analysis results were consistent with the interim results. NNT Cautions / side effects Not calculated The most frequently reported adverse drug reactions (ADRs) reported in clinical trials were insomnia, headache, weight increased, injection site reactions, agitation, somnolence, akathisia, nausea, constipation, dizziness, tremor, vomiting, upper respiratory tract infection, diarrhoea, and tachycardia. Of these, akathisia appeared to be dose-related. [1] The SPC highlights a few specific side effects [1] Injection site reactions The most commonly reported injection site related adverse reaction was pain. The majority of these reactions were reported to be of mild to moderate severity. Subject evaluations of injection site pain based on a visual analogue scale tended to lessen in frequency and intensity over time in all Phase 2 and 3 studies. Injections into the deltoid were perceived as slightly more painful than corresponding gluteal injections. Other injection site reactions were mostly mild in intensity and included induration (common), pruritus (uncommon) and nodules (rare).

4 Weight gain In the 13-week study involving the 150 mg initiation dosing, the proportion of subjects with an abnormal weight increase 7% showed a dose-related trend, with a 5% incidence rate in the group compared with rates of 6%, 8% and 13% in the paliperidone LAI 25 mg, 100 mg, and 150 mg groups, respectively. During the 33-week open-label transition/maintenance period of the long-term recurrence prevention trial, 12% of paliperidone LAI -treated subjects met this criterion (weight gain of 7% from double-blind phase to endpoint); the mean (SD) weight change from open-label baseline was +0.7 (4.79) kg. Laboratory tests - Serum prolactin In clinical trials, median increases in serum prolactin were observed in subjects of both genders who received paliperidone LAI. Adverse reactions that may suggest increase in prolactin levels (e.g. amenorrhoea, galactorrhoea and gynaecomastia) were reported overall in <1% of subjects. Class effects QT prolongation, ventricular arrhythmias (ventricular fibrillation, ventricular tachycardia), sudden unexplained death, cardiac arrest, and Torsade de pointes may occur with antipsychotics. Cases of venous thromboembolism, including cases of pulmonary embolism and cases of deep vein thrombosis, have been reported with antipsychotic medicinal products (frequency unknown). Cost within PbR tariff? Yes Cost 1 x 50mg, x 75mg, x 100mg, x 150mg, Comparative costs of other Drug Example dose* Cost medicines (prices from MIMS, Flupenthixol 50mg by deep IM 1.53 June 2011) (Depixol Conc) injection every 4 wks Fluphenazine 25mg by deep IM 2.26 (Modecate) injection every 4 wks Haloperidol 100mg by deep IM 5.06 (Haldol Decanoate) injection every 4 wks Olanzapine 300mg by deep IM (ZypAdhera) injection every 4 wks Pipotiazine 50mg by deep IM (Piportil Depot) injection every 4 wks Risperidone 37.5mg by deep IM (Risperdal Consta) injection every 2 wks Zuclopenthixol (Clopixol) 200mg by deep IM injection every 4 wks 1.99 * The example doses are typically the maintenance doses but are not necessarily clinically equivalent.

5 Potential number of patients & usage in Suffolk PCT Schizophrenia is relatively common and the prevalence is similar around the world. The lifetime risk for schizophrenia is estimated to be one person in 100, and appears to be the same for men and women up to age 60 years. [9] Data supplied by the Prescription Pricing Division in May 2010 for antipsychotic LAIs, indicates that about 150,000 items were prescribed in primary care in England for the year to March Flupentixol decanoate, fluphenazine decanoate and zuclopenthixol decanoate were the most commonly prescribed depot injections accounting for approximately 70% of the total number of LAIs prescribed. Risperidone LAI is considerably more expensive than firstgeneration antipsychotic depot injections: although accounting for about a fifth of the items prescribed, it was associated with three quarters of the total cost ( 7 million). No data is currently available on olanzapine LAI, or on the prescribing of antipsychotic LAIs in secondary care. Points for consideration Although there is evidence from -controlled trials that paliperidone LAI is effective in reducing symptoms and preventing relapse, there is currently no evidence from clinical trials for any clinical or costeffectiveness advantage of paliperidone LAI over any other antipsychotic LAI. Long-term safety and efficacy remains to be established in comparison to other LAIs, including well-established first-generation agents such as flupentixol. Non-inferiority of paliperidone LAI to risperidone LAI, at the proposed initial dose regimen, has only been established in one short-term trial (13 weeks). Paliperidone is the major active metabolite of risperidone, so the adverse-event profiles are similar. Paliperidone LAI offers some practical advantage over some alternative LAIs, as it does not require reconstitution, can be stored at room temperature and offers a choice of intramuscular injection sites (gluteal or deltoid muscles) for maintenance dosing. Any decision to prescribe paliperidone LAI should take into account evidence for effectiveness, its side-effect profile, patient (or carer's) preferences and cost. Is the drug on the WSH or IHT formularies? Decisions from other bodies Comments sought from West Suffolk Hospital - No Ipswich Hospital - No Cambridgeshire JPG not considered Norfolk TAG not considered SMC not considered AWMSG not considered Suffolk Mental Health Partnership Trust Dr s Vivien Peeler, Bob Peckitt, John Bellhouse, Albert Michael, Hadrian Ball, Stephen Dye & Jenny Axford Decision review date TBC

