Risperidone 24 A Ad Final

Application for Inclusion to the 19th Expert Committee on the
Selection and Use of Essential Medicines:
RISPERIDONE
January 6, 2013
Submitted by:
Jasleen Salwan, Hiwot Woldu, M.D., Anna Rosen, M.D., and Craig L. Katz, M.D.
The Mount Sinai School of Medicine
Program in Global Mental Health
New York, New York, USA
Contact: Craig L. Katz, M.D., 001 212-860-8665, [email protected]
TABLE OF CONTENTS
Page 3
Summary Statement
Page 4
Focal Point Person in WHO
Page 5
Name of the Organizations Consulted
Page 6
International Nonproprietary Name
Page 7
Formulations Proposed for Inclusion
Page 8
International Availability
Page 16
Listing Requested
Page 17
Public Health Relevance
Page 21
Treatment Details
Page 28
Comparative Effectiveness
Page 44
Comparative Safety
Page 55
Comparative Cost and Cost-Effectiveness
Page 66
Regulatory Status
Page 68
Pharmacoepial Standards
Page 69
Text for the WHO Model Formulary
Page 72
APPENDIX- Letters of Support
1. Summary Statement of the Proposal for Inclusion of Risperidone

Risperidone, a benzisoxazole derivative atypical antipsychotic medication, is proposed for inclusion in the WHO Model List
of Essential Medications for treatment of schizophrenia, mania, and autism. To date, the list of essential medications does not
include atypical antipsychotics, which play a critical role in the treatment of psychotic disorders. This application provides a
systematic review of the use, efficacy, safety, availability, and cost-effectiveness of risperidone compared with both typical
and other atypical antipsychotic medications.
In the United States, risperidone is the most commonly reported atypical antipsychotic medication prescribed. It is approved
for use in schizophrenia, mania of bipolar disorder, and irritability and aggression of autism. It is also effectively used in
other instances of psychosis, including schizoaffective disorder, depression with psychotic features, and psychosis secondary
to general medical conditions, including infectious diseases, and may be effective in other conditions such as major
depression, various anxiety disorders including OCD, delirium, dementia and substance abuse disorders. Risperidone is
effective for widespread treatment in children, adolescents, adults, and the elderly.
Evidence shows that risperidone is often more effective in the treatment of psychosis than the most commonly prescribed
typical psychotic medication, haloperidol, which is included in the current list of WHO essential medications with
chlorpromazine and fluphenazine. In multiple studies, risperidone is more likely than haloperidol to improve scores in the
Positive and Negative Syndrome Scale (PANSS), reduce relapse rates of psychosis, improve cognitive function in
schizophrenia, and improve manic symptoms in bipolar disorder.
Because risperidone has a different side effect profile than typical antipsychotic medications like haloperidol, it provides an
essential alternative treatment for those people who cannot tolerate the older medications. Much psychosis may go undertreated because of discontinuation of typical antipsychotics due to side effects. Risperidone has fewer reported
extrapyramidal side effects and akathisia than typical antipsychotics, and studies show less mortality associated with
risperidone than with haloperidol. Although it is associated with metabolic disturbances, the overall side effect profile of
risperidone is encouraging when compared not only with typical antipsychotic medications, but with other medications in its
own class. Studies show less weight gain and onset of diabetes than olanzapine and less cholesterol elevation than other
atypical antipsychotics.
Risperidone represents a class of medication, atypical antipsychotics, that should be included in the essential medications list.
Within its class, the choice of risperidone offers a uniquely good balance of efficacy, safety, minimal monitoring, and costeffectiveness. Risperidone is an important treatment option that can reduce the global disease burden of psychosis, mania,
and autism.
2. Focal Point Person(s) in the World Health Organization
Dr. K Weerasuriya, Medical Officer

Medicines Access and Rational Use (MAR)
Essential Medicines and Health Products (EMP)
3. Name of the Organization(s) Consulted and Supporting the Application

-
Ministry of Health, Belize

Ministry of Health and the Environment, Saint Vincent/Grenadines
Sumandeep Vidyapeeth University, Vadadora (Gujarat), India
SEE APPENDIX FOR LETTERS OF SUPPORT
4.
International Nonproprietary Name (INN, generic name) of the medicine
risperidone
5. Formulations of Risperidone Proposed for Inclusion
Core List
Tablets 0.25 mg, 1 mg, 2 mg
Complementary List
Oral Solution: 1 mg/mL 30 mL bottle

Risperidone long-acting depot microspheres formulation for deep intramuscular administration 25 mg vial/kit
6. International Availability
Name
Rispa
Manufacturer
Sigma, Austral.
Country
Australia
Form
(Form Not Given)
Risperdal
Janssen-Cilag, Austral.
Australia
(Form Not Given)
Rixadone
Alphapharm, Austral.
Australia
(Form Not Given)
Aleptan
Lannacher, Austria
Austria
(Form Not Given)
Belivon (FM)
Organon, Austria
Austria
(Form Not Given)
Risperdal
Janssen-Cilag, Austria
Austria
(Form Not Given)
Rispolin (FM)
Janssen-Cilag, Austria
Austria
(Form Not Given)
Risperdal
Janssen-Cilag, Belg.
Belgium
(Form Not Given)
Torendo
HCS, Neth.
Belgium
(Form Not Given)
Esquidon
Merck, Braz.
Brazil
(Form Not Given)
Respidon
Torrent, Braz.
Brazil
(Form Not Given)
Ripevil
GSK, Braz.
Brazil
(Form Not Given)
Risleptic
Arrow, Braz.
Brazil
(Form Not Given)
Risperdal
Janssen-Cilag, Braz.
Brazil
(Form Not Given)
Risperix
Aspen, Braz.
Brazil
(Form Not Given)
Riss (DI)
Eurofarma, Braz.
Brazil
(Form Not Given)
Viverdal
Uniao Quimica, Braz.
Brazil
(Form Not Given)
Zargus
Biosintetica, Braz.
Brazil
(Form Not Given)
Risperdal
Janssen-Ortho
Canada
0.5 MG Tablet; 0.25 MG Tablet; 1
Risperdal M-Tab
Janssen-Ortho
Canada
0.5 MG disintegrating tablet; 1 M
Dagotil
Royal, Chile
Chile
(Form Not Given)
Goval
Pharma Investi, Chile
Chile
(Form Not Given)
Radigen
Medipharm, Chile
Chile
(Form Not Given)
Risperdal
Janssen-Cilag, Chile
Chile
(Form Not Given)
Spiron
Andromaco, Chile
Chile
(Form Not Given)
Apo-Risper
Apotex, Cz.
(Form Not Given)
Medorisper
Medochemie, Cz.
Ridoner
ICN, Cz.
Rileptid
Egis, Cz.
Risepro
Valeant, Cz.
Rispen
Zentiva, Cz.
Rispera
Teva, Cz.
Czech
Republic
Czech
Republic
Czech
Republic
Czech
Republic
Czech
Republic
Czech
Republic
Czech
Republic
(Form Not Given)

(Form Not Given)
(Form Not Given)
(Form Not Given)
(Form Not Given)
(Form Not Given)
Risperdal
Janssen-Cilag, Cz.
Risperigamma (FM)
Worwag, Cz.
Risperstad (FM)
Stada, Cz.
Rispolux
Sandoz, Cz.
Risset (FM)
Pliva, Cz.
Rorendo
KRKA, Cz.
Unispera (FM)
Belupo, Cz.
Ripexal
(Form Not Given)
Hexal, Denm.
Czech
Republic
Czech
Republic
Czech
Republic
Czech
Republic
Czech
Republic
Czech
Republic
Czech
Republic
Denmark
Risperanne
Sandoz, Denm.
Denmark
(Form Not Given)
Risperdal
Janssen-Cilag, Denm.
Denmark
(Form Not Given)
Rispolept
Abacus, Denm.
Denmark
(Form Not Given)
Rispazin
Leiras, Fin.
Finland
(Form Not Given)
Risperdal
Janssen-Cilag, Fin.
Finland
(Form Not Given)
Risperdal
Janssen-Cilag, Fr.
France
(Form Not Given)
Risperdalconsta
Janssen-Cilag, Fr.
France
(Form Not Given)
Risperdaloro
Janssen-Cilag, Fr.
France
(Form Not Given)
Risocon (DI)
Mibe, Ger.
Germany
(Form Not Given)
Rispenon
Tiefenbacher, Neth.
Germany
(Form Not Given)
Rispe-Q (FM)
Juta, Ger.
Germany
(Form Not Given)
Risperdal
Janssen
Germany
Risperdal
Janssen-Cilag, Ger.
Germany
(Form Not Given)
Risperdoc (FM)
Docpharm, Ger.
Germany
(Form Not Given)
Risperigamma
Worwag, Ger.
Germany
(Form Not Given)
Rispimed
Regiomedica, Neth.
Germany
(Form Not Given)
Rispimed (FM)
Regiomedica, Cz.
Germany
(Form Not Given)
Rispimedica (FM)
Basics, Neth.
Germany
(Form Not Given)
Adovia
Pharmacypria, Gr.
Greece
(Form Not Given)
Axelabron
Ferakon, Gr.
Greece
(Form Not Given)
Belasperdal-S
SJA, Gr.
Greece
(Form Not Given)
Capulton
Farmex, Gr.
Greece
(Form Not Given)
Depolan (DI)
Gap, Gr.
Greece
(Form Not Given)
Depredon
Kleva, Gr.
Greece
(Form Not Given)
Dixine
Lavipharm, Gr.
Greece
(Form Not Given)
Evitrat
Unipharma, Gr.
Greece
(Form Not Given)
Helposper
Help, Gr.
Greece
(Form Not Given)
Isipredon
Heremco, Gr.
Greece
(Form Not Given)
(Form Not Given)

