New Medicines Committee Briefing November 2011

New Medicines Committee Briefing November 2011 Paliperidone long-acting injection (Xeplion ) for schizophrenia Paliperidone palmitate long-acting injection (Xeplion ) is to be reviewed for use within: Summary: Primary Care Secondary Care Xeplion (paliperidone palmitate) is long-acting atypical antipsychotic injection 1. Xeplion is licensed for maintenance treatment of schizophrenia in adult patients stabilised during with paliperidone or risperidone 1. NICE recommends the use of depot/long-acting injectable antipsychotic medication in patients who would prefer such treatment after an acute episode and where avoiding covert nonadherence (either intentional or unintentional) to antipsychotic medication is a clinical priority within the treatment plan 2. SMC did not accept paliperidone long-acting injection (Xeplion ) for the licensed indication 3. Paliperidone long-acting injection has been shown to be significantly more efficacious compared to placebo in the acute treatment of schizophrenia 4,5,6,7 and for maintenance treatment 8,9. Paliperidone long-acting injection has been shown to be non-inferior to risperidone long-acting injection 10. Xeplion is a black triangle drug ( ) and is monitored intensively by the CHM and MHRA 1. 1

Formulary application: Consultant submitting application: Clinical Director supporting application: Dr Richard Hodgson (Consultant Psychiatrist) Dr Christine Leaman Dr Hodgson has requested that Xeplion be considered for inclusion in the North Staffordshire Joint Formulary for the treatment of schizophrenia. In the formulary application Dr Hodgson states: Benefits of Xeplion - reduction in mortality, reduction in morbidity, improved safety, improved tolerability, convenient administration and savings in non-drug costs; Advantages over existing formulary agents- compared to risperidone depot injection (Risperidal Consta ) Xeplion requires less frequent administration (Xeplion is a monthly injection; Risperidal Consta is a 2-weekly injection), no refrigeration (Xeplion is stored at room temperature; Risperidal Consta requires refrigeration) and is cheaper compared to Risperidal Consta at higher doses. Dr Hodgson suggests that Xeplion would be used as a first-line atypical antipsychotic depot injection for patients non-compliant with oral medication; patients currently prescribed risperidone long-acting injection may also be changed to Xeplion. Background: Schizophrenia is a major psychiatric disorder, or cluster of disorders, characterised by psychotic symptoms that alter a person s perception, thoughts and affect behaviour. Each person with the disorder will have a unique combination of symptoms and experiences. Symptoms of the condition are divided in 2 categories: positive and negative. Positive symptoms cause an excess of cognitive function and include delusions and hallucinations. Negative symptoms supress normal function and include apathy and poor social activity 1,11. Antipsychotics are used in the management of schizophrenia and can be classed as either typical or atypical. Typical antipsychotics work by blocking dopaminergic receptors. Atypical antipsychotics also block dopamine receptors but also act on a range of other receptors, particularly serotonergic receptors. Atypical antipsychotics may be better tolerated and associated with less extrapyramidal symptoms than typical antipsychotic drugs 12,13. The key objectives in the management of schizophrenia are to treat symptoms during acute episodes of illness and to prevent future relapses 13. Long-acting depot injections are usually used for maintenance therapy especially when compliance with oral treatment is unreliable. For patients with schizophrenia, non-adherence to medication is a major risk factor for relapse and re-hospitalisation 12,13. Paliperidone palmitate is a long-acting atypical antipsychotic injection; paliperidone is the major active metabolite of risperisdone 1. 2

Xeplion is the palmitate ester of paliperidone. The ester is nearly insoluble that is administered as an aqueous suspension. After IM injection Xeplion slowly dissolves at the injection site and is enzymatically hydrolysed to paliperidone 1. Current formulary status: The North Staffordshire Joint Formulary currently lists the following agents: 4.2 DRUGS USED IN PSYCHOSES AND RELATED DISORDERS 4.2.2 Antipsychotic depot injections Flupentixol decanoate 2 Restriction: Initiation under direction of a psychiatrist Fluphenazine decanoate 2 Restriction: Initiation under direction of a psychiatrist Haloperidol decanoate 2 Restriction: Initiation under direction of a psychiatrist Risperidone 2 Restriction: Initiation under direction of a psychiatrist MTRAC Zuclopenthixol decanoate 2 Restriction: Initiation under direction of a psychiatrist Zuclopenthixol acetate Restriction: Initiation under direction of a psychiatrist Risperidone IM MTRAC recommendation VS02/19 (date 11/02) For the treatment of schizophrenia - RESTRICTED USE Therapeutic class and mode of action 1 : Paliperidone palmitate is a long-acting atypical antipsychotic injection ; paliperidone is the major active metabolite of risperidone. Licensed indication 1 : Maintenance treatment of schizophrenia in adult patients stabilised during with paliperidone or risperidone. In selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, Xeplion may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed. Dosage and administration 1 : Administration: Deep intra-muscular injection. Dose: Recommended initiation dose- 150 mg on day 1 and 100 mg on day 8 (both administered in the deltoid muscle to attain therapeutic concentrations rapidly) Recommended monthly maintenance dose- 75 mg every month (administered in either the deltoid or gluteal muscle); 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. Adjustment of the maintenance dose may be made monthly. 3

