Any treatment that offers even a small advantage in preventing relapse in schizophrenia must be clinically and economically advantageous. Paliperidone palmitate long-acting injection might be just such a treatment
Celia Feetam BPharm MSc MRPharmS FCMHP
Aston Pharmacy School, Aston University, Birmingham, UK
Paliperidone palmitate (Xeplion®) is an atypical antipsychotic long-acting injection for the treatment of schizophrenia. Paliperidone is the major active metabolite of risperidone and its palmitate ester has demonstrated comparable efficacy to risperidone long-acting injection. It has been shown to reduce relapse, hospital admissions and the length of inpatient stay. Consequently this, together with several practical advantages over risperidone long-acting injection, promises significant cost savings, making it a preferred, cost-effective option for many clinicians as well as patients.
Paliperidone palmitate (Xeplion®) is an atypical antipsychotic long-acting injection used to treat schizophrenia, a major heterogeneous chronic psychiatric disorder characterised by symptoms that alter a person’s perception, thoughts and behaviour. Each person with the disorder has a unique combination of symptoms and experiences and ideally should have individualised treatment. Schizophrenia is a progressive condition in which recurrent relapses can lead to decreased functioning, cognitive impairment and increasing need for care and support. It has recently been estimated that 220,000 people in England are currently living with schizophrenia,(1) although this may be an underestimate.(2) Lifetime prevalence in the West is generally considered to be 0.4–1.4%.(3)
The burden of schizophrenia
Schizophrenia is associated with a wide-ranging social and financial burden. The total annual cost of schizophrenia to society in England was £6.7 billion in 2004/5.4 In 2012, it was reported to have increased to £11.8 billion per year. About one-third of societal costs are direct expenditure on health and social care, with 49% of those with schizophrenia under the care of secondary mental health services and 31% in primary care.(1)
As with other mental illnesses, the major cost of treatment for schizophrenia is inpatient care with spending on antipsychotics in England in 2007 reported to be about £270 million, a fraction of the total cost of care. The cost of a single relapse of schizophrenia has been estimated at £25,000,(5) of which medicines account for only 3%. A significant association between non-adherence and service use and thus costs has been observed.(6) Any measures successful in improving adherence therefore are likely to decrease total direct treatment costs.
Meta-analyses of data from a number of countries concluded that a 50% improvement in adherence would decrease one-year hospitalisation rates by 12%.(7) Predicted excess total service use costs due to non-adherence is estimated to be over £5000 per year in the UK.(8)
There is currently no cure for schizophrenia but there is good evidence to support the use of antipsychotics, both for the amelioration of an acute psychotic episode as well as in maintenance treatment and relapse prevention. A meta-analysis of studies comparing antipsychotics with placebo in the management of acute episodes as well as in preventing relapse showed that compared to placebo, antipsychotics significantly reduced relapse in the first year as well as re-admission rates. No significant difference was noted between typical and atypical agents.(9)
Schizophrenia can be a naturally relapsing condition, but poor medicines adherence, the aetiology of which is multifactoral,(10) presents a major challenge to the long-term management of the condition. Poor adherence to treatment in schizophrenia is generally reported to be up to 50% but ranges from 20% to 90%(11,12) and in practice can jeopardise the proven benefits of antipsychotic therapy leading to poor outcomes for patients and increased costs to society.
Long-acting injectable antipsychotics were developed in an attempt to improve such adherence but high quality evidence to support a positive effect of these formulations on adherence and the prevention of relapse is sparse. Only a small benefit over oral therapy has previously been demonstrated.(13) One of the problems may be that the design and methodology of clinical trials investigating this area are inappropriate and bias against the long-acting formulation.(14)
In a recent systematic review of long-term studies however, long-acting injectable antipsychotics reduced relapse rates of outpatients with schizophrenia from an average of 33.2% to 21.5%. This represents a 10% absolute risk reduction and a 30% relative risk reduction for relapse.(15)
A nationwide cohort study in Finland concluded that the use of such long-acting formulations was associated with a significantly lower risk of re-hospitalisation than oral formulations of the same compounds.(16) In 2009, it was reported that between 25% and 33% of patients with schizophrenia in the UK were prescribed a long-acting injectable antipsychotic.(17)
Paliperidone palmitate injection (Xeplion®) was launched in the UK in 2011 for maintenance treatment of schizophrenia in adult patients stabilised with paliperidone or risperidone, and in selected adults with schizophrenia and previous responsiveness to oral paliperidone or risperidone. It may be used without prior stabilisation with oral treatment if psychotic symptoms are mild to moderate and a long-acting injectable treatment is needed.(18) Paliperidone palmitate is the palmitate ester of paliperidone, 9-hydroxyrisperidone, the major active metabolite of risperidone, and is formulated as an aqueous suspension of nonoparticles.