(Form Not Given)
(Form Not Given)
(Form Not Given)
(Form Not Given)
(Form Not Given)
(Form Not Given)
1 MG coated tablet; 2 MG coated
Lassen
Farmanic, Gr.
Greece
(Form Not Given)
Leterzin
Panagiotis, Gr.
Greece
(Form Not Given)
Lucipral
Balu, Gr.
Greece
(Form Not Given)
Muistin
Verisfield, Gr.
Greece
(Form Not Given)
Nerve
Med-One, Gr.
Greece
(Form Not Given)
Novoris
Novofarm (Novofarm), Gr.
Greece
(Form Not Given)
Orotral
SM, Gr.
Greece
(Form Not Given)
Preridon
Alapis, Gr.
Greece
(Form Not Given)
Psychordal
Viofar, Gr.
Greece
(Form Not Given)
Ribex (DI)
Vianex (Vianex), Gr.
Greece
(Form Not Given)
Rifocus
Gerolymatos, Gr.
Greece
(Form Not Given)
Rigenin (FM)
Labochem, Cz.
Greece
(Form Not Given)
Ripepral
Verisfield, Gr.
Greece
(Form Not Given)
Ripetomar (FM)
Labochem, Cz.
Greece
(Form Not Given)
Risenar
Minerva (Minerva), Gr.
Greece
(Form Not Given)
Risgal
Galenus, Gr.
Greece
(Form Not Given)
Risidral
Pharmanel, Gr.
Greece
(Form Not Given)
Rispadim (FM)
Labochem, Cz.
Greece
(Form Not Given)
Rispalm
Polychronus, Gr.
Greece
(Form Not Given)
Rispedep (FM)
Labochem, Cz.
Greece
(Form Not Given)
Rispedolet (FM)
Labochem, Cz.
Greece
(Form Not Given)
Rispedospes (FM)
Labochem, Cz.
Greece
(Form Not Given)
Rispefar
Specifar, Gr.
Greece
(Form Not Given)
Rispelen
Elpen (Elpen), Gr.
Greece
(Form Not Given)
Rispemar (FM)
Labochem, Cz.
Greece
(Form Not Given)
Rispen
Gabriel, Gr.
Greece
(Form Not Given)
Rispenet
Faran, Gr.
Greece
(Form Not Given)
Risperascol
Alet, Gr.
Greece
(Form Not Given)
Risperdal
Janssen-Cilag, Gr.
Greece
(Form Not Given)
Risperinin (FM)
Labochem, Cz.
Greece
(Form Not Given)
Risperit (FM)
Labochem, Cz.
Greece
(Form Not Given)
Risperom
Integris, Gr.
Greece
(Form Not Given)
Risperoprol
Proel, Gr.
Greece
(Form Not Given)
Rispersan
Santa, Gr.
Greece
(Form Not Given)
Rispogen
Genepharm, Gr.
Greece
(Form Not Given)
Sperelax
Biospray, Gr.
Greece
(Form Not Given)
Wisperdon
Proton, Gr.
Greece
(Form Not Given)
Zafitral
Rafarm, Gr.
Greece
(Form Not Given)
Rileptid
Egis, Hong Kong
Hong Kong
(Form Not Given)
10
Risperdal
Janssen, Hong Kong
Hong Kong
(Form Not Given)
Risperigamma
Worwag, Hong Kong
Hong Kong
(Form Not Given)
Hunperdal
Gedeon Richter, Hung.
Hungary
(Form Not Given)
Perdox
Vera, Hung.
Hungary
(Form Not Given)
Rileptid
Egis, Hung.
Hungary
(Form Not Given)
Ripedon
Solamed, Hung.
Hungary
(Form Not Given)
Rispe
Ratiopharm, Hung.
Hungary
(Form Not Given)
Risperdal
Janssen-Cilag, Hung.
Hungary
(Form Not Given)
Rispolux
Sandoz, Hung.
Hungary
(Form Not Given)
Rispons
Actavis, Hung.
Hungary
(Form Not Given)
Ronkal (FM)
Zentiva, Hung.
Hungary
(Form Not Given)
Rosipin
Medico Uno, Hung.
Hungary
(Form Not Given)
Torendo
KRKA, Hung.
Hungary
(Form Not Given)
Ziperid
Valeant, Hung.
Hungary
(Form Not Given)
Neripros
Pharos, Indon.
Indonesia
(Form Not Given)
Nodiril
Actavis, Indon.
Indonesia
(Form Not Given)
Persidal
Mersifarma, Indon.
Indonesia
(Form Not Given)
Risperdal
Alkermes, Indon.
Indonesia
(Form Not Given)
Rizodal
Guardian, Indon.
Indonesia
(Form Not Given)
Zofredal
Kalbe, Indon.
Indonesia
(Form Not Given)
Perdamel
Clonmel, Irl.
Ireland
(Form Not Given)
Resdal (FM)
Niche, Irl.
Ireland
(Form Not Given)
Rispal
Pinewood, Irl.
Ireland
(Form Not Given)
Rispatal
Chanelle, Irl.
Ireland
(Form Not Given)
Risperdal
Janssen-Cilag, Irl.
Ireland
(Form Not Given)
Risperger
Gerard, Irl.
Ireland
(Form Not Given)
Rispone
Rowex, Irl.
Ireland
(Form Not Given)
Risperdal
Janssen-Cilag, Israel
Israel
(Form Not Given)
Risperidex
Dexcel, Israel
Israel
(Form Not Given)
Rispond
Trima, Israel
Israel
(Form Not Given)
Speridone
Tedec Meiji, Israel
Israel
(Form Not Given)
Belivon
JC Healthcare, Ital.
Italy
(Form Not Given)
Risperdal
Janssen-Cilag, Ital.
Italy
(Form Not Given)
Risperdal
Janssen, Jpn
Japan
(Form Not Given)
Risperdal
Janssen-Cilag, Malaysia
Malaysia
(Form Not Given)
Rozidal
Ranbaxy, Malaysia
Malaysia
(Form Not Given)
Limbik
Psicofarma, Mex.
Mexico
(Form Not Given)
Reskizof
Pisa, Mex.
Mexico
(Form Not Given)
Risperdal
Janssen-Cilag, Mex.
Mexico
(Form Not Given)
11
Rispolux
Sandoz, Mex.
Mexico
(Form Not Given)
Silderec
Probiomed, Mex.
Mexico
(Form Not Given)
Upmotev
Teva, Mex.
Mexico
(Form Not Given)
Belivon (FM)
Janssen-Cilag, Neth.
Netherlands
(Form Not Given)
Risperdal
Janssen-Cilag, Neth.
Netherlands
(Form Not Given)
Ridal
Douglas, NZ
New Zealand
(Form Not Given)
Risperdal
Janssen-Cilag, NZ
New Zealand
(Form Not Given)
Risperon
Mylan, NZ
New Zealand
(Form Not Given)
Risperdal
Janssen-Cilag, Norw.
Norway
(Form Not Given)
Aspidon
Torrent, Philipp.
Philippines
(Form Not Given)
Renuvie
Medichem, Philipp.
Philippines
(Form Not Given)
Rileptid
Egis, Philipp.
Philippines
(Form Not Given)
Risdin
MedChoice, Philipp.
Philippines
(Form Not Given)
Rispedin
Shine, Philipp.
Philippines
(Form Not Given)
Risperdal
Janssen, Philipp.
Philippines
(Form Not Given)
Rispond
Brown & Burk, Philipp.
Philippines
(Form Not Given)
Apo-Risperid
Apotex, Pol.
Poland
(Form Not Given)
Disaperid
Biogened, Pol.
Poland
(Form Not Given)
Doresol
Jelfa, Pol.
Poland
(Form Not Given)
Galperinon
Galena, Pol.
Poland
(Form Not Given)
Lioxam (FM)
Grunenthal, Pol.
Poland
(Form Not Given)
Mepharis (FM)
Mepha, Pol.
Poland
(Form Not Given)
Nodir
Polfarmex, Pol.
Poland
(Form Not Given)
Orizon
Orion, Pol.
Poland
(Form Not Given)
Ranperidon
Ranbaxy, Pol.
Poland
(Form Not Given)
Rispen
Zentiva, Pol.
Poland
(Form Not Given)
Risperatio (FM)
Ratiopharm, Pol.
Poland
(Form Not Given)
Risperiwin (FM)
Winthrop, Pol.
Poland
(Form Not Given)
Risperon
Lek-Am, Pol.
Poland
(Form Not Given)
Rispofren (FM)
Biofarm, Pol.
Poland
(Form Not Given)
Rispolept
Janssen-Cilag, Pol.
Poland
(Form Not Given)
Rispolux
Sandoz, Pol.
Poland
(Form Not Given)
Risset
Farmacom, Pol.
Poland
(Form Not Given)
Ryspolit
Polpharma, Pol.
Poland
(Form Not Given)
Speridan
Actavis, Pol.
Poland
(Form Not Given)
Torendo
KRKA, Pol.
Poland
(Form Not Given)
Ziperid
ICN, Pol.
Poland
(Form Not Given)
Belivon (FM)
Janssen-Cilag, Port.
Portugal
(Form Not Given)
Itraxel
Normal, Port.
Portugal
(Form Not Given)
12
Lergitec
Atral, Port.
Portugal
(Form Not Given)
Lotin (DI)
Pentafarma, Port.
Portugal
(Form Not Given)
Perdin
Merck, Port.
Portugal
(Form Not Given)
Ripax (DI)
KRKA, Port.
Portugal
(Form Not Given)
Risperdal
Janssen, Port.
Portugal
(Form Not Given)
Smissen (FM)
Cinfa, Port.
Portugal
(Form Not Given)
Zoridal
Decomed, Port.
Portugal
(Form Not Given)
Ridal
Douglas, Singapore
Singapore
(Form Not Given)
Risperdal
Janssen-Cilag, Singapore
Singapore
(Form Not Given)
Perizal
Specpharm, S.Afr.
South Africa
(Form Not Given)
Risperdal
Janssen-Cilag, S.Afr.
South Africa
(Form Not Given)
Risperlet
Janssen-Cilag, S.Afr.
South Africa
(Form Not Given)
Risponz
Zydus, S.Afr.
South Africa
(Form Not Given)
Zoxadon
Pharma Dynamics, S.Afr.
South Africa
(Form Not Given)
Arketin
Qualigen, Spain
Spain
(Form Not Given)
Atornil (FM)
Ferrer, Spain
Spain
(Form Not Given)
Diaforin
Brainpharma, Spain
Spain
(Form Not Given)
Neclav (DI)
Farmalider, Port.
Spain
(Form Not Given)
Risfarmal (FM)
Brainpharma, Spain
Spain
(Form Not Given)
Rispemylan
Mylan, Spain
Spain
(Form Not Given)
Risperdal
Janssen-Cilag, Spain
Spain
(Form Not Given)
Risperdal
Janssen-Cilag, Swed.
Sweden
(Form Not Given)
Risperdal
Janssen-Cilag, Switz.
Switzerland
(Form Not Given)
Risperdal
Janssen-Cilag, Thai.
Thailand
(Form Not Given)
Nodirep
Bio-Gen, Turk.
Turkey
(Form Not Given)
Perilife
Frik, Turk.
Turkey
(Form Not Given)
Restela
Deva, Turk.
Turkey
(Form Not Given)
Ricus
Biofarma, Turk.
Turkey
(Form Not Given); (Form Not G
Ripesil
Ali, Turk.
Turkey
(Form Not Given)
Risperdal
Janssen-Cilag, Turk.
Turkey
(Form Not Given)
Rixol
Bilim, Turk.
Turkey
(Form Not Given)
Rixper
Fako, Turk.
Turkey
(Form Not Given)
Neirispin
Zdorovje, Ukr.
Ukraine
(Form Not Given)
Ridonex
Gedeon Richter, Ukr.
Ukraine
(Form Not Given)
Rileptid (FM)
Egis, Ukr.
Ukraine
(Form Not Given)
Risperon
Interfarma, Ukr.
Ukraine
(Form Not Given)
Risset
Pliva, Ukr.
Ukraine
(Form Not Given)
Risperdal
Janssen-Cilag, UK
United
Kingdom
(Form Not Given)
13
Rispeva
Teva, Irl.
Risperdal
Janssen Pharmaceuticals
Risperdal
Janssen, USA
Risperdal Consta
Risperdal M-Tab
Risperidone
Amneal Pharmaceuticals
Risperidone
Apotex
Risperidone
Apotex (Canada)
Risperidone
Aurobindo Pharma
Risperidone
Aurobindo Pharma (India)
Risperidone
Aurolife Pharma
Risperidone
Barr Laboratories
Risperidone
BayPharma
Risperidone
Bio-Pharm
Risperidone
Dr Reddy's Laboratories
Risperidone
Gen-Source RX
Risperidone
Risperidone
Jubilant Cadista
Pharmaceuticals
Mylan Pharmaceuticals
Risperidone
Par Pharmaceutical
Risperidone
Patriot Pharmaceuticals
Risperidone
Qualitest Pharmaceuticals
Risperidone
Roxane Laboratories
Risperidone
Sandoz
Risperidone
Teva Pharmaceuticals
Risperidone
Torrent Pharma
Risperidone
Watson Laboratories
Risperidone
Wockhardt (India)
14
United
Kingdom
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
United
States
(Form Not Given)

(Form Not Given)
12.5 MG Powder for Suspension

0.5 MG Tablet, Disintegrating; 1
1 MG/ML Solution

1 MG/ML Solution
1 MG/ML Solution

1 MG/ML Solution
1 MG/ML Solution

0.5 MG Tablet; 0.5 MG Tablet, D

Tablet, Disintegrating
0.5 MG Tablet, Disintegrating; 0.

1 MG/ML Solution

1 MG/ML Solution
Risperidone
Wockhardt USA
Risperidone
Zydus Pharmaceuticals
Risperidone M-TAB
Patriot Pharmaceuticals
Risperidone ODT
Dr Reddy's Laboratories
Risperidone ODT
Zydus Pharmaceuticals
Ridal
Giempi, Venez.
United
States
United
States
United
States
United
States
United
States
Venezuela
Risperdal
Janssen-Cilag, Venez.
Venezuela
(Form Not Given)
Risperid
Roemmers, Venez.
Venezuela
(Form Not Given)
Sources
The above information was obtained from the following international drug name databases:
Lexi-Comp ONLINE
Micromedex
15

(Form Not Given)
7. Listing for risperidone is requested as an individual medication.
16
8. Information Supporting the Public Health Relevance of Risperidone

