Local Policy Recommendation

Transcription

1 Local Policy Recommendation Aripiprazole (Abilify Maintena ) prolonged-release (PR) suspension for injection/long-acting antipsychotic injection (LAI) Recommendation: Red Aripiprazole prolonged-release (PR) suspension for injection is recommended as a treatment option in the maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole where both of the following criteria are met; where treatment is in line with the recommendations within NICE CG178 for the use of depot or long-acting injectable antipsychotic medication and where treatment is in line with the Lancashire Care Guidance for Prescribing Second Generation Long Acting Antipsychotic Injections Paliperidone palmitate (Xeplion ) prolonged release suspension for injection Recommendation: Red Paliperidone palmitate is recommended as a treatment option for the maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone and in selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed where both of the following criteria are met; where treatment is in line with the recommendations within NICE CG178 for the use of depot or long-acting injectable antipsychotic medication and where treatment is in line with the Lancashire Care Guidance for Prescribing Second Generation Long Acting Antipsychotic Injections Please note a full new medicine review has not been carried out for the production of the above recommendation. Two national bodies (SMC and AWMSG) have performed a full assessment of the evidence, safety and cost effectiveness of this medicine and these documents have been used in the preparation of the local policy recommendation. NHS Midlands and Lancashire CSU Page 1 of 13

2 1. Background The purpose of this paper is to provide a summary of information regarding the use of the second generation long-acting antipsychotic injections (LAIs), aripiprazole and paliperidone palmitate in adults. Indications 1 Risperidone LAI is indicated for the maintenance treatment of schizophrenia in patients currently stabilised with antipsychotics. Paliperidone palmitate LAI is indicated for 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 palmitate 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. It is an active metabolite of risperidone. Aripiprazole LAI is indicated for maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole. Relevant Guidance NICE Clinical Guideline 178 Psychosis and Schizophrenia in adults: treatment and management from (February 2014) 2 NICE Evidence summaries: new medicines (ESNM) 39. Schizophrenia: aripiprazole prolongedrelease suspension for injection (March 2014) 3 Scottish Intercollegiate Guidelines Network (SIGN 131). Management of schizophrenia (April 2013) 4 Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology (2011) 5 Scottish Medicines Consortium guidance 962/14 Aripiprazole prolonged-release suspension for injection (May 2014) 6 Scottish Medicines Consortium Recommendation 713/11 Paliperidone palmitate prolongedrelease suspension for injection (October 2011) 7 All Wales Medicines Strategy Group Recommendation Advice number 2512 Paliperidone palmitate prolonged-release suspension for injection (October 2012) 8 NHS Midlands and Lancashire CSU Page 2 of 13

3 2. Proposed place in therapy NICE CG 178 recommends an orally administered antipsychotic as the preferred option, in conjunction with psychological interventions. The choice should take into account the different risk profiles and potential impact on the patient. 2 NICE CG 178 recommends considering offering depot or long-acting injectable antipsychotic medication to people with psychosis or schizophrenia who would prefer such treatment after an acute episode or where avoiding covert non-adherence (intentional or unintentional) to antipsychotic medication is a clinical priority within the treatment plan. 2 NICE CG 178 states that when initiating depot/long-acting injectable antipsychotic medication, the service user s preferences and attitudes towards mode of administration (regular intramuscular injections) as well as organisational procedures (e.g. home visits and location of clinics) should be taken into account. 