ATC codes:
N05AB02
Indication
Schizophrenia or other primary psychotic disorders
ICD11 code:
6A4Z
INN
Fluphenazine
Medicine type
Chemical agent
List type
Core
Formulations
Parenteral > General injections > IM:
25 mg per mL in ampoule (decanoate) ;
25 mg per mL in ampoule (enanthate)
EML status history
Sex
All
Age
Adolescents and adults
Therapeutic alternatives
Patent information
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Wikipedia
DrugBank
Expert Committee recommendation
The Expert Committee recalled the request made by the 2021 Committee for therapeutic alternatives to be reviewed for the square box listings for chlorpromazine, fluphenazine and haloperidol for treatment of schizophrenia and related psychotic disorders. The Expert Committee accepted the rationale applied by the WHO Department of Mental Health and Substance Use in identifying suitable therapeutic alternatives and made the following recommendations.
For immediate-acting first-generation antipsychotics, chlorpromazine (oral formulations only) should be included as a therapeutic alternative to oral haloperidol. This recommendation, coupled with the recommendation to remove chlorpromazine injection, effectively removes the independent listing for chlorpromazine from the EML.
For long-acting first-generation antipsychotics, haloperidol decanoate and zuclopenthixol decanoate should be included as therapeutic alternatives to fluphenazine.
Background
Chlorpromazine, fluphenazine and haloperidol have all been included on the EML for use in the treatment of schizophrenia and related psychotic disorders since the first EML was published in 1977.
At its meeting in 2021, the Expert Committee considered a review of square box listings on the EML and EMLc and recommended that all square box listings be qualified to explicitly indicate the recommended therapeutic alternatives. The Committee requested that the therapeutic alternatives for chlorpromazine, fluphenazine and haloperidol be reviewed and updated in 2023 (1). Thus, the EML Secretariat invited the WHO Department of Mental Health and Substance Use to submit an application reviewing the therapeutic alternatives for these medicines.
In a separate application to the 2023 Expert Committee meeting, the WHO Collaborating Centre for Research and Training in Mental Health and Service Evaluation at the University of Verona, Italy, proposed the deletion of chlorpromazine intramuscular injection from the EML.
Public health relevance
About 24 million people in the world are estimated to have schizophrenia (2). The prevalence of schizophrenia ranges from 0.2% to 0.4% across countries, while its incidence is reported to be 18.7 per 100 000 person-years (3). Globally, 129 million disability-adjusted life-years are attributable to mental health disorders, 11.7% of which are attributable specifically to schizophrenia spectrum disorders. Schizophrenia is also associated with relevant direct and indirect healthcare costs, and it is considered the costliest mental health condition per person globally (2,4). People with schizophrenia have a life expectancy about 14 years lower than the general population (5).
Benefits
The application stated that according to the most recent and high-quality meta-analysis evidence on both acute and maintenance treatment of schizophrenia spectrum disorders, differences exist between first-generation antipsychotics in terms of efficacy, tolerability and certainty of evidence.
The applicants examined two recent meta-analyses: a 2019 systematic review and network meta-analysis (402 randomized controlled trials, 53 463 participants) which evaluated the comparative efficacy and tolerability of 32 oral antipsychotics for acute treatment of adults with schizophrenia (6); and a 2022 systematic review and meta-analysis (537 randomized controlled trials, 76 382 participants) which investigated the response of subgroups of patients with schizophrenia to different antipsychotic medicines (7). The evidence for first-generation antipsychotics was reviewed according to the following criteria.
• Demonstration of better efficacy in comparison with placebo for acute and/or maintenance treatment, considering the effect size as clinically meaningful when the confidence interval included a standardized mean difference of ≥ 0.3 for continuous outcomes, or a risk ratio of ≤ 0.6 for dichotomous outcomes.
• A moderate to high certainty of evidence according to grading of recommendations, assessment, development, and evaluations (GRADE)/confidence in network meta-analysis (CINeMA) approach for acute or maintenance treatment, or both.
The first-generation antipsychotics identified as meeting the above criteria were oral chlorpromazine, immediate-acting haloperidol, long-acting haloperidol decanoate, fluphenazine enantate/decanoate and zuclopenthixol decanoate. When compared head-to-head with the first-generation antipsychotics already listed in the EML, no statistically significant differences were found.
Harms
Different side-effect profiles of the different first-generation antipsychotics were observed, although tolerability outcomes were rarely reported and were likely imprecise. In general, chlorpromazine had a higher risk of weight gain and anticholinergic effects compared with haloperidol, however haloperidol was associated with higher risks of extrapyramidal symptoms, akathisia and hyperprolactinaemia than chlorpromazine.
Cost / cost effectiveness
Not applicable.
WHO guidelines
The medicines proposed in the application are recommended in the 2023 WHO Mental Health Gap Action Programme (mhGAP) guidelines (8).
Availability
The proposed medicines are available in branded and generic forms.
Other considerations
In consideration of a separate application at the meeting, the Expert Committee recommended the deletion of chlorpromazine immediate-release injection from the core list of the EML.
1. The selection and use of essential medicines. Report of the WHO Expert Committee, 2021 (including the 22nd WHO Model List of Essential Medicines and the 6th WHO Model List of Essential Medicines for Children). Geneva: World Health Organization; 2021 (WHO Technical Report Series, No. 1035; https://apps.who.int/iris/handle/10665/351172, accessed 6 October 2023).
2. World mental health report: Transforming mental health for all. Geneva: World Health Organization; 2022 (https://apps.who.int/iris/handle/10665/356119, accessed 6 October 2023).
3. Jongsma HE, Turner C, Kirkbride JB, Jones PB. International incidence of psychotic disorders, 2002-17: a systematic review and meta-analysis. Lancet Public Health. 2019;4(5):e229–e44.
4. Christensen MK, Lim CCW, Saha S, Plana-Ripoll O, Cannon D, Presley F, et al. The cost of mental disorders: a systematic review. Epidemiol Psychiatr Sci. 2020;29:e161.
5. Hjorthøj C, Stürup AE, McGrath JJ, Nordentoft M. Years of potential life lost and life expectancy in schizophrenia: a systematic review and meta-analysis. Lancet Psychiatry. 2017;4(4):295–301.
6. Huhn M, Nikolakopoulou A, Schneider-Thoma J, Krause M, Samara M, Peter N, et al. Comparative efficacy and tolerability of 32 oral antipsychotics for the acute treatment of adults with multi-episode schizophrenia: a systematic review and network meta-analysis. Lancet. 2019;394(10202):939–51.
7. Leucht S, Chaimani A, Krause M, Schneider-Thoma J, Wang D, Dong S, et al. The response of subgroups of patients with schizophrenia to different antipsychotic drugs: a systematic review and meta-analysis. Lancet Psychiatry. 2022;9(11):884–93.
8. Mental Health Gap Action Programme (mhGAP) guideline for mental, neurological and substance use disorders. Third edition. Geneva: World Health Organization; 2023 (https://iris.who.int/handle/10665/374250, accessed 21 November 2023).