These nanoparticles dissolve very slowly from the injection site before being hydrolysed to paliperidone and absorbed into the systemic circulation. This extended period of time for release allows for monthly dosing. Release of the active substance starts as early as day 1, peaks at day 14 and lasts for up to at least four months.(19) Treatment initiation requires two doses of 150mg and 100mg to be injected into the deltoid muscle separated by seven days. Maintenance treatment involves monthly injections given either into the deltoid or gluteal muscle. The recommended dose is 75mg every month but can range between 50–150mg based on individual weight and tolerability.
As therapeutic plasma concentrations of paliperidone are achieved rapidly after administratrion into the deltoid muscle, oral supplementation with either risperidone or paliperidone is not necessary. In common with the other two atypical long-acting injections, but in contrast to the oily depot injections of typical antipsychotics, no test dose is required, although it is recommended that the tolerability of either oral risperidone or paliperidone be confirmed before treatment with paliperidone palmitate is started.
The pharmacology, pharmacokinetics and efficacy of paliperidone palmitate have been reviewed previously in this journal;(19) however, a meta-analysis of efficacy studies has since been published. Five short-term trials comparing paliperidone palmitate with placebo and two of flexibly dosed paliperidone palmitate versus flexibly dosed risperidone long-acting injection were included.(20) Fewer people left the placebo-controlled studies early if they were randomised to paliperidone palmitate and those receiving any dose of paliperidone palmitate were significantly less likely to show no improvement in global state than those randomised to placebo.
In a single trial specifically designed to study recurrence, those randomised to paliperidone palmitate were less likely to experience a recurrence of psychosis than those allocated to placebo. In the other studies where recurrence was recorded only as an adverse event, subjects who received paliperidone palmitate were also less likely to experience a recurrence of psychotic symptoms.
Like risperidone, paliperidone caused significant serum prolactin elevation and weight gain was greater than in the placebo groups. In the head-to-head comparisons with risperidone long-acting injection, no significant differences were shown in terms of numbers leaving the study early for any reason or rates of recurrence of psychotic symptoms. Those randomised to paliperidone palmitate were significantly less likely to use anticholinergic medicines than those who received long-acting risperidone injection.
An important place in therapy
Long-acting antipsychotic formulations clearly have an important place in the management of schizophrenia and paliperidone palmitate is a useful addition to the options available. It has several practical advantages over risperidone long-acting injection (Risperdal Consta®), and, as a result, the uptake of Xeplion® in the UK has been mirrored by a decline in the use of Risperdal Consta®.
Paliperidone palmitate comes ready mixed in pre-filled syringes in three strengths and does not require reconstitution. This saves nursing time and makes administration easier. It does not require cold storage and this reduces wastage due to a break in the cold chain as well as storage and transport costs.
As it has a faster onset of action than risperidone long-acting injection, the length of inpatient stay may be reduced. Because release of the active substance begins as early as day 1, in contrast to risperidone injection, oral supplementation is not required for the first few weeks of treatment and this can also reduce costs.
Paliperidone palmitate maintenance treatment is given monthly, while risperidone is given every two weeks. This saves time as well as transport costs. These practical advantages are very likely to more than offset the slightly higher cost of a year’s treatment with paliperidone palmitate compared with a year’s treatment with long acting risperidone injection.