2 The same criteria recommended for the use of oral antipsychotic medication should also be taken into account in relation to the risks and benefits of the drug regimen (i.e. relative potential to cause extrapyramidal, metabolic, cardiovascular, hormonal and other side-effects). Small test doses as per BNF or SPC should be used initially. Currently risperidone is the only long-acting antipsychotic injection (LAI) on the Lancashire Care formulary. However it is proposed that two other LAIs are added to the formulary: aripiprazole and paliperidone. No new patients would be initiated on risperidone LAI due to paliperidone palmitate LAI having a number of practical advantages over risperidone LAI (some flexibility around dose administration schedules - if less than 6 weeks have elapsed since the last injection, then the previously stabilised dose should be administered as soon as possible, followed by injections at monthly intervals 1 ; no post-injection monitoring is required; ready-to-use pre-filled injection with no special storage conditions). Aripiprazole also does not require refrigeration. In line with risperidone LAI, a RAG rating of RED is proposed for aripiprazole and paliperidone LAIs. In view of the high cost of second generation antipsychotic LAIs it is proposed that these medicines should be reserved for patients who have failed to respond to first generation antipsychotic depot injections or for whom first generation antipsychotic depot injections are not tolerated or unsuitable due to for example, side-effects. In order to clarify how clinicians choose between the various options, a treatment pathway is being developed. Adherence to current antipsychotic medication must be taken into account along with patient preference. Prescribing must be within the licensed indications as outlined above and in the SPCs. NHS Midlands and Lancashire CSU Page 3 of 13

4 3. Aripiprazole (Abilify Maintena ) prolonged-release (PR) suspension for injection/long-acting antipsychotic injection (LAI) Recommendation: Red Aripiprazole prolonged-release (PR) suspension for injection is recommended as a treatment option in the maintenance treatment of schizophrenia in adult patients stabilised with oral aripiprazole where both of the following criteria are met; where treatment is in line with the recommendations within NICE CG178 for the use of depot or long-acting injectable antipsychotic medication and where treatment is in line with the Lancashire Care Guidance for Prescribing Second Generation Long Acting Antipsychotic Injections Please note a full new medicine review has not been carried out for the production of the above recommendation. Two national bodies (SMC and AWMSG) have performed a full assessment of the evidence, safety and cost effectiveness of this medicine and these documents have been used in the preparation of the local policy recommendation. Summary of supporting evidence: Aripiprazole LAI is an atypical antipsychotic which acts as a partial agonist at dopamine D2 and serotonin 5-HT1a receptors and an antagonist at serotonin 5-HT2a receptors. Evidence SMC (April 2014) states: Two double-blind randomised controlled trials: one non-inferiority active comparator study comparing with oral aripiprazole and the other placebo-controlled, support the use of aripiprazole PR injection. 9,10 Inclusion criteria for both trials were as follows: eligible patients were aged 18 to 60 years, with a current diagnosis of schizophrenia (according to Diagnostic and Statistical Manual of Mental Health Disorders, Fourth Edition, Text Revision [DSM-IV-TR] criteria). They had at least a 3-year disease history, symptoms of exacerbation on interruption or stopping antipsychotic treatment, were currently treated with at least one antipsychotic and were considered by the investigator to require chronic antipsychotic treatment and would benefit from treatment with aripiprazole PR injection. The active comparator study was a 38 week, randomised, double-blind (only during maintenance phase), trial (n=662) designed to establish the efficacy, safety, and tolerability of aripiprazole PR 400mg injection (could be reduced to 300mg) (n=265) administered monthly compared to once daily oral aripiprazole tablets mg (n=266) as maintenance treatment, in adult patients with schizophrenia. 