Economic analysis of paliperidone long-acting injectable for chronic schizophrenia in Portugal

Figures & data

Table 1. Doses used to treat patients and data sources.

Reason for administration	Treatment	Dosing regimen	Source
Maintenance of stable schizophrenia	PP-LAI	69.3 mg monthly	Average of Gopal et al.^37, Fleischhacker et al.^21
	RIS-LAI	40.3 mg every 2 weeks	Average of Fleischhacker et al.^21, Kissling et al.^22, Lee et al.^23, Olivares et al.^24, Lindenmayer et al.^25
	HAL-LAI	122 mg monthly (55% every 4 weeks, 45% every 2 weeks)	Weighted average from 11 clinical trials reported by Adams et al.^19 and Quraishi et al.^26
	oral-OLZ	15.8 mg daily	Weighted average from 12 head-to-head trials reported by Komossa et al.^27
Treatment of relapsed outpatient	PP-LAI	84.9 mg monthly	Average of Gopal et al.^37, Pandina et al.^28, Hough et al.^29, Nasrallah et al.^30, Pandina et al.^31
	RIS-LAI	50 mg every 2 weeks*	Risperdal Consta summary of product characteristics^13
	HAL-LAI	150 mg per 4 weeks administered every 1–3 weeks	Pro-rated from PP-LAI dose
	oral-OLZ	15.9 mg daily	Average of 15 head-to-head trials from Komossa et al.^27, Jayaram et al.^32 and Lieberman et al.^33
Treatment of hospitalized patient	PP-LAI	150 mg week 1, 100 mg week 2, then 82.8 mg every 4 weeks’ maintenance	Xeplion summary of product characteristics^15, Hough et al.^29
	RIS-LAI	50 mg every 2 weeks*	Risperdal Consta summary of product characteristics^13; Meltzer et al.^34
	HAL-LAI	150 mg per 4 weeks administered every 1–3 weeks then 122 mg every 4 weeks	Pro-rated from PP-LAI dose; maintenance dose as above
	oral-OLZ	20.7 mg/day	Weighted average dose from nine trials as reported by Komossa et al.^27

LAI, long-acting injection; PP, paliperidone palmitate (Xeplion); RIS, risperidone microspheres (Risperdal Consta).

* The maximum allowable dose was used, since the average dose in three trials by Kane et al.¹², Chue et al.³⁵, and Eerdekens et al.³⁶ was 58.2 mg, but they included a dose of 75 mg, which is not commercially available.

Figure 1. Model used for the pharmacoeconomic analysis.

Table 2. Clinical input rates, utility scores, and their sources.

Clinical state	Treatment	Rate	Source
Adherence	PP-LAI	0.872	RIS rate from Olivares et al.^24 adjusted via Mehnert et al.^41
	RIS-LAI	0.823	Olivares et al.^40
	HAL-LAI	0.592	Average of rates from Bartkó et al.^42, Heyscue et al.^43, Ritmannsberger et al.^55, Valenstein et al.^56
	oral-OLZ	0.537	Average of 1-year rates reported by Ascher-Svanum et al.^47, Guo et al.^44, Hamilton et al.^45, Ritmannsberger et al.^55, Valenstein et al.^56, Yu et al.^46
Stable schizophrenia	PP-LAI	0.769	Calculation: 1 − (non-hospitalized exacerbations + hospitalization rates)
	RIS-LAI	0.712	Calculation: 1 − (non-hospitalized exacerbations + hospitalization rates)
	HAL-LAI	0.633	Calculation: 1 − (non-hospitalized exacerbations + hospitalization rates)
	oral-OLZ	0.605	Calculation: 1 − (non-hospitalized exacerbations + hospitalization rates)
Emergency room visits for relapse	PP-LAI	0.067	Hospitalization rate × ratio of ER visits:hospitalizations^47
	RIS-LAI	0.084	Hospitalization rate × ratio of ER visits:hospitalizations^47
	HAL-LAI	0.107	Hospitalization rate × ratio of ER visits:hospitalizations^47
	oral-OLZ	0.115	Hospitalization rate × ratio of ER visits:hospitalizations^47
Hospitalization for relapse	PP-LAI	0.164	Gopal et al.^20, Hough et al.^29
	RIS-LAI	0.204	Olivares et al.^24
	HAL-LAI	0.260	RIS rate x ratio HAL:RIS rates in Csernansky et al.^48
	oral-OLZ	0.280	Rabinowitz et al.^49
Utilities for health states	Stable disease	0.890	Average: Briggs et al.^50, Cummins et al.^51, Lenert et al.^52, Oh et al.^53, Revicki et al.^54
	Relapsed outpatient	0.659	Average: Briggs et al.^50, Cummins et al.^51, Lenert et al.^52
	Relapsed inpatient	0.490	Average: Lenert et al.^52, Revicki et al.^54