Antipsychotics have been shown to be efficacious in treating a range of mental illnesses, including schizophrenia and bipolar
disorder in both adults and youth (Leucht, Heres, Kissling, & Davis, 2011) (Malhi, Adams, Cahill, Dodd, & Berk, 2009) (Correll,
Kratochvil, & March, 2011) (Pfeifer, Kowatch, & DelBello, 2010), major depressive disorder in adults (Pae, Forbes, & Patkar,
2011) (Anderson et al., 2008) and Tourette syndrome and irritability associated with autism disorders in youth (Pfeifer et al.,
2010). At $16.1 billion a year, antipsychotics comprise the fifth-largest share of the U.S. prescription market by spending (IMS,
2012), and its market is growing. In 2008, antipsychotics were used for specific indications in 14.3 million outpatient visits in
the U.S., up from 6.2 million in 1995 (Alexander, Gallagher, Mascola, Moloney, & Stafford, 2011).
Atypical, or second-generation, antipsychotics have traditionally been distinguished from typical (first-generation)
antipsychotics based on their comparatively minimal association with extra-pyramidal symptoms (Farah, 2005) (Markowitz,
Brown, & Moore, 1999). However, at present, the medical community has not reached a consensus on the definition of
atypicality (Farah, 2005). Among the various definitions that have emerged, salient characteristics include efficacy in treating
both the positive and negative symptoms of schizophrenia (Farah, 2005) (B J Kinon & Lieberman, 1996), efficacy in treating
schizophrenic patients unresponsive to traditional antipsychotics (Goldstein, 2000), and reduced ability to cause prolactin
elevation (Goldstein, 2000).
Risperidone is a benzisoxazole derivative atypical antipsychotic indicated for treatment of schizophrenia, bipolar mania, and
irritability associated with autistic disorder (Pharmaceuticals, 2012). It is both effective and widely prescribed (Farah, 2005).
Among the second-generation antipsychotics, risperidone conforms the least to the atypicality criteria (Farah, 2005). EPS and
tardive dyskinesia have been reported in the literature (Rosebush & Mazurek, 1999) (Bassitt & de Souza Lobo Garcia, 2000), as
has persistent elevation of prolactin levels relative to other atypical (Bruce J Kinon, Gilmore, Liu, & Halbreich, 2003). That said,
other research has shown risperidone to reduce the risks of EPS relative to haloperidol (Schillevoort, Boer, Herings, & Roos,
2001).
The mental disorders that risperidone is approved to treathave a high global disease burden. As of 2000, 12% of the worlds
disability-adjusted life years, or years of life lost due to disability, illness, or premature death, was attributable to mental and
neurological disorders; this figure is projected to increase to 15% by 2020 (World Health Organization, 2000). Schizophrenia
alone accounts for 2.6% of total DALYs in people aged 15-44 and is the 8th leading cause of DALYs for that age group; bipolar
affective disorder, the 9th leading cause, accounts for 2.5% (World Health Organization, 2000). While autism is not among the
leading causes of worldwide DALYs listed by the WHO, it has been estimated to have a prevalence rate of 0.64% in Europe
within the age range of birth through early adulthood (Wittchen et al., 2011).
In developing countries, between 76% and 85% of people with serious mental illness receive no services (The WHO World
Mental Health Survey Consortium, 2004). Even in the developed world, approximately half of people with severe mental
disorders go untreated (Wang et al., 2007).
In the U.S., risperidone is among the most commonly reported atypical antipsychotic drugs. In 2008, it was used for specific
indications in over 12 million outpatient visits (Alexander et al., 2011). In a prospective, observational review of prescription
practices for schizophrenia in 27 countries spanning 4 continents (N=5836), risperidone was among the most frequently
prescribed antipsychotic monotherapies, second only to olanzapine (Dossenbach et al., 2008). Similarly, in one study of firsthospitalized patients with bipolar disorder in the Cincinnati, Ohio area of the United States (n=58), risperidone and olanzapine
were the most frequently prescribed atypical antipsychotics (Fleck, Hendricks, DelBello, & Strakowski, 2002). In the U.S., 71%
of bipolar disorder patients are treated with atypical antipsychotics (Ventimiglia, Kalali, & McIntyre, 2009).
17
The target population for risperidone includes children and adolescents as well as adults. From 2003-2004, risperidone
was the most frequently prescribed antipsychotic agent in the U.S. outpatient setting for patients under 20 years of age (Aparasu
& Bhatara, 2007). Risperidone accounted for 43.81% of outpatient visits involving antipsychotics in that age group, while
atypical agents overall comprised 99% of children and adolescent outpatient visits involving antipsychotics (Aparasu & Bhatara,
2007). More broadly, atypical antipsychotics are increasingly being used to treat diverse patient groups, including elderly
nursing home residents as well as both publicly and privately insured children and adolescents (Crystal, Olfson, Huang, Pincus,
& Gerhard, 2009).
We evaluate the appropriateness of current prescription practices of risperidone in the Comparative Effectiveness
section, drawing comparisons to typical and other atypical antipsychotics. Overall, we find risperidone to be advantageous in
treating schizophrenia, mania, and autism.
References
Alexander, G. C., Gallagher, S. A., Mascola, A., Moloney, R. M., & Stafford, R. S. (2011). Increasing off-label use of
antipsychotic medications in the United States , 1995 2008. Pharmacoepidemiology and drug safety, 20, 177-184.
doi:10.1002/pds
Anderson, I. M., Ferrier, I. N., Baldwin, R. C., Cowen, P. J., Howard, L., Lewis, G., Matthews, K., et al. (2008). Evidence-based
guidelines for treating depressive disorders with antidepressants: a revision of the 2000 British Association for
Psychopharmacology guidelines. Journal of psychopharmacology (Oxford, England) (Vol. 22, pp. 343-96).
doi:10.1177/0269881107088441
Aparasu, R. R., & Bhatara, V. (2007). Patterns and determinants of antipsychotic prescribing in children and adolescents, 20032004. Current medical research and opinion, 23(1), 49-56. doi:10.1185/030079906X158075
Bassitt, D. P., & de Souza Lobo Garcia, L. (2000). Risperidone-induced tardive dyskinesia. Pharmacopsychiatry, 33(4), 155-6.
Correll, C. U., Kratochvil, C. J., & March, J. S. (2011). Developments in pediatric psychopharmacology: focus on stimulants,
antidepressants, and antipsychotics. The Journal of clinical psychiatry, 72(5), 655-70. doi:10.4088/JCP.11r07064
Crystal, S., Olfson, M., Huang, C., Pincus, H., & Gerhard, T. (2009). Broadened use of atypical antipsychotics: safety,
effectiveness, and policy challenges. Health affairs (Project Hope), 28(5), w770-81. doi:10.1377/hlthaff.28.5.w770
Dossenbach, M., Pecenak, J., Szulc, A., Irimia, V., Anders, M., Logozar-Perkovic, D., Peciukaitiene, D., et al. (2008). Long-term
antipsychotic monotherapy for schizophrenia: disease burden and comparative outcomes for patients treated with
olanzapine, quetiapine, risperidone, or haloperidol monotherapy in a pan-continental observational study. The Journal of
clinical psychiatry, 69(12), 1901-15.
Farah, A. (2005). Atypicality of atypical antipsychotics. Primary care companion to the Journal of clinical psychiatry, 7(6), 26874.
18
Fleck, D. E., Hendricks, W. L., DelBello, M. P., & Strakowski, S. M. (2002). Differential prescription of maintenance
antipsychotics to African American and white patients with new-onset bipolar disorder. The Journal of clinical psychiatry,
63(8), 658-64.
Goldstein, J. M. (2000). The new generation of antipsychotic drugs: how atypical are they? The international journal of
neuropsychopharmacology, 3(4), 339-349.
IMS. (2012). Top Therapeutic Classes by U.S. Spending. 2010 U.S. Prescription Sales Information. Retrieved August 13, 2012,
from http://www.imshealth.com/deployedfiles/ims/Global/Content/Corporate/Press Room/Top-line Market Data/2010 Topline Market Data/2010_Top_Therapeutic_Classes_by_Sales.pdf
Jablensky, A. (2000). Epidemiology of schizophrenia: the global burden of disease and disability. European archives of
psychiatry and clinical neuroscience, 250(6), 274-85.
Kinon, B J, & Lieberman, J. a. (1996). Mechanisms of action of atypical antipsychotic drugs: a critical analysis.
Psychopharmacology, 124(1-2), 2-34.
Kinon, Bruce J, Gilmore, J. a, Liu, H., & Halbreich, U. M. (2003). Hyperprolactinemia in response to antipsychotic drugs:
characterization across comparative clinical trials. Psychoneuroendocrinology, 28(Suppl 2), 69-82. doi:10.1016/S03064530(02)00128-2
Leucht, S., Heres, S., Kissling, W., & Davis, J. M. (2011). Evidence-based pharmacotherapy of schizophrenia. The international
journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale
Neuropsychopharmacologicum (CINP), 14(2), 269-84. doi:10.1017/S1461145710001380
Malhi, G. S., Adams, D., Cahill, C. M., Dodd, S., & Berk, M. (2009). The management of individuals with bipolar disorder: a
review of the evidence and its integration into clinical practice. Drugs, 69(15), 2063-101. doi:10.2165/11318850000000000-00000
Markowitz, J. S., Brown, C. S., & Moore, T. R. (1999). Atypical antipsychotics. Part I: Pharmacology, pharmacokinetics, and
efficacy. The Annals of pharmacotherapy, 33(1), 73-85.
Pae, C.-U., Forbes, A., & Patkar, A. a. (2011). Aripiprazole as adjunctive therapy for patients with major depressive disorder:
overview and implications of clinical trial data. CNS drugs, 25(2), 109-27. doi:10.2165/11538980-000000000-00000
Pfeifer, J. C., Kowatch, R. a, & DelBello, M. P. (2010). Pharmacotherapy of bipolar disorder in children and adolescents: recent
progress. CNS drugs, 24(7), 575-93. doi:10.2165/11533110-000000000-00000
Pharmaceuticals, J. (2012). Full U.S. Prescribing Information. Risperidal.com. Retrieved August 15, 2012, from
http://www.risperdal.com/prescribing.html
Rosebush, P. I., & Mazurek, M. F. (1999). Neurologic side effects in neuroleptic-nave patients treated with haloperidol or
risperidone. Neurology, 52(4), 782-785.
19
Schillevoort, I., Boer, A. D., Herings, R. M. C., & Roos, R. A. C. (2001). Risk of Extrapyramidal Syndromes with Haloperidol,
Risperidone, and Olanzapine. The Annals of pharmacotherapy, 35(12), 1517-1522.
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Disorders in the World Health Organization World Mental Health Surveys. JAMA, 291(21), 2581-2590.
Ventimiglia, J., Kalali, A. H., & McIntyre, R. (2009). Treatment of bipolar disorder. Psychiatry, 6(10), 12-15.
doi:10.3928/00904481-20120625-02
Wang, P. S., Aguilar-Gaxiola, S., Alonso, J., Angermeyer, M. C., Borges, G., Bromet, E. J., Bruffaerts, R., et al. (2007). Use of
mental health services for anxiety, mood, and substance disorders in 17 countries in the WHO world mental health surveys.
Lancet, 370(9590), 841-50. doi:10.1016/S0140-6736(07)61414-7
Wittchen, H. U., Jacobi, F., Rehm, J., Gustavsson, a, Svensson, M., Jnsson, B., Olesen, J., et al. (2011). The size and burden of
mental disorders and other disorders of the brain in Europe 2010. European neuropsychopharmacology: the journal of the
European College of Neuropsychopharmacology, 21(9), 655-79. Elsevier B.V. doi:10.1016/j.euroneuro.2011.07.018
World Health Organization. (2000). Burden of Mental and Behavioral Disorders. The world health report 2001 - Mental Health:
New Understanding, New Hope (pp. 19-45). Geneva.
20
9. Treatment Details for Risperidone

9.1 Dosing and Duration
Risperidone Dosage Forms (Stahl, 2011), (FDA, 2012)
Tablets 0.25 mg, 0.5 mg, 1 mg, 2 mg, 3 mg, 4 mg, 6mg
Orally disintegrating tablets 0.5 mg, 1 mg, 2 mg
Risperidone long-acting depot microspheres formulation for deep intramuscular administration 25 mg vial/kit, 37.5 mg
vial/kit, 50 mg vial/kit
Usual Dosage Range (Stahl, 2011)

Acute psychosis and bipolar disorder: 2 8 mg/day orally
Children and elderly: 0.52.0 mg/day orally
Long-acting depot: 2550mg every 2 weeks intramuscularly
Dosage Guidelines for Oral Formulations of Approved Uses of Risperidone
Risperidone has US Food and Drug Administration (FDA)-approved uses for schizophrenia, mania associated with bipolar
disorder, and irritability associated with autistic disorder.
Unless otherwise noted, oral risperidone may be administered on a once daily or twice daily schedule.
Initial Dose
Schizophrenia/Psychosis
in
non-emergent
settings- Adults
SchizophreniaAdolescents
Bipolar Mania- Adults
Titration
Target Dose
1mg/day in 2 1mg daily

divided doses
4-8 mg daily
0.5mg/day
3mg/day
1-6mg/day
1-6mg/day
1-6mg/day
2-3mg/day
Bipolar
Mania
in 0.5mg/day
children/adolescents
Irritability
associated 0.25mg/day
with autistic disorder
(<20kg)
0.5mg/day
(20 kg)
0.5-1mg
daily
1mg daily
0.5 1mg 2.5mg/day

daily
0.25-0.5mg
0.5 mg /day
at 2 weeks (<20 kg)
1 mg /day
(20 kg)
21
Effective
Dose
4-16
mg
/day
0.56mg/day
0.5-3mg
/day
(Stahl, 2011), (FDA, 2012)
Similar to the FDA, the European Medicines Agency (EMA), the Medicines and Healthcare Products Regulatory Agency
(MHRA) of the United Kingdom, and the Australian Therapeutic Goods Administration (TGA), all have approved uses
for risperidone in schizophrenia, mania associated with bipolar disorder, and behavioral disturbance in children and
adolescents associated with autism and conduct disorder. The recommended doses and age ranges are similar to the FDA
guidelines listed in the above table. The EMA, MHRA and TGA also approve the short-term use of risperidone in
treating persistent aggression in patients with moderate to severe Alzheimers dementia when there is risk of harm to self
or others and the aggression is refractory to non-pharmacological approaches (MHRA, 2011 & 2006), (EMA, 2008),
(TGA, 2010, 05, 04, 02, 1999).
Dosage Guidelines for Long-Acting Formulation of Risperidone

(Stahl, 2011)
Long acting risperidone is not recommended for patients that have not already demonstrated tolerability to oral risperidone.
Long-acting
Risperidone
Initial Dose
Titration
25mg
At >4weeks
intramuscular
gluteal injection
every 2 weeks.*
Target Dose
Effective Dose
25-50mg
IM 25-50mg IM
every 2 weeks
every 2 weeks
* Onset of action when initiating long-acting risperidone may be delayed for 2 weeks. If a patient is on an oral antipsychotic at
initiation of long-acting risperidone, oral antipsychotic should be continued for 3 more weeks. If a patient is not on oral
antipsychotics at initiation of long-acting risperidone formulation, oral antipsychotic medication should be given with the first
injection of the long-acting risperidone and continued for 3 weeks thereafter.
For missed long-acting risperidone injections 2 or more weeks late (i.e., 28 or more days following last injection), antipsychotic
coverage may be needed with oral administration for 3 weeks while reinitiating injections
The Australian Therapeutic Goods Administration (TGA), European Medicines Agency (EMA), and Medicines and
Healthcare Products Regulatory Agency (MHRA) all approve the use of long-acting risperidone in schizophrenia and
other psychotic disorders with dosing similar to those of the FDA outlined in the table above (TGA, 2010), (EMA, 2008)
(MHRA, 2008)
Special Populations
(Stahl, 2011), (FDA, 2012)
Pediatric Use of Risperidone:
22
Schizophrenia: safety and effectiveness not established for less than 13 years of age
Bipolar Mania: safety and effectiveness not established for less than 10 years of age
Autistic Disorder: safety and effectiveness not established for less than 5 years of age.
Children and elderly may need to have oral twice daily dosing during initiation and titration of risperidone and then can switch to
oral once daily when maintenance dose is reached. Dosage increases in this patient population should be in increments of no
more than 0.5mg twice daily.
Children and the elderly may require twice daily dosing during initiation and titration of risperidone dosing and can then be
switched to oral once daily dosing once maintenance dose is reached.
Pregnancy:
Risperidone is in pregnancy risk category C (there are no controlled studies in humans, but some animal studies show adverse
effects].
Patients on risperidone should be counseled about the risks and benefits of breastfeeding.
Pharmacokinetics
(Stahl, 2011), (FDA, 2012)
Risperidone is metabolized by CYP450 2D6 and has active metabolites.
- Parent drug of oral formulation: 2024 hour half-life
- Long-acting risperidone: 36 day half-life
- Long-acting risperidone has elimination phase of approximately 78 weeks after last injection
Onset of Action
(Stahl, 2011)
Improvement in psychotic as well as manic symptoms can occur within 1 week, but full effect on cognition, behavior, and
affective stabilization may take several weeks. Four to six weeks wait is generally recommended to determine efficacy of
risperidone. However, some patients may require up to 16 20 weeks for improvement of cognitive symptoms.
Long-Term Use
(Stahl, 2011), (FDA, 2012)
Risperidone is FDA approved to delay relapse in long-term treatment of schizophrenia. It is also often used for long-term
maintenance in bipolar disorder and various behavioral disorders.
Overdose
(Stahl, 2011), (FDA, 2012)
Monotherapy overdose of risperidone is rarely lethal. Acute overdose symptoms often are exaggeration of the medications
known pharmacological effects i.e., tachycardia, hypotension, sedation as well as possible convulsions and difficulty breathing.
23
Dependence or Abuse
(Stahl, 2011), (FDA, 2012)
None known. Has not been systematically studied in animals or humans.
Discontinuation
(Stahl, 2011)
Rapid oral discontinuation of risperidone may lead to worsening of symptoms and rebound psychosis. A slow tapering over 6
8 weeks is recommended for oral formulation especially when cross-titrating with another antipsychotic.
Storage and Handling of Risperidone