9 This trial consisted of 3 treatment phases: Conversion Phase, Oral Stabilisation Phase, and Double-blind Active-controlled Phase. The primary outcome was the estimated proportion of patients experiencing impending relapse, from randomisation to the end of week 26 of the double-blind phase. Impending relapse was defined as meeting one of the following criteria: Clinical Global Impression-Improvement (CGI-I) of 5 (minimally worse) and either (a) an increasein any of the following individual PANSS items (conceptual disorganisation, hallucinatorybehaviour, suspiciousness, unusual thought content) to a score of >4 with an absolute increase of 2 on that specific item since randomisation, or (b) an increase in any of the following individual PANSS items (conceptual disorganisation, hallucinatory behaviour, suspiciousness, unusual NHS Midlands and Lancashire CSU Page 4 of 13

5 thought content) to a score of >4 and an absolute increase of 4 on the combined four of these PANSS items since randomisation. Hospitalisation due to worsening of psychotic symptoms but excluding hospitalisation for psychosocial reasons. CGI-SS of 4 (severely suicidal) or 5 (attempted suicide) on part 1 and/or 6 (much worse) or 7 (very much worse) on part 2. Violent behaviour resulting in clinically relevant self-injury, injury to another or property damage. The Kaplan-Meier curves of time to impending relapse at week 26 estimated the primary outcome occurred in 7.12% of the aripiprazole 400 mg/30 0mg PR injection group and 7.76% of the oral aripiprazole 10 to 30mg group, difference; -0.64% (95% confidence interval [CI]: to 3.99), p= This demonstrated non-inferiority. The second study (n=403) was similar in design to the active-comparator trial, but with an additional stabilisation phase, during which all patients stabilised on oral aripiprazole were converted to aripiprazole 400mg/300mg PR over a 12 to 36 week period. Patients were then randomised to placebo injection (n=134) or aripiprazole injection (n=269) every 4 weeks for 52 weeks. The study found aripiprazole 400 mg/300 mg PR injection to be superior to placebo for the primary outcome of time to exacerbation of psychotic symptoms/impending relapse. 10 After a pre-planned interim analysis, after 64 impending relapse events, the primary outcome had been achieved and the study was stopped early. At the final analysis (after 80 impending relapse events), the time to impending relapse was significantly shorter in the aripiprazole than placebo group and the relapse rate was statistically significantly lower; 10% (27/269) and 40% (53/134) respectively: hazard ratio 5.03 (95% CI: 3.15 to 8.02). AWMSG (August 2014): Two further trials are discussed in the AWMSG summary for aripiprazole PR suspension for injection. The first study was completed but only interim results were provided by the company. It is therefore not discussed further here. The second study was a multi-centre, open-label mirror-image study to compare hospitalisation rates in patients with schizophrenia treated with oral antipsychotic medicines (retrospectively) to treatment with aripiprazole LAI for six months (prospectively). 11 The primary endpoint was the rate of psychiatric hospitalisation for the three month retrospective oral antipsychotic treatment period (months -4 to -1) compared to the prospective aripiprazole LAI period (months 4 to 6). After switching to aripiprazole LAI, the rate of psychiatric hospitalisation was significantly lower compared to the retrospective three month period when the same patients were receiving oral antipsychotic medication (6.6% [n = 8/121] versus 28.1% [n = 34/121] respectively; rate ratio = 0.24). Safety SMC states: The safety data from the two key studies was pooled. Adverse events were reported in 73% (389/534), 80% (213/266), 81% (106/131) and 62% (83/134) patients respectively, during the double-blind phase of the trials whilst serious adverse events were reported in 4.9% (26/534), 5.6% (15/266), 8.4% (11/131) and 6.7% (9/134) patients respectively. The most frequently reported adverse events were insomnia, akathisia, headache, weight increase, weight decrease, nasopharyngitis, injection site pain and anxiety. Extrapyramidal symptoms and extrapyramidal-related adverse events were reported in 18% (98/534) of aripiprazole 400 mg/300 mg PR injection patients, 12% (31/266) oral aripiprazole patients, 12% (16/131) aripiprazole 50 mg/25 mg PR injection patients and 9.7% (13/134) NHS Midlands and Lancashire CSU Page 5 of 13