Switching from oral paliperidone or oral risperidone- previous oral paliperidone or oral risperidone can be discontinued at the time of initiation of treatment with Xeplion. Switching from risperidone long- acting injection- initiate Xeplion therapy in place of the next scheduled injection of risperidone- the one-week initiation dosing regimen is not required. Recommended dose scheme between risperidone long-acting injection and Xeplion : Previous risperidone long acting injection dose Xeplion dose 25 mg every 2 weeks 50 mg monthly 37.5 mg every 2 weeks 75 mg monthly 50 mg every 2 weeks 100 mg monthly Elderly: Efficacy and safety in elderly >65 years have not been established. Renal impairment: Mild renal impairment- recommended initiation dose is 100 mg on day 1 and 75 mg on day 8; recommended monthly maintenance dose is 50 mg with a range of 25 to 100 mg based on patient tolerability and/or efficacy. Moderate/ severe renal impairment- not recommended. Hepatic impairment: Mild or moderate hepatic impairment- no dose adjustment required. Severe hepatic impairment- caution recommended as not been studied in the patient group. Presentation 1 : Pharmaceutical form: Strengths: Prolonged release suspension for injection. 50mg, 75mg, 100mg and 150mg prefilled syringes. Guidance: NICE Guidance 2 : NICE guidance published Relevant guidance Yes NICE Clinical Guideline 82 Schizophrenia: Core interventions in the treatment and management of schizophrenia in primary and secondary care (March 2009) NICE guidance recommends to consider offering depot/long-acting injectable antipsychotic medication to people with schizophrenia: who would prefer such treatment after an acute episode where avoiding covert non-adherence (either intentional or unintentional) to antipsychotic medication is a clinical priority within the treatment plan. 4

NICE also advises that when initiating depot/long-acting injectable antipsychotic medication: take into account the service user s preferences and attitudes towards the mode of administration (regular intramuscular injections) and organisational procedures (for example, home visits and location of clinics) take into account the same criteria recommended for the use of oral antipsychotic medication, particularly in relation to the risks and benefits of the drug regimen initially use a small test dose as set out in the BNF or SPC. Scottish Medicines Consortium (SMC) 3 : SMC recommended use within NHS Scotland: No SMC did not accept paliperidone palmitate for the maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone. The SMC stated there were weaknesses in the clinical and economic case submitted by the manufacturer. Cochrane Review: No relevant published reviews available Scottish Intercollegiate Guidelines Network (SIGN): SIGN guidelines published No MTRAC MTRAC reviewed No 5

Efficacy: Outcome measures used to evaluate efficacy of treatment of schizophrenia: Total Positive and Negative Symptom Scale (PANSS)- used for measuring symptom severity of patients with schizophrenia; constitutes four scales measuring positive and negative syndromes, their differential, and general severity of illness and is widely used in the study of antipsychotic therapy. Clinical Global Impression-Schizophrenia scale (CGI-S)- assesses positive, negative, depressive and cognitive symptoms in schizophrenia. Personal and Social Performance scale (PSP)- assesses psychosocial functioning level Acute treatment of schizophrenia Summary: Paliperidone LAI has been shown to significantly improve the PANNS score compared to placebo in the acute treatment of schizophrenia 4,5,6,7. The efficacy of Xeplion in the acute treatment of schizophrenia has been established in 4 shortterm 9-week and 13-week trials. In all 4 trials the injection was administered on days 1, 8 and 36 and in the 13-week trials on day 64 and all were multi-centre, randomised, double-blind, placebo-controlled trials in patients with acute schizophrenia. The primary endpoint in all studies was the mean change in PANNS total score from baseline to endpoint. Pandida et al 4 conducted a 13-week study in which patients (n=652) were randomised to receive paliperidone palmitate 25mg, 100mg or 150mg eq. or placebo and reported a significant improvement in PANSS total score from baseline to endpoint in all paliperidone palmitate groups versus placebo (p 0.034). A significant change in PANNS score was reported at day 8 for 25mg and 150mg dose eq and day 22 for 100mg dose eq and was maintained until end-point. Kramer et al 5 and Gopal et al 6 conducted smaller dose-response studies which support the findings of Pandida et al 4. Kramer et al 5 conducted a 9-week study in which patients (n=197) were randomised to receive paliperidone palmitate 50mg or 100mg dose eq or placebo. PANNS total scores showed significant improvement at both doses versus placebo (p 0.001) and the improvement was detected by day 8 and maintained to end-point for both doses (p 0.011). Gopal et al 6 conducted a 13-week study in which patients (n=388) received paliperidone palmitate palmitate 50mg, 100mg or 150mg eq. or placebo and reported significant improvements in PANNS total score vs. placebo for the 100mg dose (p=0.019) but not for the 50 mg dose (p=0.19). No statistical comparison was performed for the 150mg group. Nasrallah et al 7 also conducted a 13-week study (n=514) in which patients were randomised to receive 25mg, 50mg or 100mg eq doses or placebo. All paliperidone palmitate dose groups showed significant improvement vs placebo in PANNS total score (25mg and 50mg p=0.02; 100mg p<0.001). 6