(Stahl, 2011), (FDA, 2012)
Tablets- store at controlled room temperature 15-25C (59-77F). Protect from moisture and light.
Orally disintegrating tablets - store at controlled room temperature 15-25C (59-77F). Protect from moisture and light.
Oral Solution - store at controlled room temperature 15-25C (59-77F). Protect from moisture and light.
Risperidone long-acting depot microspheres formulation for deep intramuscular administration- must be kept refrigerated.
9.2 Reference to Risperidone in Existing WHO & other Clinical Guidelines
From the treatment of psychosis section of the World Health Organizations, mhGAP Intervention Guide for mental,
neurological and substance use disorders in non-specialized health settings:
If the response is inadequate to more than one antipsychotic medication using one medicine at a time at adequate dosage for
adequate duration Consider second-generation antipsychotics (with the exception of clozapine), if cost and availability is not a
constraint, as an alternative to haloperidol or chlorpromazine (WHO, 2010).
The American Psychiatric Associations Practice Guideline for Schizophrenia lists risperidone, along with olanzapine,
quetiapine, ziprasidone and aripiprazole, as first line treatment for a first episode of acute phase schizophrenia. Atypical
antipsychotics are also recommended for maintenance treatment of chronic schizophrenia (American Psychiatric Association,
2004). More recent American Psychiatric Association practice guidelines for schizophrenia are not available at the time of this
application.
24
The American Psychiatric Associations Practice Guideline for t he Treatment of Psychi at ri c Di sorders lists
risperidone as consistently efficacious in the treatment of positive symptoms and global psychopathology as well as in
increasing the likelihood of clinical response in acutely relapsed patients. Risperidone is also noted to be superior to
haloperidol in the prevention of relapse during the maintenance phase of treatment (American Psychiatric Association, 2006).
Schizophrenia treatment guidelines for United Kingdoms The National Institute for Health and Clinical Excellence recommend
both typical and atypical antipsychotics as first line for acute and maintenance treatment with the medication decision to be based
largely on tolerability and side-effect profile. The only exception is clozapine, which is reserved for treatment-resistant
schizophrenia (National Institute for Health and Clinical Excellence, 2009).
9.3 Need for Special Diagnostics, Treatment or Monitoring Facilities and Skills When Prescribing Risperidone
Prior to initiating risperidone therapy (Stahl, 2011), (FDA, 2012)

Obtain baseline weight, waist circumference, blood pressure, fasting plasma glucose and fasting lipid profile.
Monitoring while on risperidone therapy (Stahl, 2011), (FDA, 2012)
Body Mass Index (BMI) measurements monthly for the first 3 months, then quarterly.
Blood pressure, fasting lipids, fasting plasma glucose should be evaluated within 3 months and then annually. Monitor earlier
and more frequently for patients with diabetes or who have gained >5% of initial weight.
Patients with low white blood cell count (WBC) or history of drug-induced leucopenia/neutropenia should have complete
blood count (CBC) monitored frequently during the first few months, and risperidone should be discontinued if there is a
decline of WBC in the absence of other causative factors. Treatment should be suspended if absolute neutrophil count falls
below 1,000/mm3.
There is a rare, but life-threatening onset of diabetic ketoacidosis associated with atypical antipsychotics, which requires
immediate treatment. Providers should educate patients and be vigilant about rapid onset of polyuria, polydipsia, weight loss,
nausea, vomiting, dehydration, rapid respiration, weakness and clouding of sensorium, even coma.
References
American Psychiatric Association. The American Psychiatric Associations Practice Guideline for the Treatment of Psychiatric
Disorders. Compendium 2006. (2006). American Psychiatric Association, Arlington, VA.
American Psychiatric Association: Practice Guideline for the Treatment of Patients with Schizophrenia, second edition. Am J
Psychiatry 2004; 161(Feb suppl)
Australian Government Department of Health and Ageing Therapeutic Good Administration. Australian public assessment report for
risperidone. June 2010. http://www.tga.gov.au/pdf/auspar/auspar-risperdal-consta.pdf
Lass accessed: Jan 5, 2013.
25
Australian Therapeutic Goods Administration (TGA). Australian Drug Evaluation Committee 238th meeting resolutions, 3-4
February 2005. http://www.tga.gov.au/archive/committees-adec-resolutions-0238.htm
Last accessed: Jan 5, 2013.
Australian Therapeutic Goods Administration (TGA). Australian Drug Evaluation Committee 235th meeting resolutions, 12-13
August 2004. http://www.tga.gov.au/archive/committees-adec-resolutions-0235.htm
Australian Therapeutic Goods Administration (TGA). Australian Drug Evaluation Committee 223rd meeting resolutions, 1-2
August 2002. http://www.tga.gov.au/archive/committees-adec-resolutions-0223.htm
Australian Therapeutic Goods Administration (TGA). Australian Drug Evaluation Committee 206th meeting resolutions, 7 8
October 1999. http://www.tga.gov.au/archive/committees-adec-resolutions-0206.htm
European Medicines Agency (EMA). Risperdal Referral. ANNEX II: Scientific Conclusions and Grounds for the Amendment
of the Summaries of Product Characteristics, Labeling and Package Leaflet Presented by the EMEA. July 24, 2008.
http://www.emea.europa.eu/docs/en_GB/document_library/Referrals_document/Risperdal_30/WC500007979.pdf
Last accessed Jan 5, 2013.

European Medicines Agency (EMA). Risperdal Consta Referral. ANNEX II: Scientific Conclusions and Grounds for the
Amendment of the Summaries of Product Characteristics, Labeling and Package Leaflet Presented by the EMEA. July 24, 2008.
http://www.emea.europa.eu/docs/en_GB/document_library/Referrals_document/Risperdal_Consta_30/WC500008170.pdf
Medicines and Healthcare products Regulatory Agency (MHRA). Risperidone 0.5mg, 1mg, 2mg, 3mg, 4mg & 6mg Fil-coated
tablets. Aug 15, 2011. http://www.mhra.gov.uk/home/groups/par/documents/websiteresources/con126093.pdf
Medicines and Healthcare products Regulatory Agency (MHRA). Risperdal Consta 12.5mg UK Public Assessment Report. Apr
14, 2008. http://www.mhra.gov.uk/home/groups/pl-a/documents/websiteresources/con018067.pdf
Medicines and Healthcare products Regulatory Agency (MHRA). Risperidone and Autism. Variation Assessment Report. Oct
20 2006. http://www.mhra.gov.uk/home/groups/pl-p/documents/websiteresources/con2025027.pdf
National Institute for Health and Clinical Excellence. NICE Clinical Guidelines, CG82. Schizophrenia: Core interventions in
the treatment and management of schizophrenia in adults in primary and secondary care. March 2009.
http://publications.nice.org.uk/schizophrenia-cg82/other-versions-of-this-guideline
Last Accessed Oct 6, 2012.
Stahl, S M. The Prescribers Guide (Stahls Essential Psychopharmacology). (April 18, 2011). Cambridge University Press,
New York, NY.
26
US
Food
and
Drug
Administration
(FDA),
Prescribing
Information.
http://www.accessdata.fda.gov/drugsatfda_docs/label/2007/020272s46s47,20588s36s37,21444s20s21lbl.pdf. Last Accessed Oct
6, 2012.
World Health Organization (WHO), mhGAP Intervention Guide for mental, neurological and substance use disorders in nonspecialized health settings. (2010)http://www.who.int/mental_health/evidence/mhGAP_intervention_guide/en/index.html. Last
accessed Oct 6, 2012.
27
10. Summary of the Comparative Effectiveness of Risperidone in a Variety of Clinical Settings
10.1. Identification of Clinical Evidence Regarding Risperidone

A systematic review was conducted using PubMed and Cochrane databases (last search September 2012). These catalogues
were searched for articles using keywords risperidone and comparison for PubMed and risperidone only for the Cochrane
database search. Further data was obtained through cross-referencing and a hand search of relevant literature. There were no
specifications on language.
A total of 541 abstracts in PubMed and 49 reviews in Cochrane databases were identified initially. Among these, 197 were
relevant to comparative effectiveness for risperidone. Of the 197 relevant articles, 101 were excluded due to poor study design,
small sample size, type of article (e.g. letter to the editor), and/or incomplete or non-available data. As a result, 96 studies and
review articles were included in this summary.
10.2. Summary of Available Data on Risperidone

Psychosis:
Comparison with typical (first-generation) antipsychotic medications:
In the most recent Cochrane review comparing risperidone versus typical antipsychotics (Hunter, Joy, Kennedy, Gilbody, &
Song, 2003), nine randomized controlled trials (RCT) (n=2368) showed that risperidone was more likely to produce an
improvement in the Positive and Negative Syndrome Scale (PANSS) in the short term when compared to Haloperidol. Two
randomized controlled trials (n=859) showed similar superior improvement with risperidone in the long term as well. In a
smaller two year outcomes study, risperidone and haloperidol exhibited similar efficacy in maintenance treatment of
schizophrenia, but the patients on risperidone reported less anxiety and depressive symptoms (Marder et al., 2003). In another
study, risperidone showed significantly superior PANSS scores compared to haloperidol, perphenazine and zuclopenthixol
(Glick, Shkedy, & Schreiner, 2006). Although chlorpromazine is one of the most widely used typical antipsychotic medications worldwide
and is included in the List of Essential Medications, there are no well-designed studies that compare chlorpromazine with risperidone at the time
of this proposal. As for the third antipsychotic medication on the current list of essential medications, fluphenazine, we are aware of one study in
which patients were switched from either oral haloperidol or fluphenazine to risperidone and were found to have improved symptoms and a
reduced side-effect burden ( Popovic et al., 2011)
In one RCT (N= 367), risperidone was found to reduce relapse at one-year follow up compared to haloperidol. Risperidone was
associated with a lower attrition rate in studies for both short-term (N=3066, 16 RCTs) and long-term trials (N: 1270, 4 RCTs)
(Hunter et al., 2003). A double-blind prospective study at 40 sites revealed patients on risperidone have a lower risk of relapse
than those treated with haloperidol (Csernansky, Mahmoud, & Brenner, 2002). A naturalistic study with 4,783 participants also
found that patients on risperidone or olanzapine monotherapy were less likely to experience relapse than those treated with
haloperidol (Dossenbach et al., 2005).
28
Risperidone is associated with more significant and wide-ranging improvements in cognitive functioning compared to
haloperidol (Gallhofer, Bauer, Lis, Krieger, & Gruppe, 1996; Green et al., 1997; Harvey, Rabinowitz, Eerdekens, & Davidson,
2005). With regards to long-term memory dysfunction, risperidone is associated with marginally superior efficacy compared to
typical antipsychotic medications (Thornton, Van Snellenberg, Sepehry, & Honer, 2006). The relative superiority of risperidone
on spatial working memory performance compared to haloperidol is likely due to the impairments in spatial working memory
associated with benztropine, which was used more frequently with patients on haloperidol (McGurk et al., 2004).
Oral risperidone administered with lorazepam was found to be as effective as intramuscular treatment with haloperidol and
lorazepam for acute psychotic agitation (Currier et al., 2004). Risperidone and olanzapine monotherapy showed similar efficacy
as haloperidol in acute reduction of psychotic symptoms in children (Sikich, Hamer, Bashford, Sheitman, & Lieberman, 2004).
Comparison with other atypical (second-generation) antipsychotic medications:
In a Cochrane review that included 45 blinded randomized controlled trials (n=7760) comparing risperidone versus other atypical
antipsychotics, risperidone improved the PANSS total score slightly more than quetiapine (9 RCTs, n=1953) and ziprasidone (3
RCTs, n=1016) but slightly less than olanzapine (15 RCTs, n= 2390) (Komossa et al., 2011). The minimal difference in efficacy
between atypical antipsychotics is also reflected in other studies (Addington et al., 2009; Klemp et al., 2011; Malla et al., 2004;
McEvoy et al., 2007; Miller et al., 2008; Mullen, Jibson, & Sweitzer, 2001; Robinson et al., 2006; Sauriol et al., 2001; Sikich et
al., 2008; Zhang et al., 2011; Zhong, Sweitzer, Hamer, & Lieberman, 2006). A double-blind RCT and a naturalistic study with
1901 participants showed slight advantage in efficacy with risperidone compared to olanzapine (Conley & Mahmoud, 2001;
Kasper, Rosillon, & Duchesne, 2001). Contrary to these studies, a double blind comparison between olanzapine versus
risperidone reported slight efficacy advantage in favor of olanzapine (Tran et al., 1997).
In a Cochrane review comparing risperidone versus olanzapine for schizophrenia (Jayaram & Hosalli, 2005), both medications
were found to be equally effective (2 RCTs, n = 552). One randomized controlled study (n=279) reported better outcome with
olanzapine for re-hospitalization and relapse by 12 months (Soares-Weiser, Bchard-Evans, Howard Lawson, Davis, & AscherSvanum, 2012), a finding that was also observed in a retrospective comparison of risperidone and olanzapine (Sethuraman,
Taylor, Enerson, & Dunayevich, 2005). Clozapine has also been associated with a significantly lower re-hospitalization risk
compared to risperidone (Tiihonen et al., 2011) and has also been associated with consistent superiority in efficacy compared to
typical antipsychotics followed by olanzapine and risperidone (Citrome, 2012). A meta-analysis of time to all-cause treatment
discontinuation showed favorable results for olanzapine versus risperidone (Soares-Weiser et al., 2012). A lower dropout rate for
olanzapine compared to risperidone was also observed in a multi-center study (Pelagotti, Santarlasci, Vacca, Trippoli, &
Messori, 2004). However, the greater adherence to olanzapine treatment might be associated with the dose frequency of the
medication rather than any inherent superiority in efficacy or tolerability of olanzapine (Diaz, Neuse, Sullivan, Pearsall, &
Woods, 2004).
A treatment response trajectory from the CATIE chronic schizophrenia trial found that olanzapine treated patients were more
likely to stay in the trajectory of responders compared to other atypical antipsychotics including risperidone (Levine, Rabinowitz,
Faries, Lawson, & Ascher-Svanum, 2012). Maintaining remission for 6 months was highest with olanzapine followed by
quetiapine, perphenazine, ziprasidone and risperidone groups (Levine, Rabinowitz, Ascher-Svanum, Faries, & Lawson, 2011).
These findings were not reflected in a smaller randomized, controlled trial where remission rate did not significantly differ
between haloperidol, risperidone, and olanzapine (Crespo-Facorro et al., 2011).
There is some evidence for cognitive improvement after treatment with atypical antipsychotic medications in early psychosis. In
a randomized double-blind 52-week comparison, risperidone, quetiapine and olanzapine were all associated with significant
29
improvements in neurocognition with no significant difference in efficacy between medications (Keefe et al., 2007). Another
study found that cognitive improvement with atypical antipsychotics might be due to practice effects such as familiarity and
procedural learning. No significant difference in improvement of cognition was found between olanzapine and risperidone in
this study either (Goldberg et al., 2007). Quetiapine showed similar efficacy as risperidone in neuropsychological performance
and social competence (Harvey, Patterson, Potter, Zhong, & Brecher, 2006; Zhong et al., 2006). A small study found slight
neurocognitive advantages with paliperidone ER compared to risperidone (Kim et al., 2012).
A review of antipsychotic use in children and young adults found second-generation antipsychotics improved clinical global
impressions and diminished positive and negative symptoms in schizophrenia. There was not a significant difference n efficacy
between individual atypical antipsychotics (Seida et al., 2012).
Comparison with Placebo:
In a Cochrane review comparing risperidone versus placebo (Rattehalli, Jayaram, & Smith, 2010), risperidone showed 20%
greater reduction in Brief Psychiatric Rating Scale (BPRS)/PANSS score than placebo in seven randomized controlled trails (n =
856), and fewer participants on risperidone needed an additional psychotropic during the trial period (1 RCT, n=186). Placebo
and risperidone showed similar Clinical Global Impressions (CGI) global scores in 3 RCTs (n=397). Placebo arm had lower
attrition rate (10 RCTs, n=1363), but fewer participants left the trial in the risperidone arm due to lack of efficacy (5 RCTs, n =
888).
Comparison of risperidone long-acting injection with typical and atypical antipsychotic medications:
Risperidone long-acting injection (RLAI) showed rates of symptomatic remission as well as psychosocial improvement
comparable to intramuscular long-acting typical antipsychotics, and both classes were significantly more efficacious than Per-os
(PO) formulations (Barak & Aizenberg, 2012). Long-acting risperidone was also associated with lower rates of hospitalization
(Grimaldi-Bensouda et al., 2012; Tiihonen et al., 2011) but did not have an effect on treatment adherence in first-episode
schizophrenia patients (Weiden et al., 2009). RLAI showed superior efficacy compared to paliperidone palmitate (Fleischhacker
et al., 2012).
Bipolar Disorder:
A Cochrane review of acute mania identified six trials (n=1343) examining risperidone as monotherapy or in combination with
lithium or an anticonvulsant (Jennifer M Rendell, Gijsman, Bauer, Goodwin, & Geddes, 2006). Risperidone was found to be
effective in reducing manic symptoms comparable in efficacy to haloperidol.
Comparison with other medications:
A double blind randomized controlled trial found that risperidone, lithium and haloperidol all have equivalent efficacy in the
management of acute mania (Segal, Berk, & Brook, 1998). There does not seem to be any difference between risperidone and
haloperidol either as monotherapy or as adjunctive treatment (Jennifer M Rendell et al., 2006; Small, Klapper, Milstein,
30
Marhenke, & Small, 1996). However, a meta-analysis of seven randomized clinical trials (n=2037) found haloperidol shows
faster improvement in mania than risperidone, olanzapine, ziprasidone, quetiapine, and aripiprazole (Goikolea et al., 2012).
There is limited data comparing risperidone with other treatments for prevention of mania or depressive episodes in bipolar
disorder (J M Rendell & Geddes, 2006), and optimal treatment is a combination of evidence based therapy and individualized
treatment regimens (Gitlin & Frye, 2012). There is support for risperidones superior efficacy in preventing mania compared to
aripiprazole, ziprasidone, olanzapine, lithium, quetiapine and lamotrigine (Popovic et al., 2011). Depot risperidone has been
reported as effective maintenance treatment in bipolar disorder with effect noted predominantly for preventing mania (Gigante,
Lafer, & Yatham, 2012).
In a multi-site randomized clinical trial of mania in children ages 6 through 15 years old, risperidone was found to be more
effective than lithium or divalproex, but the magnitude of the effect was affected by presence of attention deficit hyperactivity
disorder (ADHD) and study site related characteristics (Vitiello et al., 2012). These findings of superior efficacy of risperidone
compared to divalproex (Pavuluri et al., 2010) and lithium or divalproex were supported by other randomized controlled trials
(Geller et al., 2012). A review of antipsychotic use in children and young adults found second-generation antipsychotics
improved clinical global impressions in Bipolar Disorder. There was not a significant difference in efficacy between individual
atypical antipsychotics (Seida et al., 2012). This finding is supported in other studies (Gentile, 2011).
Comparison with Placebo:

In comparison to placebo, two trials found risperidone monotherapy to be significantly more efficacious in reducing manic
symptoms, leading to response, remission and sustained remission. In five trials, risperidone both as monotherapy and as
adjunctive treatment was found to have significantly lower incidence of failure to completing treatment when compared to
placebo (Jennifer M Rendell et al., 2006).
Irritability and Aggression in Autism:

There is limited data comparing risperidone with other medications for irritability and aggression in autism. A Cochrane review
of risperidone in autism (Jesner, Aref-Adib, & Coren, 2007) identified three relatively small, randomized controlled trials
showing some evidence of risperidone efficacy in irritability, repetition, and social withdrawal.
A meta-analysis of 22 studies including 6 placebo-controlled and 16 open-label studies found significant evidence for
effectiveness of risperidone in improvement of behavioral symptoms in children with autistic spectrum disorder (Sharma &
Shaw, 2012). Risperidone has the most evidence for efficacy, followed by aripiprazole in irritability of autism (Elbe & Lalani,
2012).
In a Cochrane review of atypical antipsychotics for disruptive behavior disorders in children and youths (Loy, Merry, Hetrick, &
Stasiak, 2012), authors conducted meta-analyses that showed improvement in the irritability subscale of the Aberrant Behavior
Checklist (ABC) with risperidone (n=225). There was also some improvement with risperidone in conduct problems as
measured by the Conners Parent Rating Scale-Conduct Problem Subscale (CPRS- CP).
A review of antipsychotic use in children and young adults found second-generation antipsychotics improved clinical global
impressions and behavior symptoms in disruptive behavior disorders. But, there was not a significant difference in efficacy
between individual atypical antipsychotics (Seida et al., 2012). Lithium and risperidone have similar efficacy in treating
disruptive behavior disorders (Ipser & Stein, 2007).
31
Other indications:
A meta-analysis of double-blind, randomized, placebo-controlled trials found one-third of serotonin reuptake inhibitor-resistant
obsessive compulsive disorder (OCD) patients benefitted from an augmentation with antipsychotics. Authors concluded that
based on a favorable risk-benefit ratio, risperidone is preferable to quetiapine and olanzapine (Dold, Aigner, Lanzenberger, &
Kasper, 2012).
There is some data on antipsychotic medications in tic disorders and Tourette syndrome. Risperidone has the best evidence level
for atypical antipsychotics and is considered first-line treatment for tics with aripiprazole as the second choice (Bruggeman et al.,
2001; Roessner et al., 2012).
A randomized trial found no significant difference in anti-depressive properties between risperidone, quetiapine, olanzapine and
ziprasidone in patients acutely admitted with psychosis (Kjelby, Jorgensen, Kroken, Loberg, & Johnsen, 2011). A Cochrane
review on second-generation antipsychotics for major depressive disorder and dysthymia included 28 RCTs (n=8487) comparing
amisulpride, aripiprazole, olanzapine, risperidone and quetiapine. Quetiapine was found to be more effective than placebo.
Risperidone and olanzapine showed efficacy when used for treatment augmentation (Komossa, Depping, Gaudchau, Kissling, &
Leucht, 2010).
A double-blind RCT showed no statistically significant difference between citalopram and risperidone in the treatment psychotic
symptoms or agitation in patients with dementia (Pollock et al., 2007). Risperidone showed efficacy superior to placebo in
dementia-associated agitation and psychosis (Katz et al., 1999).
A Cochrane review of antipsychotic medications for delirium found risperidone, olanzapine and low-dose haloperidol have
similar efficacy in decreasing the degree and duration of delirium (Lonergan, Britton, Luxenberg, & Wyller, 2007). Another
systematic review found similar efficacy in delirium improvement between risperidone, quetiapine, haloperidol, chlorpromazine
and olanzapine (Seitz, Gill, & van Zyl, 2007).
There is very little evidence for the efficacy of risperidone in substance addiction. A Cochrane review on antipsychotic
medications for cocaine dependence found risperidone to be superior to placebo in lowering the number of dropouts (Amato,
Minozzi, Pani, & Davoli, 2007). A 14-week double-blind study comparing risperidone to olanzapine in reducing marijuana and
cocaine craving as well as use found no significant improvement with either medication. There was also no statistically
significant difference in effect between olanzapine and risperidone (Akerele & Levin, 2007).
10.3. Summary of Available Estimates of Comparative Effectiveness of Risperidone

In the treatment of psychosis, risperidone is more efficacious in improving positive and negative symptoms than haloperidol. It
shows lower attrition rates as well as better relapse prevention compared to haloperidol. Risperidone also yields better
improvement in neurocognitive domains than haloperidol.
In comparisons of risperidone with other atypical antipsychotics for treatment of psychosis, all second-generation antipsychotic
medications appear to have similar efficacy though some studies show slight superiority with clozapine and olanzapine.
Risperidone is effective in reducing symptoms of mania both as monotherapy and as adjunctive treatment. Compared to other
atypical antipsychotics in treating mania, risperidone has better efficacy and tolerability data making it a more desirable choice
32
within this medication group for the treatment of mania. There is some evidence that risperidone may also be superior to lithium
and divalproex in the management of acute mania.
In irritability and behavioral disturbance associated with autism, evidence supports the relative efficacy of risperidone. Among
atypical antipsychotic medications, risperidone has the most evidence for efficacy, followed by aripiprazole, in irritability of
autism
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43
11. Summary of Comparative Evidence on Safety of Risperidone

A systematic review was conducted using PubMed and Cochrane databases (last search September 2012). These catalogues
were searched for articles using keywords risperidone and comparison for PubMed and risperidone only for the Cochrane
database search. Further data was obtained through cross-referencing and a hand search of relevant literature. There were no
specifications on language.
A total of 541 abstracts in PubMed and 49 reviews in Cochrane databases were identified initially. Among these, 125 were
relevant to comparative evidence on safety for risperidone. Of the 125 relevant articles, 53 were excluded due to poor study
design, small sample size, type of article (e.g. letter to the editor), and/or Incomplete or non-available data. As a result 72 studies
and review articles were included in this summary.
Estimate of Total Patient Exposure to Date
Risperidone was first approved by the United States Food and Drug Administration in 1993 (FDA, 2012). There is no available
data estimating the total patient exposure of risperidone worldwide to date. A 2008 naturalistic study of 27 countries in 4
continents (N=3222) found that, second to olanzapine, risperidone is the most commonly prescribed atypical antipsychotic
(Dossenbach et. al., 2008). In the United States, risperidone also continues to be one of the most commonly prescribed atypical
antipsychotic medications. In 2008, there were 12.02 million U.S. prescriptions for risperidone (Alexander et. al., 2011).
Common Adverse Effects
(Micromedex 2.0, 2012)
Common side effects include edema, rash, hyperprolactinemia, weight gain, altered lipid or glucose metabolism, abdominal pain,
constipation, diarrhea, extra-pyramidal symptoms (including Parkinsonism), sedation, akathisia, tremor, cough, and fatigue.
Serious side effects include sudden cardiac death, cerebrovascular events, seizure, neuroleptic malignant syndrome, and effects
of bone marrow suppression such as leukopenia, neutropenia, and thrombocytopenia.
Psychosis
Comparison with typical antipsychotic medications
In a Cochrane review comparing risperidone versus typical antipsychotic medications (Hunter, Joy, Kennedy, Gilbody, & Song,
2003), ten randomized control trials (n=2702) found that risperidone resulted in significantly fewer general movement disorders
44
including extrapyramidal side effects compared to typical antipsychotic medications. Eleven RCTs (n=2524) showed that
significantly fewer persons on Risperidone used antiparkinsonian medications compared to those on typical antipsychotics.
Four randomized control trials (n=1708) found risperidone was associated with more weight gain than conventional
antipsychotics. It was also associated with higher likelihood of rhinitis than typical antipsychotics (3 RCTs, n=656).
Risperidone was found to have similar sexual side effect burden as typical antipsychotics in 2 RCTs (N=106). (Hunter et al.,
2003).
In one study risperidone treatment was associated with adverse effects on eye movement activity whereby there was a decreased
peak velocity and accuracy of saccadic eye movements compared to haloperidol treatment (Sweeney et al., 1997).
A population based cohort study of 75,445 elderly (age >65) new users of antipsychotic medications showed haloperidol to be
associated with increased risk of mortality compared to risperidone. Lowest risk was with quetiapine use. (K F Huybrechts et al.,
2012) Another study found similar associations with mortality risk, with haloperidol having the greatest risk and loxapine the
lowest (Schneeweiss, Setoguchi, Brookhart, Dormuth, & Wang, 2007). This risk trend was also seen in patients with dementia
(Kales et al., 2012).
Comparison with other atypical antipsychotic medications