6 placebo patients. Most frequently, akathisia in 8.2% (44/534) and Parkinsonism in 6.9% (37/534) patients. There was no relevant difference between aripiprazole 400 mg/300 mg PR injection and oral aripiprazole in relation to suicide-related adverse events (including completed suicide, suicidal ideation and suicide attempt; 1.1% (6/534) and 0.4% (1/266)) in the two studies. In the non-inferiority active comparator study with oral aripiprazole, there was a higher incidence of neutropenia in the aripiprazole LAI 400 mg/300 mg group (2.3% [6/260]) compared with the oral aripiprazole group (0.8% [2/258]). Neutropenia typically started around day 16 after 1 st injection and lasted a median of 18 days 9. AWMSG states: When licensing aripiprazole LAI, the Committee for Medicinal Products for Human Use (CHMP) concluded that the safety profile appeared favourable and similar to that of oral aripiprazole. A total of 1,624 adult patients with schizophrenia have been exposed to aripiprazole LAI. The most frequent treatment related adverse events reported in patients receiving aripiprazole LAI 400 mg were increased weight, akathisia, insomnia, and injection site pain. A higher frequency of extrapyramidal symptoms was reported in the aripiprazole LAI 400 mg group compared to the oral aripiprazole group (18.4% versus 11.7%). In one study, a higher incidence of low white blood cell (WBC) count was observed in the aripiprazole LAI 400 mg group compared to oral aripiprazole (2.3% versus 0.8%). 11 Although three of the six patients in the aripiprazole LAI 400 mg group had low WBC at baseline, CHMP considered leukopenia to be of potential clinical relevance and identified it as a risk related to this formulation. 4. Paliperidone palmitate (Xeplion ) prolonged release suspension for injection Recommendation: Red Paliperidone palmitate is recommended as a treatment option for the maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone and in selected adult patients with schizophrenia and previous responsiveness to oral paliperidone or risperidone, without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed where both of the following criteria are met; where treatment is in line with the recommendations within NICE CG178 for the use of depot or long-acting injectable antipsychotic medication and where treatment is in line with the Lancashire Care Guidance for Prescribing Second Generation Long Acting Antipsychotic Injections Please note a full new medicine review has not been carried out for the production of the above recommendation. Two national bodies (SMC and AWMSG) have performed a full assessment of the evidence, safety and cost effectiveness of this medicine and these documents have been used in the preparation of the local policy recommendation. Summary of supporting evidence Paliperidone palmitate LAI is licensed for 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, XEPLION may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment NHS Midlands and Lancashire CSU Page 6 of 13

7 is needed. It is the active metabolite of risperidone and an antagonist of serotonin 5-HT 2 and dopamine D 2 receptors. Evidence SMC (October 2011) states: Two similar double-blind active-comparator non-inferiority studies recruited adults who had a diagnosis of schizophrenia for at least one year and a positive and negative syndrome scale (PANSS) score of 60 to ,13 In the 1-year study patients were randomised equally to paliperidone LAI 25 to 100 mg monthly or risperidone 12.5 to 50 mg LAI fortnightly (following an initial stabilisation period with oral risperidone). 12 The initial two doses of 50 mg of paliperidone LAI on days 1 and 8 in this trial were lower than the licensed loading dose. The subsequent 3-month study patients were given the licensed 150 mg paliperidone LAI on day 1 and 100 mg on day 8, then flexible monthly dosing 50 to 150 mg thereafter. 