HAL, haloperidol; LAI, long-acting injection; OLZ, olanzapine; PP, paliperidone palmitate (Xeplion^®); RIS, risperidone microspheres (Risperdal Consta).

Table 3. Resources consumed and their costs.*

Resource	Item	Cost
Hospital/institutional care	Psychiatric hospitalization(5–89 days)	3069.95€†
	Psychiatric rehab ward/day	87.56€
	Day hospital	30.49€
	Psychiatric outpatient visit	99.32€
	Emergency room visit	112.07€
Medical care	Psychiatrist – outpatient visit	34.50€
	Psychiatrist – follow-up	24.50€
	Psychiatric nurse	3.70€
	Primary care physician	31.00€
Drugs	Xeplion	3.564€/mg
	Risperdal Consta	3.433€/mg
	haloperidol decanoate	0.068€/mg
	haloperidol tablets	0.026€/mg
	paliperidone tablets	0.715€/mg
	risperidone tablets	0.081€/mg
	clozapine tablets	0.005€/mg
	olanzapine tablets	0.122€/mg

* All costs are expressed in 2014 euros; Data source for all costs: Ministério da Saúde⁵⁹.

† Flat rate for 4–89 days, after which the cost is 87.56€/day.

Table 4. Results of the overall cost-utility analysis.

Drug	Cost*/patient	QALYs/patient	Incremental cost	Incremental QALYs	Economic outcome
oral-OLZ	4447€	0.7609	–	–	lowest cost
HAL-LAI	4474€	0.7585	27€	−0.0024	dominated
PP-LAI	5326€	0.8227	852€	0.0642	cost-effective (see Table 5)
RIS-LAI	6223€	0.7985	897€	−0.0242	dominated

HAL, haloperidol; ICER, Incremental Cost Effectiveness Ratio; LAI, long acting injectable; OLZ, olanzapine; PP, paliperidone palmitate; RIS, risperidone microspheres; QALY, quality adjusted life year.

* All costs are in 2014 euros.

Table 5. Results of the final incremental analysis of PP-LAI over oral-OLZ.

Drug	Cost*/patient	QALYs/patient	Incremental cost	Incremental QALYs	Economic outcome
oral-OLZ	4447€	0.7609	–	–	lowest cost
PP-LAI	5326€	0.8227	880€	0.062	14,247€†

ICER, Incremental Cost Effectiveness Ratio; LAI, long acting injectable; OLZ, olanzapine; PP, paliperidone palmitate; QALY, quality adjusted life year.

* All costs are in 2014 euros.

† Incremental Cost-Effectiveness Ratio as compared with oral-OLZ; NICE threshold for cost-effectiveness ≈24,800€ (approximate equivalent of £20,000 using the average 2014 exchange rate)⁶¹.

Table 6. Clinical outcomes.

Drug	Remission days	Relapse days	Emergencyroom visits	Hospitalizations
PP-LAI	326.6	37.4	0.122	0.288
RIS-LAI	312.8	51.2	0.168	0.394
HAL-LAI	284.5	79.5	0.250	0.623
oral-OLZ	286.0	78.0	0.242	0.615

HAL, haloperidol; LAI, long acting injectable; OLZ, olanzapine; PP, paliperidone palmitate; RIS, risperidone microspheres.