In a Cochrane review that included 45 blinded randomized control trials (n=7760) comparing risperidone versus other atypical
antipsychotics (Komossa et al., 2011), risperidone was found to produce somewhat more extrapyramidal side effects than other
atypical antipsychotics. It was associated with higher use of antiparkinsonian medications compared to olanzapine (13 RCTs, n
= 2599), clozapine (6 RCTs, n=304), Ziprasidone (2RCTs, n=822) and quetiapine (6 RCTs, n = 1715). One randomized control
trial showed more Parkinsonism with risperidone compared to sertindole (n=321). In the trials reviewed, risperidone was
associated with increased prolactin levels (Komossa et al., 2011) and menstrual irregularities (McEvoy et al., 2007) compared to
other atypical antipsychotics.
Risperidone was reported to cause less weight gain than clozapine (3RCTs, n = 373), olanzapine (13 RCTs, n = 2116), and
sertindole (2 RCTs, n =328), and less cholesterol elevation than quetiapine (5 RCTs, n=1433). Risperidone caused more weight
gain than amisulpride (3 RCTs, n=585), and it had more cholesterol increase than aripiprazole (1 RCT, n=83) and ziprasidone (2
RCTs, n=767). Other smaller trials and reviews reflected similar results on the level of weight gain among different atypical
antipsychotic medications (Bushe, Slooff, Haddad, & Karagianis, 2012; Hasnain, W Victor, & Hollett, 2012; Klemp et al., 2011;
Moisan, Grgoire, Gaudet, & Cooper, 2005; Newcomer, 2005, 2007; Patel et al., 2009; Robinson et al., 2006; Sikich et al., 2008;
Wood et al., 2012). This was also seen in a study focusing on non-Euro-American Societies (Bou Khalil, 2012), in Latin
American populations (Brunner et al., 2006), and a Swiss psychiatric population (Choong et al., 2012). A head to head, multinational comparison found risperidone and sertindole showed similar levels of weight gain (De Hert, Mittoux, He, & Peuskens,
2010). There is a greater risk of diabetes with olanzapine than with risperidone (Ramaswamy, Masand, & Nasrallah, 2006).
This risk was found to be dose dependent in olanzapine, risperidone, and quetiapine. Aripiprazole and ziprasidone were not
associated with an increased risk of diabetes (Ulcickas Yood et al., 2011).
Studies reviewed showed risperidone causes fewer seizures than clozapine (2 RCTs, n=354), prolongs QTc interval less than
sertindole (2RCTs, n =495), causes less sexual dysfunction in men than in sertindole (2RCTs, n=437) and may also be less
sedating than clozapine and quetiapine (Komossa et al., 2011). Clozapine is associated with significantly higher rate of nocturnal
enuresis compared to risperidone, olanzapine and quetiapine (Harrison-Woolrych, Skegg, Ashton, Herbison, & Skegg, 2011).
45
In a Cochrane review comparing risperidone versus olanzapine for schizophrenia (Jayaram & Hosalli, 2005), participants on
either medication experienced some extrapyramidal symptoms (2 RCTs, n=419). Olanzapine was associated with more weight
gain, which was significant and quick in onset (2RCTs, n =984). Those on olanzapine were more likely to leave the study due to
weight gain or metabolic side effects (1 RCT, n = 667). Risperidone was associated with abnormal ejaculation (2 RCTs, n = 370)
and relatively more frequent insomnia. In a more recent study, the level of insomnia in risperidone long-acting injectable was
found to be similar to that experienced with paliperidone palmitate (Fleischhacker et al., 2011). A meta-analysis found that
patients treated with risperidone have a slightly higher rate of anticholinergic drug use than patients on olanzapine (Sauriol et al.,
2001)
In a double-blind randomized controlled multicenter trial, suicidal ideation was significantly associated with clinician observed
akathisia in first-episode schizophrenia. The study showed increased akathisia with haloperidol compared to risperidone but
there was no significant difference with respect to suicidal ideation (Seemller et al., 2012)
In children treated with atypical antipsychotics, short-term metabolic effects and extrapyramidal symptoms were found to be
frequent. Risperidone resulted in less weight gain than olanzapine and clozapine but more than quetiapine and aripiprazole.
Risperidone was also associated with more hyperprolactinemia than other atypical psychotic agents. Unlike olanzapine and
quetiapine, risperidone showed no increase in triglyceride and cholesterol levels (Cohen, Bonnot, Bodeau, Consoli, & Laurent,
2012). These side effect profiles of antipsychotics in children and young adults have been replicated in other studies as well
(Ben Amor, 2012; Maayan & Correll, 2011; Pringsheim, Lam, Ching, & Patten, 2011; Seida et al., 2012).
In the elderly population, atypical antipsychotic medications showed little variation in their comparative safety profiles in
nursing home residents (Krista F Huybrechts et al., 2012). A study of risk of falls and fractures in community-dwelling older
persons also found no significant difference between atypical antipsychotics (Chatterjee, Chen, Johnson, & Aparasu, 2012).
Comparison with Placebo
In a Cochrane review comparing risperidone versus placebo (Rattehalli, Jayaram, & Smith, 2010), 5 randomized control trials
(n=723) showed approximately 24% of all participants receiving either placebo or risperidone developed extrapyramidal effects.
Participants on the risperidone arm gained more weight in 2 RCTs (n=303) and had elevated prolactin compared to placebo in 2
RCTs (n =323). 1 study reported 3 participants on risperidone had prolonged QTc (n=198).
In a double-blind comparison between risperidone, quetiapine and placebo, risperidone was associated with more weight gain,
parkinsonism, akathisia and plasma prolactin changes when compared to placebo (Potkin et al., 2006)
Bipolar Disorder
A Cochrane review of Risperidone in acute mania (Rendell, Gijsman, Bauer, Goodwin, & Geddes, 2006) identified 6 trials
(n=1343) on risperidone as monotherapy or in combination with lithium, or an anticonvulsant. There is limited and somewhat
conflicting data on comparison of risperidones safety with other medications for bipolar mania. A double blind randomized
controlled trial found risperidone and haloperidol to have comparable extrapyramidal side effects (Segal, Berk, & Brook, 1998),
while other studies show risperidone causes less extrapyramidal symptoms and sedation but more weight gain than haloperidol
(Rendell et al., 2006). Risperidone and olanzapine have been associated with higher risk of hospitalization than quetiapine. In
rapid cyclers, risperidone was associated with a higher risk of hospitalization than olanzapine (Gianfrancesco, Rajagopalan,
Goldberg, & Wang, 2007).
46
Irritability and Aggression in Autism

There is sparse literature comparing the safety of risperidone with other medications for irritability and aggression in autism. A
Cochrane review of risperidone in autism (Jesner, Aref-Adib, & Coren, 2007) with three relatively small, randomized controlled
trials showed weight gain as the most notable side effect associated with risperidone.
In a Cochrane review of atypical antipsychotics for disruptive behavior disorders in children and youths (Loy, Merry, Hetrick, &
Stasiak, 2012), a meta-analysis of two studies (n = 138) showed an average weight gain of 2.37 kilograms more with risperidone
than with placebo.
Summary of comparative safety of risperidone against comparators:

Risperidone is associated with less adverse side effects than haloperidol and appears to have better tolerability.
In comparison to other atypical antipsychotics, risperidone is associated with significant increase in prolactin. It is also
associated with marginally more extrapyramidal side effects.
Due to the limitations on the quantity and quality of available data, it is unclear if risperidones other side effects are significantly
different from those of other atypical antipsychotic medications. One of the most frequent adverse effects with risperidone is
weight gain. Weight gain in risperidone is less than in clozapine, olanzapine and sertindole, but more than amisulpride.
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55
12. Summary of Available Data on Comparative Cost and Cost-Effectiveness of Risperidone within its Pharmacological
Class/Therapeutic Group
12.1 Range of Costs

All cost information was obtained from the International Drug Price Indicator Guide1
Source
MEDEOR/TZ
Package
100 Tab-cap
Package Price
(Tablets)
$ 3.91
Unit Price
0.0391/tab-cap
Buyer Prices
Source
Package
Package Price
SAFRICA
OECS/PPS
BDS
CRSS
30 Tab-cap (Tablets)
20 Tab-cap (Tablet)
$ 1.19
$ 1.24
$ 1.35
$ 16.01
Median Price
0.0647/tab-cap
High/Low Ratio 4.03
Unit Price
0.0397 /tab-cap
0.0620 /tab-cap
0.0674 /tab-cap
0.1601 /tab-cap
Lowest Price 0.0397/tab-cap

Highest Price 0.1601/tab-cap
Supplier Information
MEDEOR/TZ: Action Medeor International Healthcare, Tanzania
SAFRICA: South Africa Department of Health
OECS/PPS: Organisation of Eastern Caribbean States Pharmaceutical Procurement Service
BDS: Barbados Drug Service
CRSS: Caja Costarricense de Seguro Social, Costa Rica
1
http://erc.msh.org/dmpguide/index.cfm?search_cat=yes&display=yes&module=dmp
56
12.2 Comparative Cost-Effectiveness

A systematic review of the cost-effectiveness literature on risperidone was conducted (last search October 2012). A PubMed
search using the keywords risperidone cost effectiveness yielded 165 articles. Of these, 40 were deemed relevant based on the
criteria that they expressed cost-effectiveness as a range of cost per routine outcome. Three of the relevant articles were
excluded based on small sample size and/or poor study design. A search of the Cochrane Database of Systematic Reviews using
the same keywords yielded no additional relevant articles.
The studies are sorted into three categories: those focusing on risperidone for the treatment of schizophrenia, schizoaffective
disorder, or psychosis; those focusing on bipolar disorder; and those focusing on risperidone long-acting injection (RLAI). The
overall evidence suggests that risperidone can be recommended from a cost-effectiveness standpoint, as it is at worst cost-neutral
compared to other atypical antipsychotic medications as well as typical antipsychotics.
Schizophrenia, Schizoaffective Disorder, Psychosis