Maintenance therapy in schizophrenia Summary: Patients treated with paliperidone LAI demonstrated a significantly longer time-torelapse compared to placebo 8. The efficacy of paliperidone LAI in maintaining symptomatic control and delaying time-torelapse in patients with schizophrenia was established in a double-blind, placebo-controlled, flexible-dose study (n=848). The study included a 33-week open-label acute treatment and stabilisation phase, a randomised-double blind placebo-controlled phase to observe for relapse 8, and a 52-week open-label extension period 9. Doses of paliperidone LAI used in the study included 25, 50, 75 and 100mg eq administered monthly (he 75mg dose was allowed only in the 52-week open-label extension). Subjects initially received flexible doses (25-100mg dose eq) in the 9-week open label transition period and 24-week maintenance phase. At the maintenance phase end-point 410 stabilised patients then entered a double-blind phase of variable duration where patients were randomised to continue paliperidone palmitate (at the stabilised dose) or placebo; patients remained in this phase until relapse, withdrawal or the end of study. Patients could then be entered into a 52-week, open-label extension phase. A recurrent event was defined as time to the first emergence of one or more of the followinghospitalisation (for symptoms of schizophrenia), pre-specified changes in PANSS score or clinically significant deliberate self-injury or aggressive behaviour. The study was stopped early after a pre-planned interim analysis of 312 patients showed that paliperidone LAI was more effective than placebo as a significantly longer median time to relapse was seen in the patients treated with paliperidone LAI compared to placebo (p<0.0001). Relapse event rates were 10% in the paliperidone LAI group and 34% in the placebo group. A final analysis (of 408 patients) confirmed the interim assessment. In the open-label extension phase of the study 9 improvements from baseline to end-point were observed on PANSS, PSP and CGI-S assessment. Compared to risperidone LAI Summary: Paliperidone LAI has been shown to be non-inferior to risperidone LAI 15. Fleishhacker et al 15 compared Paliperidone LAI with risperidone LAI in a 53-week non-inferiority study (n=749). Patients were randomised to flexibly-dosed paliperidone LAI every 4-weeks (25, 50, 75 or 100mg dose eq) or flexibly dosed risperidone every 2 weeks (25, 37.5 or 50mg). Patients on the risperidone group received supplementation with oral risperidone. The primary outcome was change from baseline to endpoint in PANNS total score. The primary outcome was change from baseline to endpoint in PANSS total score. The mean change was -11.6 (SD 21.2) in the paliperidone group and -14.4 (SD 19.8) in the risperidone group. The difference between the groups (least-squares means) was -2.6 points (95%CI -5.8 to 0.6). As the pre-specified non-inferiority margin was -5, the trial failed to demonstrate that paliperidone was not inferior to long-acting risperidone. However, the authors concluded that non-inferiority was not established because patients had been initiated with suboptimal initial dosing of paliperidone and because of the use of the gluteal initiation site as this sit e o administration is associated with lower initial exposure. 7