Table

Parameter	Drug rate changed	Base case	Value where PP-LAI is cost saving	% difference	Value where PP-LAI not cost-effective	% difference	Value where PP-LAI QALYs not highest	% difference
Adherence	PP-LAI	0.872	Resistant	n/a	0.65	−22%	0.164	−71%
(primary)	oral-OLZ	0.380	Resistant	n/a	Resistant	n/a	Resistant	n/a
Adherence	PP-LAI	0.400	Resistant	n/a	Resistant	n/a	Resistant	n/a
(2nd line)	oral-OLZ	0.400	Resistant	n/a	Resistant	n/a	Resistant	n/a
relapse rate	PP-LAI	0.166	Resistant	n/a	0.31	−14%	0.77	+60%
	oral-OLZ	0.473	Resistant	n/a	Resistant	n/a	Resistant	n/a
Stable + non-adherent	PP-LAI	0.148	Resistant	n/a	Resistant	n/a	Resistant	n/a
	oral-OLZ	0.071	Resistant	n/a	Resistant	n/a	Resistant	n/a
Dropout rate	PP-LAI	0.202	Resistant	n/a	0.32	+12%	0.65	+45%
	oral-OLZ	0.343	Resistant	n/a	Resistant	n/a	Resistant	n/a
Clozapine relapse	clozapine	0.402	Resistant	n/a	Resistant	n/a	Resistant	n/a
Drug cost/mg	PP-LAI	3.564€	2.3€	−35%	4.74€	+33%	n/a
	oral-OLZ	0.122€	0.475€	+289%	Resistant	n/a	n/a
Hospital cost/stay	n/a	3069.95€	5700€	+86%	800€	−74%	n/a

n/a, not applicable; resistant means that results do not change to favor the other drug, even if the rates are at the extremes (i.e. either 0% or 100%). For example, in the case of secondary adherence, all results will always favor PP-LAI over oral-OLZ, even if the rate for PP-LAI is 0% or the oral-OLZ rate is 100%.

Gopal S, Vijapurkar U, Lim P, et al. A 52-week open-label study of the safety and tolerability of paliperidone palmitate in patients with schizophrenia. J Psychopharmacol 2010;25:685-97

 PubMed Web of Science ®Google Scholar

Fleischhacker W, Gopal S, Lane R, et al. A randomized trial of paliperidone palmitate and risperidone long-acting injectable in schizophrenia. Int J Neuropsychopharmacol 2011;22:1-12

 Google Scholar

Kissling W, Heres S, Lloyd K, et al. Direct transition to long-acting risperidone - analysis of long-term efficacy. J Psychopharmacol 2005;19:15-21

 PubMed Web of Science ®Google Scholar

Lee M, Ko Y, Lee S, et al. Long-term treatment with long-acting risperidone in Korean patients with schizophrenia. Hum Psychopharmacol 2006;21:399-407

 PubMed Web of Science ®Google Scholar

Olivares J, Rodrigues-Morales A, Diels J, et al. Long-term outcomes in patients with schizophrenia treated with risperidone long-acting injection or oral antipsychotics in Spain: Results from the electronic Schizophrenia Treatment Adherence Registry (e-STAR). Eur Psychiatry 2009;24:287-96

 PubMed Web of Science ®Google Scholar

Lindenmayer J-P, Khan A, Eerdekens M, et al. Long-term safety and tolerability of long-acting injectable risperidone in patients with schizophrenia or schizoaffective disorder. Eur Neuropsychopharmacol 2007;17:138-44

 PubMed Web of Science ®Google Scholar

Adams CE, Fenton MP, Quraishi S, et al. Systematic meta-review of depot antipsychotic drugs for people with schizophrenia. Br J Psychiatry 2001;179:290-9

 PubMed Web of Science ®Google Scholar

Quraishi SN, David A, Brasil MA, et al. Depot haloperidol decanoate for schizophrenia. Cochrane Database Syst Rev 1999;Issue 1:CD001361