13 The primary endpoint was change in PANSS score from baseline to endpoint in the per protocol population (570 and 765 patients in the respective studies). The pre-specified noninferiority margin (lower confidence interval) was 5 points. At baseline, the mean PANSS total score was 82 in the 1-year study. The mean change in PANSS score from baseline to endpoint was and in the paliperidone LAI and risperidone LAI groups, respectively. The difference between paliperidone LAI and risperidone LAI and in the leastsquare mean for change in PANSS score was -2.6 (95% confidence interval (CI): to 0.61) and therefore non-inferiority of paliperidone LAI to risperidone LAI was not demonstrated. It has been suggested that the reason non-inferiority was not demonstrated in the 1-year study was potential sub-therapeutic levels at the beginning of the study as a result of a lower loading dose than the licensed dose which was used for the 3-month study. In the 3 month study, the mean baseline PANSS total score was 84 and the mean change from baseline to endpoint in PANSS score was in the paliperidone LAI group and in the risperidone LAI group. 13 The difference between paliperidone LAI and risperidone LAI in the least-square mean for change in PANSS score was 0.4 (95% CI: to 2.38) and therefore non-inferiority of paliperidone LAI to risperidone LAI was demonstrated. In a third double-blind study, 410 adults with schizophrenia as defined in DSM-IV for at least one year were stabilised with a PANSS total score 75 and scores 4 for PANSS items P1 (delusions), P2 (conceptual disorganisation), P3 (hallucinatory behaviour), P6 (suspiciousness/persecution), P7 (hostility), G8 (uncooperativeness) and G14 (poor impulse control) on monthly im flexible doses of paliperidone LAI 25mg to 100mg and then randomised to continue their maintenance dose of paliperidone LAI or receive placebo. 14 The primary outcome was time-to-first relapse, defined as: hospitalisation for symptoms of schizophrenia; 25% increase in PANSS score for patients with an initial score >40 or a 10- point increase for patients with an initial score 40; deliberate self-injury; aggressive behaviour; suicidal or homicidal ideation; or an increase for two consecutive assessments of scores for individual PANSS items P1, P2, P3, P6, P7, P8 to 5 for patients with initial scores 3 or to 6 for patients with initial scores of 4. The study was stopped at a pre-planned interim analysis after 68 relapse events when data from 312 patients indicated that paliperidone LAI, compared to placebo, significantly NHS Midlands and Lancashire CSU Page 7 of 13

8 delayed time-to-first relapse. The median time to relapse in the placebo group was 163 days and could not be estimated in the paliperidone LAI group. Relapse rates were significantly lower in the paliperidone LAI group than in the placebo group: 10% (15/156) versus 34% (53/156). AWMSG (October 2012) states: In addition to the 3 month double-blind study summarised above, AWMSG summarised an open-label study in a Chinese population. This open-label, rater-blinded, parallel group, phase III trial evaluated the non-inferiority of paliperidone palmitate LAI when compared with risperidone LAI for the treatment of 413 adult Chinese patients with acute schizophrenia. 15 Patients with an established diagnosis of schizophrenia and a PANSS total score between 60 and 120 (inclusive) at screening were randomised to receive either paliperidone palmitate LAI or risperidone LAI with oral risperidone. At endpoint, the mean change in total PANSS score in the per protocol set (n= 413) was and in the paliperidone palmitate LAI and risperidone LAI treatment arms respectively, with a weighted difference in means of -2.3 (95% CI to 0.63). The lower limit of the 95% CI was within the pre-specified non-inferiority margin of -5.5, allowing the conclusion that paliperidone palmitate LAI is non-inferior to risperidone LAI. However, this was not supported by analysis of the ITT data set. Safety SMC states: The overall adverse effect profile of paliperidone LAI appears similar to that of risperidone LAI. In the comparisons to risperidone LAI, rates of adverse events were similar, except in the 1-year comparison where paliperidone LAI was associated with a higher incidence of severe psychiatric adverse events (18% versus 14%), mainly psychotic disorder and schizophrenia. AWMSG states: Adverse event rates were similar for paliperidone palmitate LAI and risperidone LAI in the 13 week pivotal study 13 (57.9% versus 52.8%) with serious adverse events being reported in 6.8% paliperidone palmitate LAI patients compared with 4.8% of risperidone LAI patients. 13 Of note, the incidence of injection site-related adverse events was higher for paliperidone palmitate LAI patients than for risperidone LAI patients: injection site pain (5.1% versus. 