Pandida et al 10 consequently conducted a 13-week double-blind, non-inferiority study between paliperidone LAI and risperidone LAI (n=1220). Unlike the trial conducted by Fleischacker et al, patients in the paliperidone group were given a loading dose of paliperidone LAI: 150mg eq followed on day eight by 100mg eq, both administered into a deltoid muscle. Paliperidone and risperidone LAIs were flexibly dosed, depending on efficacy and tolerability: paliperidone 50 to 150mg eq monthly and risperidone 25 to 50mg fortnightly. Patients received oral risperidone supplementation (as is usually practice at initiation) for the first four weeks or matching placebo. Paliperidone LAI was non-inferior to risperidone LAI with regard to the difference in mean PANSS total scores, 0.4 (95%CI -1.6 to 2.4), as the CI does not include the non-inferiority margin of -5. Non-inferiority was also demonstrated in a study in chinese patients 16 in an open-label parallelgroup study. Paliperidone LAI was non-inferior to risperidone LAI with regard to the difference in mean PANSS score -2.3 (95% CI -5.2 to 0.63); pre-determined non-inferiority margin -5.5. Safety and adverse effects 1 : Contraindications: Hypersensitivity to active ingredient, risperidone or any excipients. Adverse effects: Most frequently reported ADRs in clinical trials were insomnia, headache, weight gain, injectionsite reactions, agitation, somnolence, akathesia, nausea, constipation, dizziness, tremor, vomiting, upper respiratory tract infection, diarrhoea and tachycardia 1. For additional information regarding adverse effects refer to the Summary of Product Characteristics 1. Drug Interactions 1 : Caution when prescribing with other drugs known to prolong the QT interval eg class IA and class III antiarrhythmics, some antihistamines, some other antipsychotics and some antimalarials. Refer to the Summary of Product Characteristics for details of interactions 1. 8

Cost analysis Costs of in secondary care: Xeplion pre-filled syringe size Secondary Care (inc. VAT) 50mg 220.70 75mg 293.88 100mg 376.88 150mg 471.11 Expenditure in secondary care for a 6-month period: (January 2011- June 2011): Xeplion pre-filled syringe size Expenditure in Combined Health Care Expenditur e UHNS Quantity used Expenditure Quantity Expenditure used 50mg Nil Nil Nil Nil 75mg 9 3391.96 Nil Nil 100mg 10 4826.94 Nil Nil 150mg 1 587.76 Nil Nil Total 21 8806.66 Nil Nil Estimated cost: Dr Hodgson estimates that 50 new patients per year will be prescribed Xeplion Minimum dose: 25mg every month= 293.88x12= 2,648.45 Maximum dose: 150mg every month= 471.11X12= 5,653.32 The estimated annual cost for 50 patients to be treated is therefore between 132,422 and 282,666 9

Comparison with other therapy: Long acting injections (administered as deep intramuscular injections) Formulary Dose regimen* Annual cost in status # secondary care (inc VAT) Paliperidone palmitate A 25mg to 150mg every month 2648-5653 Risperidone F 25mg to 50mg every 2 weeks 2486-4454 Pipotiazine palmitate NF 50mg to 100mg every 4 weeks 2337-3825 Fluphenazine decanoate F 12.5mg to 100mg every 2 to 5 weeks 70-297 Haloperidol decanoate F 50mg to 300mg every 4 weeks 260-345 Zuclopenthixol decanoate F 200mg to 500mg every 1 to 4 weeks 285-1046 Flupentixol decanoate F 50mg to 300mg every 2 to 4 weeks 219-527 Olanzapine embonate A 150mg to 300mg every 2 weeks or 300mg to 405mg every 4 weeks 3473-6946 # F= formulary; NF=non-formulary; A= formulary application under consideration *Doses are for general comparison and do not imply therapeutic equivalence Compared to risperidone 50mg every 2 weeks (maximum licensed dose) 10