 Google Scholar

Komossa K, Rummel-Kluge C, Hunger H, et al. Olanzapine versus other atypical antipsychotics for schizophrenia. Cochrane Database Syst Rev 2010;Issue 3:CD006654

 Web of Science ®Google Scholar

Pandina G, Lane R, Gopal S. A double-blind study of paliperidone palmitate and risperidone long-acting injectable in adults with schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2011;35:218-26

 PubMed Web of Science ®Google Scholar

Hough D, Gopal S, Vijapurkar U. Paliperidone palmitate maintenance treatment in delaying the time-to-relapse in patients with schizophrenia: a randomized, double-blind, placebo-controlled study. Schizophr Res 2010;116:107-17

 PubMed Web of Science ®Google Scholar

Nasrallah HA, Gopal S, Gassmann-Mayer C. A controlled, evidence-based trial of paliperidone palmitate, a long-acting injectable antipsychotic, in schizophrenia. Neuropsychopharmacology 2010;35:2072-82

 PubMed Web of Science ®Google Scholar

Pandina GJ, Lindenmayer J-P, Lull JM. A randomized, 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;30:235-44

 PubMed Web of Science ®Google Scholar

European Medicines Agency. Risperdal Consta® summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/Referrals_document/Risperdal_Consta_30/WC500008170.pdf. Accessed July 7, 2015

 Google Scholar

Jayaram MB, Hosalli P, Stroup TS. Risperidone versus olanzapine for schizophrenia. Cochrane Database Syst Rev 2006;Issue 2:CD005237

 PubMed Web of Science ®Google Scholar

Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353:1209-23

 PubMed Web of Science ®Google Scholar

European Medicines Agency. Xeplion® summary of product characteristics. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002105/WC500103317.pdf. Accessed July 7, 2015

 Google Scholar

Meltzer HY, Lindenmayer JP, Kwentus J. A six month randomized controlled trial of long acting injectable risperidone 50 and 100mg in treatment resistant schizophrenia. Schizophr Res 2014;154:14-22

 PubMed Web of Science ®Google Scholar

Kane J, Eerdekens M, Lindenmayer J-P, et al. Long-acting injectable risperidone: efficacy and safety of the first long-acting atypical antipsychotic. Am J Psychiatry 2003;160:1125-32

 PubMed Web of Science ®Google Scholar

Chue P, Eerdekens M, Augustyns I, et al. Comparative efficacy and safety of long-acting risperidone and risperidone oral tablets. Eur Neuropsychopharmacol 2005;15:111-17

 PubMed Web of Science ®Google Scholar

Eerdekens M, Van Hove I, Remmerie B, et al. Pharmacokinetics and tolerability of long-acting risperidone in schizophrenia. Schizophr Res 2004;70:91-100

 PubMed Web of Science ®Google Scholar

Mehnert A, Diels J. Mehnert A, Diels J. Impact of administration interval on treatment retention with long-acting antipsychotics in schizophrenia. Presented at the Tenth Workshop on Costs and Assessment in Psychiatry -Mental Health Policy and Economics; 25-27 March 2011, Venice, Italy

 Google Scholar

Olivares JM, Peuskens J, Pecenak J, et al. Clinical and resource-use outcomes of risperidone long-acting injection in recent and long-term diagnosed schizophrenia patients: results from a multinational electronic registry. Curr Med Res Opin 2009;25:2197-206

 PubMed Web of Science ®Google Scholar

Bartkó G, Herceg I, Zador G. Clinical symptomatology and compliance in schizophrenia patients. Acta Psychiatr Scand 1988;77:74-6

 PubMed Web of Science ®Google Scholar

Heyscue BE, Levin GM, Merrick JP. Compliance with depot antipsychotic medication by patients attending outpatient clinics. Psychiatr Serv 1998;49:1232-4