0.8 %); injection site induration (1.5% versus. 0.3 %); and injection site swelling (1.0% versus. 0.2%). Other common AEs (occurring in 5% of patients) were insomnia, headache and somnolence in the paliperidone palmitate LAI treatment arm, and insomnia and headache in patients treated with risperidone LAI. 16 Insomnia, injection site pain and anxiety occurred at a 2% higher incidence in paliperidone palmitate LAI treated patients than in the risperidone LAI treatment group; only constipation was 2% more frequent in patients receiving risperidone LAI. 13 Additionally, there was a higher incidence of discontinuation due to psychiatric AEs in the paliperidone palmitate group. 16 NHS Midlands and Lancashire CSU Page 8 of 13

9 Cochrane summary A Cochrane review of paliperidone palmitate LAI for schizophrenia was identified and published in June Its objective was to compare the effects (efficacy, adverse effects and safety) of paliperidone palmitate LAI with any other treatment for people with schizophrenia and schizophrenia-like illnesses by identifying relevant RCTs. Seven RCTs were included in the review three of these were summarised by SMC/AWMSG as above. 12, 13, 14 Both published and unpublished data were used, with a total of 4184 participants being randomised and trial size ranging from 247 to 1220 participants. Five RCTs compared paliperidone palmitate LAI to placebo 14, 18,19,20,21 and two compared it to risperidone LAI 13, 22. Five studies were excluded. Three on the basis that paliperidone palmitate LAI was not compared to another intervention and two open-label studies which were not randomised. In relation to the quality of the trials, each used various strategies to conceal the identity of the study drug, but in at least one trial 19 (not included in SMC/AWMSG summaries) blinding was compromised and the affected data were excluded from the analysis. Only 41% to 85% of people randomised to paliperidone palmitate completed the six out of seven trials designed to last between 64 days and 13 weeks. Hough , a study of time to relapse, defined the time to first relapse as one or more of these events: hospitalisation, 25% increase in PANSS total score for two consecutive assessments for patients with PANSS > 40 at randomisation OR a 10-point increase in PANSS for patients with PANSS < 40 at randomisation, clinically significant unsafe behaviour, or increase in pre-specified PANSS subscores. A significant difference to time to recurrence between participants randomised to paliperidone palmitate and placebo was found (n = 312, 1 RCT, RR 0.28 CI 0.17 to 0.48, NNT 5 over 24 weeks CI 4 to 6). The 18, 19, 20, 21 remaining four studies did not include recurrence as a specific outcome, but did report recurrence of psychosis as an adverse event. The participants randomised to paliperidone palmitate in these four studies were found to be significantly less likely to experience the recurrence of psychotic symptoms than those receiving placebo (n = 1772, 4 RCTs, RR 0.67 CI 0.53 to 0.84, NNTB 17 CI 12 to 36). Evidence of heterogeneity was found in this outcome. Neither of the studies comparing paliperidone LAI with risperidone LAI 13, 22 defined recurrence as a specific outcome, but as an adverse event. The pooled data suggested less recurrence with risperidone LAI, but was narrowly insignificant (n = 1961, 2 RCTs, RR 1.23 CI 0.98 to 1.53). The authors of the review concluded that: in short-term studies, paliperidone palmitate is a more effective antipsychotic than placebo and the adverse effects of paliperidone palmitate are similar to those of oral paliperidone, oral risperidone, and risperidone long-acting injection. Furthermore in two short-term studies, flexibly-dosed paliperidone palmitate, with mean doses of 70 to 110 mg every four weeks, is roughly equivalent in efficacy and tolerability to flexibly-dosed risperidone long-acting injection, with mean doses of 35 mg every two weeks. However, they also state that, Given the limited duration of these trials, the low rates of completion and other issues of study quality, we can make only tentative inferences about the long-term efficacy and safety of paliperidone palmitate for people with schizophrenia, which is often a chronic illness. NHS Midlands and Lancashire CSU Page 9 of 13