Twenty-eight studies examined the cost-effectiveness of risperidone for the treatment of schizophrenia, schizoaffective disorder,
or psychosis. Of these, four reviews of the literature were identified, three that were multi-country studies and one based in the
U.S. The review papers did not provide a firm conclusion as to the cost-effectiveness of risperidone compared with olanzapine
or with typical antipsychotics. One review of pharmacoeconomic studies on olanzapine for the treatment of schizophrenia in the
U.S., the U.K., Spain, the Netherlands, and Germany concluded that while the data suggests that olanzapine is more costeffective than risperidone, additional studies are required to confirm this (Foster & Goa, 1999). However, a similar study by the
same authors that centered on risperidone concluded that despite high acquisition costs, risperidone may reduce the overall
treatment costs of schizophrenia compared to standard treatment regimens by reducing hospitalization (Foster & Goa, 1998).
Another review of the literature on risperidone compared to conventional antipsychotics concluded that risperidone provided
improved clinical as well as quality of life outcomes in a manner that was either cost-neutral or at best cost-saving. The U.S.based review, which identified 17 relevant articles written between 1975 and 2002, noted that while studies based on trial
settings have tended to find risperidone more costly than haloperidol, those based on cohort designs and decision models have
generally found it to be less costly (Basu, 2004). Taken together, published reviews of the literature on the comparative costeffectiveness of risperidone suggest at the very least that there is insufficient evidence to conclude that risperidone lacks costeffectiveness relative to olanzapine or to atypical antipsychotics.
A large multi-country retrospective chart review was more conclusive on comparative cost than on comparative effectiveness.
The Risperidone Olanzapine Drug Outcomes studies in Schizophrenia (RODOS) program reported health economic data
comparing risperidone and olanzapine for patients with diagnoses of schizophrenia or schizoaffective disorder (n=1901) across
61 inpatient treatment centers in Australia, Austria, Denmark, Great Britain, Germany, the Netherlands, Norway, Spain, and
Sweden. Together with a companion paper that reported efficacy data, the study concluded that risperidone was significantly
less costly (U.S. $159.9 compared to $297.5) and possibly more effective based on physician ratings (Barbui, Lintas, &
Percudani, 2005) (Kasper, Jones, & Duchesne, 2001).
The vast majority of studies in this section were conducted in countries with a very high Human Development Index (HDI) based
on the 2011 United Nations Development Programme Human Development Report (United Nations Development Programme,
2011): two in Australia, two in Belgium, two in Canada, one in the Czech Republic, one in France, one in Greece, three in Spain,
one in Slovenia, one in Sweden, two in the U.K., and five in the U.S.
57
A review of cost-effectiveness from the perspective of the Australian health sector across a range interventions for schizophrenia
concluded that switching patients currently on olanzapine to risperidone would result in AUD $27 million in cost saving.
However, the report found that risperidone would be the most cost-effective option only for patients who experience moderate to
severe side effects on typical antipsychotics-- for patients without such side effects the author recommended low-dose typicals.
Replacing typical antipsychotics with risperidone had a cost per DALY of AUD 20,000 among the patient population with
troublesome side-effects and AUD 48,000 overall (Vos et al., 2005) (Magnus, Carr, Mihalopoulos, Carter, & Vos, 2005). A 2year decision-analytic model based on guidelines issued by the Australian Pharmaceutical Benefits Advisory Committee
concluded that risperidone dominated haloperidol in terms of cost per favorable outcome, defined as the patient being in a
response phase at the end of the 2-year period. Risperidone had a total cost of $15,549.00 and a probability of 78.9% of
producing a favorable outcome compared to $18,332.00 and 58.9% for haloperidol, respectively (Alison Davies et al., 1998).
While these figures may be somewhat outdated, more recent pharmacoeconomic evaluations were absent from the literature.
In an observational, non-randomized cost-effectiveness study of schizoppublhrenic patients in Belgium (n=265), no statistically
significant differences were observed between risperidone and olanzapine upon net-benefit regression. Total 2-year costs were
nearly identical, and health outcomes, measured using the EQ-5D index of health-related quality of life, were numerically better
for risperidone but statistically indistinguishable (De Ridder & De Graeve, 2009). A 1-year semi-Markov model studying the
treatment of schizophrenia in the Belgian healthcare system found that risperidone, at a cost of $36,125 and an effectiveness rate
of 69.4%, dominated both olanzapine ($36,574/69.4%) and haloperidol ($36,262/67.3%). Effectiveness was measured based on
a modified version of TWiST (time without symptoms and toxicity) as the average time over a 1-year period spent in a health
state defined as response with no-side effects or response with bearable side effects (Lecomte et al., 2000).
According to a semi-Markov model using data from the Clinical Antipsychotic Trials for Intervention Effectiveness Study in
Canada, risperidone was both less costly over a 5-year period and more effective in terms of QALYs than quetiapine and
olanzapine ($21,831/3,025 compared to $26,233/3,022 and $28,563/2,982, respectively). Risperidone was less effective but less
costly than ziprasidone, which had an incremental cost of $218,060 per QALY gained (McIntyre et al., 2010). A 1-year
population-based study in Quebec comparing schizophrenic patients prescribed olanzapine with those prescribed olanzapine
found that among patients who had not been hospitalized for mental illness prior to treatment, risperidone was both less costly
and more effective in preventing hospitalization. Among patients with prior hospitalization, olanzapine was more effective but
also more costly, with an ICER of CA$86,918 per year of additional effective treatment (Cooper, Moisan, Abdous, & Grgoire,
2008).
An open intent-to-treat study in the Czech Republic compared charts of schizophrenic patients treated with risperidone (n=67) to
those treated with classical neuroleptics (n=67) and concluded that risperidone was significantly more expensive without leading
to statistically distinguishable outcomes (Hosk & Bahbouh, 2002).
A 5-year Markov model from the perspective of the French National Health Insurance found that zuclopenthixol had a 55%
effectiveness rate, as measured by time without relapse, compared to 43% for risperidone, while realizing cost savings of 1100
per patient (Hansen, Franois, Toumi, & Lanon, 2002).
A decision analytic model tailored to the Greek healthcare system found that palperidone extended release may result in a greater
number of stable days at a lower cost than risperidone (272.5 days at 7,030 compared to 265.5 days at 7,082). However,
risperidone was cheaper and more effective than quetiapine (260.7 / 8,321), ziprasidone (260.5/7,713), and aripiprazole (258.6
/ 7,807) (Geitona et al., 2008).
58
A decision analytic model for reducing schizophrenia relapses in Spain found that risperidone dominated haloperidol at an ICER
of 4,353/QALY compared to 4,593/QALY (Garca-Ruiz et al., 2012). A 12-month Markov model from the perspective of
third party payers in Spain found that risperidone was dominated by ziprasidone in terms of cost per time with psychotic
symptoms controlled and without adverse reactions. Among a cohort of 1000 patients, ziprasidone had 9610 effective months at
a cost of 9,444,512 compared to 9503 months/10,339,961 for risperidone. According to the authors, few other studies have
investigated cost per clinical event prevented among drugs for schizophrenia (Bobes, Caas, Rejas, & Mackell, 2004).
A population-level comparison of different clinical interventions for reducing the burden of schizophrenia in Spain found that
typical antipsychotics alone cost $45, 833 per DALY averted whereas generic risperidone cost a somewhat less $45, 022 per
DALY averted. Addition of psychosocial treatment and case management to either typical antipsychotics or generic risperidone
significantly enhanced cost effectiveness according this measure.
Combining typical antipsychotics with psychosocial
treatment/case management cost U.S. $25,069 per DALY averted, and combining generic risperidone with psychosocial
treatment/case management led to the most cost effective clinical intervention at $24, 672 cost per DALY averted (GutierrezRecacha, Chisholm, Haro, Salvador-Carulla, & Ayuso-Mateos, 2006).
A decision analytic model comparing amisulpride, aripiprazole, haloperidol (oral formulation), haloperidol (depot formulation),
olanzapine, quetiapine, risperidone (oral formulation), risperidone (depot formulation) and ziprasidone for the treatment of
outpatient chronic schizophrenia from the perspective of the Slovenian healthcare payer concluded that risperidone and
olanzapine were the most cost-effective in terms of keeping patients in remission (Obradovic, Mrhar, & Kos, 2007).
In a Markov model study examining 5-year treatment strategy options in Sweden, risperidone and other atypical antipsychotics
were found to be more cost-effective as well as clinically superior to haloperidol; each atypical had a cost per QALY of
approximately 490,000 Swedish kroner compared to 500,140 for haloperidol. However, risperidone was slightly dominated by
sertindole (Lindstrm, Eberhard, Fors, Hansen, & Sapin, 2011).
A Markov model comparing the cost-effectiveness of aripiprazole, olanzapine, quetiapine, and risperidone in the UK for treating
stable schizophrenic patients found that risperidone was second to aripiprazole in terms of cost per QALYs gained (Andrew
Davies et al., 2008). A retrospective chart review of patients in the U.K. with schizophrenia or schizoaffective disorder (n=501)
concluded that risperidone had both a shorter mean time to effectiveness and a lower cost than olanzapine. While incidence of
adverse effects was similar, patients on risperidone had an average of 9 fewer days in the hospital (Taylor, Wright, & Libretto,
2003).
Based on the projections of a 1-year Monte Carlo Micro-Simulation model in the U.S., olanzapine Oral Disintegrating
Tablet (Total Cost $9808, Mean QALYs 0.747) dominated Risperidone ODT and was cost-effective compared with Risperidone
standard oral tablets (ICER > $30,000) (Ascher-Svanum et al., 2012). However, risperidone and risperidone ODT dominated
aripiprazole and aripiprazole ODT, respectively, at costs/mean QALYs of $8881/0.718 compared to $12,598/0.715 and
$10,922/0.731 compared to $12,863/0.728. A separate U.S. micro-simulation model study also found oral olanzapine to be
dominant over oral risperidone in terms of cost per QALY (Furiak et al., 2009). In contrast, a decision analysis model evaluating
the cost-effectiveness of atypical antipsychotics for treating schizophrenia based on the Positive and Negative Symptom Scale
found that risperidone dominated both olanzapine and haloperidol. For 16 weeks of treatment, risperidone had a cost of $13,409
per patient and a clinical efficacy of 63%, compared to $13,591.57/60% for olanzapine and $15,513.38/34% for haloperidol
(Bounthavong & Okamoto, 2007). A multi-attribute utility theory study analysis analyzing efficacy in terms of 1-year relapse
prevention, adverse effects, cost, and adherence, (assigned weights of 35%, 35%, 20%, and 10%, respectively), found that
risperidone was neither the most dominated nor the most dominant. Specifically, aripiprazole had the highest utility score at
75.8, followed by ziprasidone (71.8), risperidone (69.0), quetiapine, and olanzapine (65.9) (Bettinger, Shuler, Jones, & Wilson,
2007).
59
A comparison of risperidone and olanzapine for the treatment of psychosis in the elderly at an inpatient center in Virginia found
that the cost of risperidone was one-third that of olanzapine, while treatment outcomes, assessed using the Positive and Negative
Syndrome Scale for Schizophrenia, the Cohen-Mansfield Agitation Inventory, and length of hospitalization, were statistically
indistinguishable (Verma, Orengo, Kunik, Hale, & Molinari, 2001).
Overall, the evidence in very high HDI countries suggests that risperidone is at least cost-neutral relative to both typical
antipsychotics and to other atypicals. Given the comparable efficacy of olanzapine to risperidone, data comparing the costeffectiveness of these two drugs are of particular importance. Few articles found olanzapine to be dominant over risperidone,
and thus it is safe to conclude that risperidone is at least cost-neutral relative to its closest competitor on efficacy.
Two studies were based in countries with a high HDI: one in Brazil and one in Mexico. A 5-year Markov model using data from
a municipality in Southern Brazil found that risperidone as well as haloperidol were more cost-effective than olanzapine, with
cost/utility ratios in U.S. dollars per QALY at 1414.90 and 944.89 compared to 2470.57 (Lindner, Marasciulo, Farias, & Grohs,
2009). In Mexico, a 5-year decision analytic Markov model determined that olanzapine was comparable in terms of cost to
risperidone and was slightly more effective in terms of preventing relapse and clinical outcome scores on the Brief Psychiatric
Rating Scale (Palmer, Brunner, Ruz-flores, Paez-agraz, & Revicki, 2002). While it is important to be cautious in drawing
conclusions from only two studies, these findings suggest that the risperidone may not be as well established as a cost-effective
drug in less developed countries.
Bipolar Disorder
Three papers on the cost-effectiveness of risperidone for the treatment of bipolar disorder were identified, all in very high HDI
countries.
A discrete event simulation model based on four randomized controlled trials conducted in the Netherlands found that the
combination of lithium and risperidone was less costly than that of lithium and quetiapine for the management of acute mania in
bipolar I disorder (monotherapy options were more costly than combination therapy). Over an 84 day time horizon,
lithium/risperidone cost 2,365 per patient compared to 2,555 for lithium/quetiapine. Meanwhile, switching from
lithium/risperidone to the lower side-effect combination of lithium/quetiapine is predicted to prevent 1530 serious side effects but
at an additional cost of 1,900,000 per 10,000 patients (Klok et al., 2007).
In the treatment of bipolar disorder with atypical antipsychotics in the U.S., one study found that risperidone was associated with
statistically indistinguishable overall health care costs and effectiveness in terms of preventing hospitalization to aripiprazole. In
addition, risperidone had statistically significantly lower pharmacy costs than aripiprazole (Kim, You, Pikalov, Van-Tran, &
Jing, 2011). In contrast, a randomized open-label trial in the U.S. comparing 1-year cost-effectiveness of initial treatment with
olanzapine (n=229) to risperidone (n=229) found that the two were equivalent in terms of cost, with higher antipsychotic costs
for olanzapine offset by the resulting reduction in costs for additional services such as hospitalization. Olanzapine was found to
have significantly higher social effectiveness than risperidone based on the Lehman Quality of Life Scale (Tunis et al., 2006).
The relative paucity of studies on bipolar disorder necessitates caution in interpreting the findings. At the very least, the available
data do not suggest that risperidone is less cost-effective compared to other interventions.
60
Risperidone Long-Acting Injection

In the literature on RLAI, two studies were conducted in very high HDI countries, one in Spain and one in the U.S. One study
was also conducted in Taiwan, which is not listed separately in the 2011 Human Development Report.
A 24-month observational study of schizophrenic patients enrolled in the international electronic Schizophrenia Treatment
Adherence database concluded that switching to RLAI from previous antipsychotic treatment was cost-effective because it
prevented relapsing and hospitalization (Olivares, Rodriguez-Martinez, Burn, Alonso-Escolano, & Rodriguez-Morales, 2008).
A 1-year mirror image analysis using the Taiwanese national claim-based database found that while RLAI was associated with
reduction of service uses in schizophrenia treatment, this was offset by the rise in medication and outpatient costs (Chang, Tang,
Huang, McCrone, & Su, 2012).
A one-year micro-simulation economic decision model in the U.S. found that olanzapine LAI dominated RLAI, at costs/QALYs
of $14,063/0.711 compared to $15,207/0.667 (Furiak et al., 2011).
One study was conducted in a country with a medium HDI. RLAI was found to be more cost-effective than quetiapine and
olanzapine for long-term maintenance treatment of schizophrenia in China based on a decision analytical model that calculated
costs per successfully treated patient. Successful treatment was defined as responding to initial treatment and neither requiring a
change in treatment nor having more than two episodes of clinical deterioration over a 2-year time period (Yang et al., 2009).
Two multi-country reviews of the literature were also identified. A review of cost-effectiveness studies on risperidone longacting injection (1999-2011) concluded that overall costeffectiveness in a wide array of different healthcare systems and
diverse patient populations has been demonstrated with RLAI (P. Chue & Chue, 2012). A separate review of cost-effectiveness
studies concluded that RLAI has demonstrated overall effectiveness in keeping medical costs down and reducing healthcare
resource utilization as well as hospitalization rates (Keith, 2009).
Among the studies reviewed in the first paper, a discrete event simulation model studying the treatment of schizophrenia from
the perspective of the German healthcare system found that over a 5-year time period, long-acting risperidone avoided 0.22 and
0.33 relapses per patient while realizing cost savings of 2017 and 6096 per patient compared with haloperidol depot and
olanzapine, respectively. A discrete event model for Canada found that over a 5-year time period, long-acting risperidone saved
Can$6908 and Can$13,130 while avoiding 0.28 and 0.54 relapses per patient compared with haloperidol depot and oral
risperidone, respectively in the treatment of high-risk, non-compliant patients with schizophrenia (P. S. Chue, Heeg, Buskens, &
van Hout, 2005). However, not all studies showed a clear benefit. One randomized trial of U.S. Veterans Health Administration
patients with unstable schizoaffective disorder or schizophrenia (n=369) concluded that RLAI raised medication costs without
improving outcomes or lowering hospital or health care costs (Barnett, Scott, Krystal, & Rosenheck, 2012).
According the review papers identified, the comparative cost-effectiveness literature favors of RLAI.
61
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Geitona, M., Kousoulakou, H., Ollandezos, M., Athanasakis, K., Papanicolaou, S., & Kyriopoulos, I. (2008). Costs and effects of
paliperidone extended release compared with alternative oral antipsychotic agents in patients with schizophrenia in Greece:
a cost effectiveness study. Annals of general psychiatry, 7, 16. doi:10.1186/1744-859X-7-16
Gutierrez-Recacha, P., Chisholm, D., Haro, J. M., Salvador-Carulla, L., & Ayuso-Mateos, J. L. (2006). Cost-effectiveness of
different clinical interventions for reducing the burden of schizophrenia in Spain. Acta psychiatrica Scandinavica.
Supplementum, 114(432), 29-38. doi:10.1111/j.1600-0447.2006.00917.x
Hansen, K., Franois, C., Toumi, M., & Lanon, C. (2002). A pharmacoeconomic evaluation of zuclopenthixol compared with
haloperidol and risperidone in the treatment of schizophrenia. The European journal of health economics: HEPAC: health
economics in prevention and care, 3(3), 173-9. doi:10.1007/s10198-002-0128-3
Hosk, L., & Bahbouh, R. (2002). Costs and outcomes of risperidone treatment in schizophrenia in the Czech Republic.
European psychiatry: the journal of the Association of European Psychiatrists, 17(4), 213-21. Retrieved from
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economic results of an international naturalistic study. International clinical psychopharmacology, 16(4), 189-96. Retrieved
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Keith, S. (2009). Use of long-acting risperidone in psychiatric disorders: focus on efficacy, safety and cost-effectiveness. Expert
review of neurotherapeutics, 9(1), 9-31. doi:10.1586/14737175.9.1.9
Kim, E., You, M., Pikalov, A., Van-Tran, Q., & Jing, Y. (2011). One-year risk of psychiatric hospitalization and associated
treatment costs in bipolar disorder treated with atypical antipsychotics: a retrospective claims database analysis. BMC
psychiatry, 11(1), 6. BioMed Central Ltd. doi:10.1186/1471-244X-11-6
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Pharmacoeconomics of quetiapine for the management of acute mania in bipolar I disorder. Expert review of
pharmacoeconomics & outcomes research, 7(5), 459-67. doi:10.1586/14737167.7.5.459
Lecomte, P., De Hert, M., van Dijk, M., Nuijten, M., Nuyts, G., & Persson, U. (2000). A 1-year cost-effectiveness model for the
treatment of chronic schizophrenia with acute exacerbations in Belgium. Value in health: the journal of the International
Society for Pharmacoeconomics and Outcomes Research, 3(1), 1-11. doi:10.1046/j.1524-4733.2000.31001.x
Lindner, L. M., Marasciulo, A. C., Farias, M. R., & Grohs, G. E. M. (2009). Economic evaluation of antipsychotic drugs for
schizophrenia treatment within the Brazilian Healthcare System. Revista de sade pblica, 43 Suppl 1, 62-9. Retrieved from
Lindstrm, E., Eberhard, J., Fors, B. M., Hansen, K., & Sapin, C. (2011). A pharmacoeconomic analysis of sertindole in the
treatment of schizophrenia in Sweden. Nordic journal of psychiatry, 65(6), 403-13. doi:10.3109/08039488.2011.590603
Magnus, A., Carr, V., Mihalopoulos, C., Carter, R., & Vos, T. (2005). Assessing cost-effectiveness of drug interventions for
schizophrenia. The Australian and New Zealand journal of psychiatry, 39(1-2), 44-54. doi:10.1111/j.14401614.2005.01509.x
McIntyre, R. S., Cragin, L., Sorensen, S., Naci, H., Baker, T., & Roussy, J.-P. (2010). Comparison of the metabolic and
economic consequences of long-term treatment of schizophrenia using ziprasidone, olanzapine, quetiapine and risperidone
in Canada: a cost-effectiveness analysis. Journal of evaluation in clinical practice, 16(4), 744-55. doi:10.1111/j.13652753.2009.01189.x
Obradovic, M., Mrhar, a, & Kos, M. (2007). Cost-effectiveness of antipsychotics for outpatients with chronic schizophrenia.
International journal of clinical practice, 61(12), 1979-88. doi:10.1111/j.1742-1241.2007.01431.x
Olivares, J. M., Rodriguez-Martinez, A., Burn, J. a, Alonso-Escolano, D., & Rodriguez-Morales, A. (2008). Cost-effectiveness
analysis of switching antipsychotic medication to long-acting injectable risperidone in patients with schizophrenia: a 12and 24-month follow-up from the e-STAR database in Spain. Applied health economics and health policy, 6(1), 41-53.
Palmer, C. S., Brunner, E., Ruz-flores, L. G., Paez-agraz, F., & Revicki, D. A. (2002). A Cost-Effectiveness Clinical Decision
Analysis Model for Treatment of Schizophrenia. Archives of medical research, 33, 572-580.
Taylor, D. M., Wright, T., & Libretto, S. E. (2003). Risperidone Compared With Olanzapine in a Naturalistic Clinical Study: A
Cost Analysis. Journal of clinical psychiatry, 64(5), 589-597.
64
Tunis, S. L., Faries, D. E., Nyhuis, A. W., Kinon, B. J., Ascher-Svanum, H., & Aquila, R. (2006). Cost-effectiveness of
olanzapine as first-line treatment for schizophrenia: results from a randomized, open-label, 1-year trial. Value in health: the
journal of the International Society for Pharmacoeconomics and Outcomes Research, 9(2), 77-89. doi:10.1111/j.15244733.2006.00083.x
United Nations Development Programme. (2011). Human Development Report 2011: Sustainability and Equity: A Better Future
for All (pp. 1-185). New York.
Verma, S., Orengo, C. A., Kunik, M. E., Hale, D., & Molinari, V. A. (2001). Tolerability and effectiveness of atypical
antipsychotic in male geriatric inpatients. International journal of geriatric psychiatry, 227, 223-227.
Vos, T., Haby, M. M., Magnus, A., Mihalopoulos, C., Andrews, G., & Carter, R. (2005). Assessing cost-effectiveness in mental
health: helping policy-makers prioritize and plan health services. The Australian and New Zealand journal of psychiatry,
39(8), 701-12. doi:10.1111/j.1440-1614.2005.01654.x
Yang, L., Li, M., Tao, L.-bo, Zhang, M., Nicholl, M. D., & Dong, P. (2009). Cost-effectiveness of long-acting risperidone
injection versus alternative atypical antipsychotic agents in patients with schizophrenia in China. Value in health: the
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Society for Pharmacoeconomics and Outcomes Research (ISPOR). doi:10.1111/j.1524-4733.2009.00630.x
Excluded Papers
Aronson, S. M. (1997). Cost-effectiveness and quality of life in psychosis: the pharmacoeconomics of risperidone. Clinical
therapeutics, 19(1), 139-47; discussion 126-7. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/9083716
Ginsberg, G., Shani, S., & Lev, B. (1998). Cost-benefit analysis of risperidone and clozapine in the treatment of schizophrenia in
Israel. PharmacoEconomics, 13(2), 231-41. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/10178649
Jerrell, J. M. (2002). Cost-effectiveness of risperidone, olanzapine, and conventional antipsychotic medications. Schizophrenia
bulletin, 28(4), 589-605. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/12795493
65
13. Summary of the Regulatory Status of Risperidone