 PubMed Web of Science ®Google Scholar

Rittmannsberger H, Pachinger T, Keppelmuller P, et al. Medication adherence among psychotic patients before admission to inpatient treatment. Psychiatr Serv 2004;55:174-9

 PubMed Web of Science ®Google Scholar

Valenstein M, Copeland LA, Owen R, et al. Adherence assessments and the use of depot antipsychotics in patients with schizophrenia. J Clin Psychiatry 2001;62:545-51

 PubMed Web of Science ®Google Scholar

Ascher-Svanum H, Faries D, Zhu B. Medication adherence and long-term functional outcomes in the treatment of schizophrenia in usual care. J Clin Psychiatry 2006;2006:453-60

 Google Scholar

Guo X, Fang M, Zhai J, et al. Effectiveness of maintenance treatments with atypical and typical antipsychotics in stable schizophrenia with early stage: 1-year naturalistic study. Psychopharmacology (Berl) 2011;216:475-84

 PubMed Web of Science ®Google Scholar

Hamilton SH, Revicki DA, Edgell RT, et al. Clinical and economic outcomes of olanzapine compared with haloperidol for schizophrenia: results from a randomised clinical trial. Pharmacoeconomics 1999;15:469-80

 PubMed Web of Science ®Google Scholar

Yu AP, Ben-Hamadi R, Birnbaum HG, et al. Comparing the treatment patterns of patients with schizophrenia treated with olanzapine and quetiapine in the Pennsylvania Medicaid population. Curr Med Res Opin 2009;25:755-64

 PubMed Web of Science ®Google Scholar

Gopal S, Hough D, 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. Int Clin Psychopharmacol 2010;25:247-56

 PubMed Web of Science ®Google Scholar

Csernansky JG, Mahmoud R, Brenner R, et al. A comparison of risperidone and haloperidol for the prevention of relapse in patients with schizophrenia. N Engl J Med 2002;346:16-22

 PubMed Web of Science ®Google Scholar

Rabinowitz J, Lichtenberg P, Kaplan Z, et al. Rehospitalization rates of chronically ill schizophrenic patients discharged on a regimen of risperidone, olanzapine, or conventional antipsychotics. Am J Psychiatry 2001;158:266-9

 PubMed Web of Science ®Google Scholar

Briggs A, Wild D, Lees M. Impact of schizothrenia and schijophrenia treatmeft-related adverse events on qua,ity of mife: direct utimitx elicitation. Health Qual Life Outcomes 2008;6:105

 PubMed Web of Science ®Google Scholar

Cummins C, Stevens A, Kisely S. The use of olanzapine as a first and second choice treatment in schizophrenia. A West Midlands Development and Evaluation Committee Report. Birmingham, UK: Department of Public Health & Epidemiology, University of Birmingham; 1998

 Google Scholar

Lenert LA, Sturley AP, Rapaport MH, et al. Public preferences for health states with schizophrenia and a mapping function to estimate utilities from positive and negative symptom scale scores. Schiz Res 2004;71:155-75

 PubMed Web of Science ®Google Scholar

Oh PI, Lanctôt KL, Mittmann N, et al. Cost-utility of risperidone compared with standard conventional antipsychotics in chronic schizophrenia. J Med Econ 2001;4:137-56

 Google Scholar

Revicki DA, Shakespeare A, Kind P. Preferences for schizophrenia-related health states: a comparison of patients, caregivers and psychiatrists. Int Clin Psychopharmacol 1996;11:101-8

 PubMed Web of Science ®Google Scholar

Ministério da Saúde. Portaria n.° 20/2014, de 29 de Janeiro. Diário da República, 1.a série — N.° 20. http://www.acss.min-saude.pt/Portals/0/DownloadsPublicacoes/Tabelas_Impressos/Portaria%20132_2014.pdf. Accessed June 15, 2015

 Google Scholar

McCabe C, Claxton K, Culyer AJ. The NICE cost-effectiveness threshold: what it is and what that means. Pharmacoeconomics 2008;26:733-44

 PubMed Web of Science ®Google Scholar