10 Further study identified: A Comparison of Long-acting Injectable Medications for Schizophrenia (ACLAIMS) 23 This double-blind randomised controlled trial (n=311) compared the effects of paliperidone palmitate LAI (39 to 234 mg) with haloperidol decanoate LAI (25 to 200 mg) (a first-generation antipsychotic) monthly for up to 12 months. It was conducted at 22 U.S. sites and included patients aged between 18 and 65 years old who had been diagnosed with schizophrenia or schizoaffective disorder and were identified as being at risk of relapse. The primary analysis included all patients who received at least one injection and at least one post-baseline assessment (n=145 in each group). The follow-up period varied from 12 to 24 months with a median of 488 days. There was no significant difference between paliperidone and haloperidol for the primary outcome of rates of relapse. 33.8% of patients in the paliperidone group and 32.4% of those in the haloperidol group relapsed, with a hazard ratio of 0.98 (95% CI, ) for paliperidone versus haloperidol. At 6 months, the weight in the paliperidone group increased by 2.17 kg (least-squares mean, 95% CI, , p< 0.01) and decreased in the haloperidol group by 0.96 kg (least-squares mean, 95% CI, 1.88 to 0.04, p< 0.01). The haloperidol group showed significantly greater worsening of akathisia. Paliperidone caused a significantly greater rise in mean serum prolactin level in both men and women. Overall 68% in the paliperidone group, compared with 59.9% of those in the haloperidol decanoate group reported at least one adverse effect rated as either moderate or severe. Of note, 16.3% of patients in the paliperidone group experienced sialorrhea compared with 10.9% in the haloperidol decanoate group. 5. Table of costs The table below lists the basic costs of the injections but does not include other related costs such as hospital visits. Prices taken from MIMS October Drug Example regimen Cost per patient per course per year ( ) Second-generation LAIs Risperidone LAI 25 mg to 50 mg every 2 weeks Aripiprazole LAI 400 mg once per month 2865 Paliperidone LAI 25 mg to 150 mg once per month First-generation LAIs Haloperidol 30 mg to 300 mg every 4 weeks decanoate LAI Flupentixol 50 mg every 4 weeks to 300 mg every decanoate two weeks Fluphenazine 12.5 mg to 100 mg given at a dose decanoate interval of 2 to 5 weeks Zuclopenthixol decanoate 200 mg to 500 mg every one to four weeks Oral second-generation antipsychotics Amisulpride mg daily in 2 divided doses (lower doses in patients with predominantly negative symptoms) Aripiprazole 15 mg daily 564 Olanzapine 5-20 mg daily Paliperidone 3-12 mg daily NHS Midlands and Lancashire CSU Page 10 of 13

11 Quetiapine mg in 2 divided doses (standard-release); 600 mg daily (prolonged-release) (standard-release) 4125 (prolonged-release) Risperidone 4-6 mg daily According to the evidence submission for paliperidone palmitate use in NHS Scotland, the company submitting the evidence estimated the eligible population to be 1062 patients, equating to 0.02% of the Scottish population at that time. 0.02% of the 1.5 million population in Lancashire equates to 300 patients. The manufacturer of aripiprazole estimates that 15,245 people in England are currently receiving a second-generation prolonged-release antipsychotic for maintenance treatment for schizophrenia. They predict that 4% of those eligible for treatment with these drugs will receive aripiprazole prolonged-release in year 1 rising to 8% in year 2 and 12% in year 3. 3 Based on population in Lancashire of 1.5 million, this would equate to 17 people receiving aripiprazole in the first year rising to 34 in year 2 and 50 in year LMMG are asked to consider the evidence, safety and cost-effectiveness for the use of aripiprazole and paliperidone LAIs and their proposed place in therapy and to make recommendations on the RAG status. NHS Midlands and Lancashire CSU Page 11 of 13