A cost-minimisation analysis comparing paliperidone palmitate long-acting injection with long-acting risperidone injection was submitted in the UK by the manufacturer.(21) It compared costs associated with initiation and maintenance treatment of schizophrenia and presented the total costs per patient over the first year of treatment with either paliperidone palmitate or risperidone. When treatment was initiated in an inpatient setting, paliperidone palmitate was associated with an overall cost saving of £3491 per patient in year 1 compared with risperidone.
The cost-effectiveness of paliperidone palmitate versus oral atypical antipsychotics was investigated in the US. The conclusions drawn were that paliperidone palmitate may lead to fewer relapses and days in hospital resulting in potential cost savings when compared with oral atypical antipsychotics.(22)
A sub-analysis of one of the long-term pivotal studies similarly found hospitalisations significantly decreased for patients with schizophrenia treated with paliperidone palmate.(23) In another analysis from the US, paliperidone palmitate resulted in fewer relapses and lower annual total costs compared with oral atypical antipsychotics. Paliperidone palmitate was more effective and costs were reduced when the adherence rate with oral atypicals fell below 44.9%.(24)
In Sweden, the cost-effectiveness of paliperidone palmitate has been compared with risperidone and olanzapine pamoate long-acting injections using a Markov model. Relative to risperidone and olanzapine long-acting formulations, paliperidone was associated with additional quality-adjusted life years and fewer relapses and proved to be the less costly option over a five-year time horizon.
Paliperidone was therefore deemed to be cost saving in the long-term treatment of patients with schizophrenia who had experienced two or more relapses compared with either risperidone or olanzapine long-acting injections.(25)
Finally, in the UK, the interim results of a naturalistic evaluation showed that for the three years prior to paliperidone palmiate initiation, the average number of bed days per patient per year was four times higher than after initiation of paliperidone palmitate and similarly the mean number of admissions per patient per year was four-times higher before they were started on paliperidone treatment. All 132 patients had a diagnosis of schizophrenia and were followed up for one-year post-paliperidone initiation. This suggests large potential cost savings.(26)
A relapse of schizophrenia is clinically damaging and resource intensive. It is therefore costly to both the health economy and the patient. Any treatment that offers even a small advantage in preventing relapse must be clinically and economically advantageous. Paliperidone palmitate long-acting injection, with its comparable efficacy to that of risperidone long-acting injection, may be just such a treatment. Its practical advantages offset its increased acquisition costs, leading to potentially reduced total costs.
It should not be forgotten that the major cost of treatment for schizophrenia is inpatient care, with the cost of antipsychotics contributing only a fraction of the overall cost. The prime aim should therefore be to use a treatment preferred by the patient that is most likely to prevent relapse and re-admission and reduce the length of any inpatient stay necessary.
- Poor adherence in schizophrenia is generally reported to be up to 50%, but ranges from 20% to 90%, and presents a major challenge to the long-term management of the condition.
- Poor medicines adherence can jeopardise the proven benefits of antipsychotic therapy, leading to poor outcomes for patients and increased costs.
- A significant association between non-adherence and service use and costs has been observed and measures taken to improve adherence are likely to decrease total costs.
- Long-acting injectable antipsychotics have been shown to reduce relapse rates in schizophrenia from an average of 33.2% to 21.5%.
- Paliperidone palmitate injection has several practical advantages over risperidone long acting injection (Risperdal Consta) and as a result, the uptake of Xeplion in the UK has been mirrored by the decline in the use of Risperdal Consta.
- When treatment was initiated in an inpatient setting, paliperidone palmitate was associated with an overall cost saving of £3491 per patient in year 1 compared with risperidone.
- These together with its proven efficacy in preventing relapse, give it the potential to be a cost-effective treatment for schizophrenia, which should improve outcome and reduce overall costs.
- The Abandoned Illness. A report by the Schizophrenia Commission: 2012. www.rethink.org/media/514093/TSC_main_report_14_nov.pdf (accessed 12 August 2013).
- National Institute for Health and Care Excellence. Schizophrenia (update) 2009.
- National Institure for Health and Care Excellence. Costing statement. http://guidance.nice.org.uk/CG82/CostingReport/pdf/English (accessed 12 August 2013).