Comparison with equivalent doses of risperidone: Maintenance therapy: Risperidone LAI injection Equivalent paliperidone LAI Cost Dose Frequency Cost in secondary care (inc.vat) Cost per annum per patient =26 doses Dose Frequency Cost in secondary care (inc.vat) Cost per annum per patient =12 doses difference per annum between risperidone and paliperidone 25mg 2-weekly 95.60 2485.60 50mg Monthly 220.70 2648.40 + 162.80 37.5m 2-weekly 133.58 3473.08 75mg Monthly 293.88 3526.56 + 53.24 g 50mg 2-weekly 171.32 4454.32 100mg Monthly 376.88 4522.56 + 68.24 75mg ± 2-weekly 304.90 7927.40 150mg Monthly 471.11 5653.32-2274.08 + 1199.00 ± Unlicensed dose; no injection available therefore cost based on a 50mg and 25mg dose given Compared to risperidone 50mg every 2 weeks (maximum licensed dose) Some patients may require oral risperidone supplementation NB All costs are for secondary care and include VAT New patients (not taking oral paliperidone or risperidone): Risperidone LAI injection Equivalent paliperidone LAI Cost Dose Cost per annum per patient =26 doses Cost for oral risperidone during initiation Cost per annum per patient =26 doses + oral Dose Loading dose Day 1: 150mg Day 8: 100mg Cost per annum per patient =11 doses Cost per annum per patient =loading dose + 11 doses difference per annum between risperidone and paliperidone 25mg 2485.60 0.92 2486.52 50mg 847.99 2427.70 3275.69 + 789.17 37.5mg 3473.08 0.92 3474.00 75mg 847.99 3232.67 4080.66 + 606.66 50mg 4454.32 0.92 4455.24 100mg 847.99 4145.68 4993.67 + 538.43 75mg ± 7927.40 0.92 7928.32 150mg 847.99 5182.21 6030.20-1897.20 + 1574.96 ± Unlicensed dose; no injection available therefore cost based on a 50mg and 25mg dose given Compared to risperidone 50mg every 2 weeks (maximum licensed dose) Based on a dose of oral risperidone 6mg daily NB All costs are for secondary care and include VAT Summary of differences between paliperidone LAI and risperidone LAI 1,12 : Paliperidone LAI administered monthly compared with administration every 2 weeks for risperidone LAI; Initial supplementation with oral risperidone may needed during initiation with risperidone LAI that may need to be continued for 4-6 weeks oral and may also be needed during dose adjustment with the depot injection; previous oral paliperidone or risperidone can be discontinued at the time of initiation of paliperidone LAI; Paliperdone LAI does not require refridgeration- risperidone must be refridgerated. 11

References 1. XEPLION 50 mg, 75 mg, 100 mg and 150 mg prolonged release suspension for injection Summary of Product Characteristics. Janssen-Cilag Ltd. Last updated 31/03/2011. Accessed via www.medicines.org 16/8/11. 2. NICE. Clinical Guideline 82- Schizophrenia: Core interventions in the treatment and management of schizophrenia in primary and secondary care (March 2009). Accessed via http://guidance.nice.org.uk/cg82 3. Scottish Medicines Consortium (SMC). Paliperidone palmitate 50mg, 75mg, 100mg and 150mg prolonged release suspension for injection (Xeplion) No. (713/11). Accessed via http://www.scottishmedicines.org.uk/smc_advice/advice/713_11_paliperidone_palmitate _Xeplion/paliperidone_palmitate_Xeplion 4. Pandina et al. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Progress in NeuroPsychopharmacology & Biological Psychiatry, 2011; 35: 218 226. 5. Kramer et al. Paliperidone palmitate, a potential long-acting treatment for patients with schizophrenia. Results of a randomized, double-blind, placebo-controlled efficacy and safety study. International Journal of Neuropsychopharmacology 2009; 27: p1-13. 6. Gopal S et al. Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. International Clinical Psychopharmacology, 2010, 25(5): 247-56 7. Nasrallah HA et al. A controlled evidence based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology; 2010, 35(10): 207-282. 8. Hough D et al. Paliperidone palmitate maintenance treatment in delaying the time to relapse in patients with schizophrenia: A randomized, double-blind placebo-controlled study. Schizophrenia Research; 2010, 116 (23): 107117. 9. Gopal S et al. A 52-week open label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia. J Psychopharmacol,2010; 0(0): 1-13. 10. Pandina et al. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2011; 35: 218 226. 11. Sie M. Schizophrenia- clinical features and diagnosis. Clinical Pharmacist 2011; 3: 41-44. 12. British National Formulary No 61 (March 2011). BMJ and Pharmaceutical Press: London. 13. Dawda Y. Schizophrenia- long-term management. Clinical Pharmacist 2011; 3; 47-50. 14. Bishara et al. Once-monthly paliperidone injection for the treatment of schizophrenia. Neuropsychiatric Disease and Treatment, 2010; 6: 561 572. 15. Fleischhaker W et al. Optimisation of the Dosing Strategy for the Long-Acting Injectable Antipsychotic Paliperidone Palmitate: Results of Two Randomised Double-Blind Studies and Population Pharmacokinetic Simulations. Poster presented at the American Society for Pharmacology and Therapeutics. Scottsdale, AZ, 2008 Dec 7-11. 16. Li et al. A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia Progress in Neuro-Psychopharmacology & Biological Psychiatry, 2011, doi: 10.1016/j.pnpbp.2011.02.001 (article in press) 17. 12

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