12 7. References 1. Electronic Medicines Compendium accessed at on 20/11/15 2. National Institute for Health and Care Excellence Psychosis and Schizophrenia in adults: treatment and management. Clinical Guideline 178; February Accessed at on 20/11/15 3. National Institute for Health and Care Excellence Schizophrenia: aripiprazole prolonged-release suspension for injection Evidence summaries: new medicines (ESNM) 39; March Accessed at on 20/11/15 4. Scottish Intercollegiate Guidelines Network Management of schizophrenia SIGN131; April Accessed at on 20/11/15 5. Barnes T and the Schizophrenia Consensus Group of the British Association for Psychopharmacology Evidence-based guidelines for the pharmacological treatment of schizophrenia: recommendations from the British Association for Psychopharmacology (2011). Journal of Psychopharmacology 0 (0) 1-54 Accessed at on 20/11/15 6. Scottish Medicines Consortium Aripiprazole prolonged-release suspension for injection SMC No. (962/14); May Accessed at on 20/11/15 7. Scottish Medicines Consortium Paliperidone palmitate prolonged-release suspension for injection SMC No. (713/11); October Accessed at ber_2011_for_website.pdf on 20/11/15 8. All Wales Medicines Strategy Group Paliperidone palmitate prolonged-release suspension for injection Advice number 2512; October European Medicines Agency, European Public Assessment Report for Abilify Maintena EMEA/H/C/002755/ September [accessed 9 January 2014]. 10. Kane J, Sanchez R, Perry P et al. Aripiprazole intramuscular depot as maintenance treatment in patients with schizophrenia: a 52-week, multicenter, randomized, double-blind, placebo-controlled study. J Clin Psychiatry. 2012; 73: Kane J M, Sanchez R, Zhao J et al. Hospitalisation rates in patients switched from oral anti-psychotics to aripiprazole once monthly for the management of schizophrenia. Journal of Medical Economics :7, Fleischhacker WW, Gopal S, Samtani MN et al. Optimization of the dosing strategy for the longacting injectable antipsychotic Paliperidone Palmitate: Results of two double-blind studies and population pharmacokinetic simulations. 2008; Poster presented at ACNP; Scottsdale, AZ, USA; December 7-11, Pandina GL, Lane R, Gopal S 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: NHS Midlands and Lancashire CSU Page 12 of 13

13 14. Hough D, Gopal S, Vijapurkar U et al. Paliperidone Palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: Arandomised, double-blind, placebo-controlled study. Schizophr Res, 2010; 116: Li H, Rui Q, Ning X et al. A comparative study of paliperidone palmitate and risperidone long-acting injectable therapy in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry2011; 35 (4): European Medicines Agency. Assessment Report. Xeplion. Procedure No.: EMEA/H/C/2105. Mar Available at: _Public_assessment_report/human/002105/WC pdf accessed 20/10/ Nussbaum A M and Stroup T S. Paliperidone Palmitate for Schizophrenia Cochrane Database of Systematic Reviews 2012 DOI: / CD pub2 Available at A277EBC0C442093CDFDF5E9.f02t03 accessed 20/10/ Kramer M, Litman R, Hough D 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; 13 (5): Gopal S, Hough DW, Xu H 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) : Nasrallah HA, Gopal S, Gassmann-Mayer C et al. A controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology 2010; 35 (10) : Pandina GJ, Lindenmayer JP, Lull J et al. A randomized, placebo-controlled study to assess the efficacy and safety of 3 doses of paliperidone palmitate in adults with acutely exacerbated schizophrenia. Journal of Clinical Psychopharmacology 2010; 30 (3) : Fleischhacker 2010 {published and unpublished data} Johnson and Johnson Pharmaceutical Research and Development LLC. A randomized, double blind, parallel group, comparative study of flexibly dosed paliperidone palmitate (25, 50, 75, or 100 mg eq.) administered every 4 weeks and flexibly dosed risperdal consta (25, 37.5, or 50 mg) administered every 2 weeks in subjects with schizophrenia [:NCT ] 23. McEvoy J P, Byerly M, Hamer R et al. Effectiveness of paliperidone palmitate versus haloperidol decanoate for maintenance treatment of schizophrenia. A randomised clinical trial. JAMA 2014; 311 (19): Midlands and Lancashire Commissioning Support Unit, The information contained herein may be superseded in due course. All rights reserved. Produced for use by the NHS, no reproduction by or for commercial organisations, or for commercial purposes, is allowed without express written permission. Midlands and Lancashire Commissioning Support Unit, Jubilee House, Lancashire Business Park, Leyland, PR26 6TR Tel: NHS Midlands and Lancashire CSU Page 13 of 13