6 References 1. Summary of Product Characteristics Xeplion 50mg, 75mg, 10mg and 150mg prolonged release suspension for injection. Janssen-Cilag Ltd. Last revised 04/03/11 2. Martin J, editor. British National Formulary No 61. London: British Medical Association and The Royal Pharmaceutical Society of Great Britain; March 2011, p On the Horizon Future Medicines Paliperidone long-acting injection for schizophrenia. NPC/UKMI, July Pandina et al. A Randomised, Placebo Controlled Study to Assess the Efficacy and Safety of 3 Doses of paliperidone Palmitate in Adults with Acutely Exacerbated Schizophrenia. J Clin Psychopharmacol 2010; 30: Nasrallah HA et al. A controlled evidence based trial of paliperidone palmitate, a longacting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology 2010, 35 (10): Gopal S et al. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, -controlled, doseresponse study. Int Clin Psychopharmacology, 2010, 25 (5): Kramer et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, -controlled efficacy and safety study. Int J Neuropsychopharmacology 2009; 27: p Hough D et al. Paliperidone palmitate maintenance treatment in delaying the time to relapse in patients with schizophrenia: A randomized, double-blind -controlled study. Schizophrenia Research; 2010, 116 (23): Lehman A et al. Practice guideline for the treatment of patients with schizophrenia, second edition. Am J Psychiatry. 2004;161(2 Suppl):1-56

7 Appendix 1 Summary of clinical trials Ref Trial Design Trial Population Treatment Primary Endpoint 4 13-week, multicentre, doubleblind, randomised, -controlled, fixed-dose, phase 3 study 652 adult patients with an acute exacerbation of established schizophrenia (defined by DSM-IV criteria) and a baseline PANSS score of As above 518 adult patients inclusion criteria as above 6 As above 388 adult patients inclusion criteria as above 7 9-week, doubleblind, randomised, -controlled, fixed-dose, phase 2 study 8 9-week open label and 24-week, double-blind, 247 adult patients inclusion criteria as above 410 adult patients with established DSM-IV defined schizophrenia Paliperidone 25mg, n=160 Paliperidone 100mg, n=165 Paliperidone 150mg, n=163 Placebo, n=164 Patients received 150mg or injection on day 1, then the assigned fixed dose on day 8, then once monthly until study end. Paliperidone 25mg, n=129 Paliperidone 50mg, n=128 Paliperidone 100mg, n=131 Placebo, n=125 Administration schedule as above. Paliperidone 50mg, n=94 Paliperidone 100mg, n=97 Paliperidone 150mg, n=30 Placebo, n=136 Administration schedule as above. Paliperidone 50mg, n=79 Paliperidone 100mg, n=84 Placebo, n=84 Administration schedule as above. Placebo, n=204 Paliperidone, n=206 Patients received 50mg or Least squares mean change in Positive and Negative Syndrome Scale (PANSS) total scores from baseline to study end. Placebo: -2.9 Paliperidone 25mg: -8, p<0.05 vs. Paliperidone 100mg: -11.6, p<0.05 vs. Paliperidone 150mg: -12.7, p<0.05 vs. Placebo: -7 Paliperidone 25mg: -13.6, p<0.05 vs. Paliperidone 50mg: -13.2, p<0.05 vs. Paliperidone 100mg: -16.1, p<0.05 vs. Placebo: -4.2 Paliperidone 50mg: -7.9, p<0.05 vs. Paliperidone 100mg: -11, p<0.05 vs. No statistical comparison was performed on the 150mg dose as it was administered to fewer patients than planned. Placebo: +6.2 Paliperidone 50mg: -5.2, p=0.001 vs. Paliperidone 100mg: -7.8, p<0.001 vs. Primary endpoint - Time to first relapse The study was stopped early based on significant (p<0.0001) interim efficacy results

8 randomised, -controlled, flexible-dose study and a PANSS score <120 started the double blind phase injection on days 1 & 8, then once monthly 25mg, 50mg or 100mg, flexibly dosed. in favour of paliperidone. 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

9 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 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) Is the drug to be used in Suffolk? 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.

10 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) 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 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