Risperidone was originally developed by Janssen Pharmaceuticals and approved for use in schizophrenia by the United States
Food and Drug Administration (FDA) on Dec 29, 1993 (FDA, 2012). In 2003, it received FDA approval for the short-term
treatment of acute manic or mixed episodes associated with Bipolar I Disorder in adults; in 2006, for the treatment of irritability
with autism in children and adolescents 5 to 16 years old. A year later, risperidone became the first atypical antipsychotic
medication to gain FDA approval for the short-term treament of manic or mixed episodes of Bipolar I disorder in children and
adolescents aged 10 to 17, as well as for the treatment of schizophrenia in adolescents aged 13 to 17 (FDA, 2007). Risperidone
became available as a generic medication in 2008 (FDA, 2012).
Risperidone, originally developed by Janssen-Cilag, is registered with the European Medicines Agency and is approved for use
in all 27 member states of the European Union (European Medicines Agency, 2012). The indications for use are similar to those
in the U.S. including schizophrenia and moderate to severe manic episodes of mania in bipolar disorder (European Medicines
Agency, 2008).
In 2003, Janssen Pharmaceutica Inc issued a Dear Healthcare Professional letter in the United States stating changes to the
prescribing information for risperidone. It added information regarding cerebrovascular adverse events in elderly patients with
dementia-related psychosis (FDA, 2004). In 2005, the FDA issued an alert for increased mortality in patients with dementiarelated psychosis treated with atypical antipsychotics, including risperidone. At the current time, similar to other atypical
antipsychotic medications, risperidone carries a "black box warning" for dementia-related psychosis (FDA, 2005).
The long-acting injection form, Risperdal Consta, received FDA approval for treatment of schizophrenia in 2003 (FDA, 2012).
It is also registered in many countries around the world including the European Union, Australia, New Zealand, Switzerland,
Brazil, South Africa, Korea and the Philippines among others (Australian Government Department of Health and Ageing, 2010).
References
Australian Government Department of Health and Ageing Therapeutic Goods Administration. Australian public assessment
report for risperidone. June 2010.
http://www.tga.gov.au/pdf/auspar/auspar-risperdal-consta.pdf
Last accessed: Oct 6, 2012.
European Medicines Agency (EMA).
http://www.emea.europa.eu/docs/en_GB/document_library/Referrals_document/Risperdal_30/WC500007979.pdf
European Medicines Agency (EMA). Evaluation of medicines for human use. July 2008.
http://www.ema.europa.eu/docs/en_GB/document_library/Committee_meeting_report/2009/10/WC500006073.pdf
U.S. Food and Drug Administration (FDA) Orange Book. Oct, 2012.
66
http://www.accessdata.fda.gov/scripts/cder/ob/docs/obdetail.cfm?Appl_No=020272&TABLE1=OB_Rx
2012.
Last accessed: Oct 6,
U.S. Food and Drug Administration (FDA). FDA approves risperdal for two psychiatric conditions in children and adolescents.
Aug 22, 2007. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2007/ucm108969.htm
U.S. Food and Drug Administration (FDA). Public health advisory: Deaths with antipsychotics in elderly patients with
behavioral distrubances. April 2005.
http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHea
thcareProfessionals/PublicHealthAdvisories/ucm053171.htm
U.S. Food and Drug Administration (FDA). Risperdal (risperidone) dear healthcare professional letter. Aug 2004.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalProducts/ucm166518.htm
67
14. Availability of Pharmacoepial Standards for Risperidone
British Pharmacopoeia: Yes

European Pharmacopoeia: Yes
Indian Pharmacopoeia: No
International Pharmacopoeia: No
United States Pharmacopoeia: Yes
References
British Pharmacopoeia: http://www.pharmacopoeia.co.uk/
Last accessed Oct 7, 2012.
European Pharmacopoeia 7th Edition: http://www.edqm.eu/en/european-pharmacopoeia-publications-1401.html
Indian Pharmacopoeia: http://ipc.nic.in/
InternationalPharmacopoeia: http://www.who.int/medicines/publications/pharmacopoeia/overview/en/index.html
United States Pharmacopoeia: http://www.usp.org/
68
15. Proposed New Text for the WHO Model Formulary*
----------------------------INDICATIONS AND USAGE---------------------------Risperidone is an atypical antipsychotic agent indicated for:

Treatment of schizophrenia in adults and adolescents aged 13-17 years
Alone, or in combination with lithium or valproate, for the short-term treatment of acute manic or mixed
episodes associated with Bipolar I Disorder in adults, and alone in children and adolescents aged 10-17 years
Treatment of irritability associated with autistic disorder in children and adolescents aged 5-16 years
Initial Dose
Schizophrenia/Psychosis
in
non-emergent
settings- Adults
SchizophreniaAdolescents
Bipolar Mania- Adults
Titration
Target Dose
1mg/day in 2 1mg daily

divided doses
4-8 mg daily
0.5mg/day
3mg/day
1-6mg/day
1-6mg/day
1-6mg/day
2-3mg/day
Bipolar
Mania
in 0.5mg/day
children/adolescents
Irritability
associated 0.25mg/day
with autistic disorder
(<20kg)
0.5mg/day
(20 kg)
0.5-1mg
daily
1mg daily
0.5 1mg 2.5mg/day

daily
0.25-0.5mg
0.5 mg /day
at 2 weeks (<20 kg)
1 mg /day
(20 kg)
69
Effective
Dose
4-16
mg
/day
0.56mg/day
0.5-3mg
/day
--------------------DOSAGE FORMS AND STRENGTHS--------------------- Tablets 0.25 mg, 1 mg, 2 mg

Risperidone long-acting depot microspheres formulation for deep intramuscular administration 25
mg vial/kit
-------------------------------CONTRAINDICATIONS------------------------------ Known hypersensitivity to the product

---------------------------WARNINGS AND PRECAUTIONS-------------------
Cerebrovascular events, including stroke, in elderly patients with dementia-related
psychosis.
Neuroleptic Malignant Syndrome
Tardive dyskinesia
Hyperglycemia and diabetes mellitus
Hyperprolactinemia
Orthostatic hypotension
Leukopenia, Neutropenia, and Agranulocytosis: has been reported with antipsychotics,

including risperidone. Patients with a history of a clinically significant low white blood cell count
(WBC) or a drug-induced leukopenia/neutropenia should have their complete blood count (CBC)
monitored frequently during the first few months of therapy and discontinuation of risperidone
should be considered at the first sign of a clinically significant decline in WBC in the absence of
other causative factors.
Potential for cognitive and motor impairment
Seizures
Disruption of body temperature regulation
Increased sensitivity in patients with Parkinsons disease or those with dementia with
Lewy bodies
------------------------------ADVERSE REACTIONS-----------------------------The most common adverse reactions in clinical trials (10%) were somnolence, appetite
increased, fatigue, rhinitis, upper respiratory tract infection, vomiting, coughing, urinary
incontinence, saliva increased, constipation, fever, Parkinsonism, dystonia, abdominal pain,
anxiety, nausea, dizziness, dry mouth, tremor, rash, akathisia, and dyspepsia.
The most common adverse reactions that were associated with discontinuation from clinical
trials were somnolence, nausea, abdominal pain, dizziness, vomiting, agitation, and akathisia.
effects, hypotensive effects of other drugs with this potential may be enhanced.
---------------------------------DRUG INTERACTIONS---------------------------70

Due to CNS effects, use caution when administering with other centrally-acting drugs.
Avoid alcohol. Due to hypotensive, hypotensive effects of other drugs with this potential may be
enhanced
Effects of levodopa and dopamine agonists may be antagonized.
Cimetidine and ranitidine increase the bioavailability of risperidone.
Clozapine may decrease clearance of risperidone.
Fluoxetine and paroxetine increase plasma concentrations of risperidone.
Carbamazepine and other enzyme inducers decrease plasma concentrations of

risperidone.
-----------------------USE IN SPECIFIC POPULATIONS----------------------

Nursing Mothers: should not breast feed.
Pediatric Use: safety and effectiveness not established for schizophrenia less than 13
years of age, for bipolar mania less than 10 years of age, and for autistic disorder less than 5
years of age.
Elderly or debilitated; severe renal or hepatic impairment; predisposition to hypotension

or for whom hypotension poses a risk: Lower initial dose (0.5 mg twice daily), followed by
increases in dose in increments of no more than 0.5 mg twice daily. Increases to dosages
above 1.5 mg twice daily should occur at intervals of at least 1 week. (8.5, 2.4)
*(Adapted
from
www.fda.gov,
last
accessed
on
11/11/12:
http://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020272s056,020588s044,0213
46s033,021444s03lbl.pdf)
71
APPENDIX
Letters of Support
72
MINISTRY OF HEALTH
Third Floor, East Block Building
Belmopan, Belize, Central America.
Phone: 501-822-2325/2363
Fax: 501-822-2942/2055
[email protected]
REF: ADM/33/12(94)
October 1, 2012
The Secretary of the 19th Expert Committee on the Selection and Use of Essential Medicines
Medicine Access and Rational Use (MAR)
Department of Essential Medicines and Health Products (EMP)
World Health Organization
20 Avenue Appia
CH-1211 Geneva 27
Switzerland
Dear Secretariat,
I am writing to you on behalf of the Ministry of Health in Belize in support of the
application being made by Dr. Craig Katz and his colleagues at the Mount Sinai School of
Medicine to have Risperidone added to the List of Essential Medications. We have
collaborated with them for over six years on meeting mental health needs in our own
country and see their decision to make this application on behalf of people around the
world as showing great initiative and wisdom. We have much experience with Risperidone.
We believe that at least one atypical antipsychotic medication should be considered an
essential part of any formulary, and our experience definitely supports that it should be
Risperidone. I would like to make a special appeal that it be included in all of its
formulations, including the long-acting injection.
73
Respectfully,
Claudia Cayetano, M.D.

Head Psychiatrist
74
75
76

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Application for Inclusion to the 19th Expert Committee on the

Selection and Use of Essential Medicines:

Contact: Craig L. Katz, M.D., 001 212-860-8665, [email protected]

Focal Point Person in WHO

Name of the Organizations Consulted

International Nonproprietary Name

Formulations Proposed for Inclusion

Public Health Relevance

Comparative Cost and Cost-Effectiveness

Text for the WHO Model Formulary

APPENDIX- Letters of Support

1. Summary Statement of the Proposal for Inclusion of Risperidone

2. Focal Point Person(s) in the World Health Organization

Dr. K Weerasuriya, Medical Officer

3. Name of the Organization(s) Consulted and Supporting the Application

Ministry of Health, Belize

SEE APPENDIX FOR LETTERS OF SUPPORT

International Nonproprietary Name (INN, generic name) of the medicine

5. Formulations of Risperidone Proposed for Inclusion

Tablets 0.25 mg, 1 mg, 2 mg

Oral Solution: 1 mg/mL 30 mL bottle

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

Uniao Quimica, Braz.

(Form Not Given)

(Form Not Given)

0.5 MG Tablet; 0.25 MG Tablet; 1

0.5 MG disintegrating tablet; 1 M

(Form Not Given)

Pharma Investi, Chile

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)

(Form Not Given)