- National Institute for Health and Care Excellence. Schizophrenia: Core interventions in the treatment and management of schizophrenia in adults in primary and secondary care. Clinical Guideline 82 (Update) 2009. www.nice.org.uk/cg82 (accessed 12 August 2013).
- Mangalore R, Knapp M. Cost of schizophrenia in England. J Ment Health Policy Econ. 2007;10(1):23–41.
- Munro J et al. Hospital treatment and management in relapse of schizophrenia in the UK: associated costs. The Psychiatrist Online 2011;35:95-100
- Glazer W, Ereshefsky L. A pharmaco-economic model of outpatient antipsychotic therapy in ‘revolving door ’schizophrenia patients. J Clin Psychiatry 1996;57:337–45.
- Weiden P, Olfson M. Cost of relapse in schizophrenia. Schizophrenia Bull 1995;21: 419–29.
- Knapp M et al. Non adherence to antipsychotic medication regimens: associations with resource use and costs. Br J Psychiatry 2004;184:509–16.
- Leucht S et al. Antpsychotic drugs versus placebo for relapse prevention a systemtic review and meta-analysis Lancet 2012;379:2063–71.
- Feetam CL, Roberts H. Medicine taking behaviour in Schizophrenia Parts 1 & 2. Prog Neurol Psychiatry 2010;14(4–5):15–18.
- Gray R, Wykes T, Gournay K. From compliance to concordance: a review of the literature on interventions to enhance compliance with antipsychotic medication. J Psychiatric Mental Health Nurs 2002:9;227–84.
- Llorca PM. Partial compliance in schizophrenia and the impact on patient outcomes. Psychiatry Res 2008;151:235–47.
- Adams CE et al. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry 2001;179:290–9.
- Kirson, NY et al. Efficacy and effectiveness of depot versus oral antipsychotics in schizophrenia: Synthesising results across different research designs. J Clin Psychiatry 2013;April 19:doi:10.4088/JCP.12r08167.
- Leucht C et al. Oral versus depot antipsychotic drugs for schizophrenia: a critical systematic review and meta-analysis of randomised controlled long term trials. Schizophr Res 2011;127:83–92.
- Tiihonen J et al. A nationwide cohort study of oral and depot antipsychotics after first hospitalization for schizophrenia. Am J Psychiatry 2011;168:603–9.
- Barnes T et al. Antpsychotic long acting injections: prescribing practicies in the UK. Br J Psychiatry 2009;195:S37–42.
- Xeplion. Summary of product characteristics (SPC). www.medicines.org.uk/EMC/medicine/24403/ (accessed 12 August 2013).
- Lyons M, Taylor D. Modern formulations of long-acting antipsychotics. Hosp Pharm Eur 2011;59:33–7.
- Nussbaum AM, Stroup TS. Paliperidone palmitate for schizophrenia. Cochrane Database of Systematic Reviews 2012, Issue 6. Art. No: CD008296. DOI: 10.1002/14651858.CD008296.pub2.
- Scottish Medicines Consortium. www.scottishmedicines.org.uk/SMC_Advice/Advice/713_11_paliperidone_palmitate_Xeplion/paliperidone_palmitate_Xeplion_Resubmission (accessed 12 August 2013).
- Sikirica M, Crivera C, Dirani R. Cost-effectiveness of paliperidone palmitate versus oral atypicals in the US. 163rd Annual Meeting of the American Psychiatric Association (APA) New Orleans, Louisiana, USA. 22–26 May 2010: Poster No-Nr6-25.
- Kozma CM et al. Changes in schizophrenia-related hospitalisation and ER use among patients receiving paliperidone palmitate: results from a clinical trial with a 52-week open- label extension. Curr Med Res Opin 2011;27:1603–11.
- Edwards NC et al. The threshold rate of oral atypical anti-psychotic adherence at which paliperidone palmitate is cost saving. J Med Econ 2012;15:623–34.
- Mehnert A et al. Cost-effectiveness of paliperidone palmitate versus risperidone long acting injectable and olanzapine pamoate for the treatment of patients with schizophrenia in Sweden. J Med Econ 2012;15:844–61.