Fluphenazine

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Fluphenazine
Fluphenazine.svg
Fluphenazine-xtal-2012-ball-and-stick.png
Clinical data
Trade names Prolixin, Modecate, Moditen others
AHFS/Drugs.com Monograph
MedlinePlus a682172
License data
Pregnancy
category
  • AU:C
Routes of
administration 		By mouth, Intramuscular injection, depot injection (fluphenazine decanoate)
Drug class Typical antipsychotic
ATC code
Legal status
Legal status
Pharmacokinetic data
Bioavailability 2.7% (by mouth)
Metabolism unclear [2]
Elimination half-life IM 15 hours (HCl), 7–10 days (decanoate) [2]
Excretion Urine, feces
Identifiers
  • 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEBI
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard 100.000.639 OOjs UI icon edit-ltr-progressive.svg
Chemical and physical data
Formula C22H26F3N3OS
Molar mass 437.53 g·mol−1
3D model (JSmol)
  • FC(F)(F)c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCN(CCO)CC4
  • InChI=1S/C22H26F3N3OS/c23-22(24,25)17-6-7-21-19(16-17)28(18-4-1-2-5-20(18)30-21)9-3-8-26-10-12-27(13-11-26)14-15-29/h1-2,4-7,16,29H,3,8-15H2 Yes check.svgY
  • Key:PLDUPXSUYLZYBN-UHFFFAOYSA-N Yes check.svgY
   (verify)

Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication of the phenothiazine class. [2] It is used in the treatment of chronic psychoses such as schizophrenia, [2] [3] and is about equal in effectiveness to low-potency antipsychotics like chlorpromazine. [4] It is also used to treat depression in combination with nortriptyline. [5] [6] In addition to the oral form, fluphenazine comes in decanoate and enanthate depot injection versions for increased adherence. [7] Fluphenazine is given by mouth, intramuscularly, or just under the skin. [2]

Contents

Common side effects include movement problems, sleepiness, depression and increased weight. [2] Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia. [2] In older people with psychosis as a result of dementia it may increase the risk of dying. [2] It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods. [2] It is unclear if it is safe for use in pregnancy. [2] Fluphenazine decanoate should not be used by people with severe depression. [8] [9] In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal. [10]

Fluphenazine is a dopamine antagonist, blocking mesolimbic dopamine receptors. [2] [5] Fluphenazine inhibits tubulin polymerization, a property shared with other phenothiazine derivatives including perphenazine, chlorpromazine, trifluoperazine, and triflupromazine. [11]

Fluphenazine was the third antipsychotic FDA approved in the United States in 1959, and 9 years later was the first FDA approved injectable antipsychotic. [12] [13] The injectable form is on the World Health Organization's List of Essential Medicines. [14] It is available as a generic medication. [2] It was discontinued in Australia in 2017. [15]

Medical use

A 2018 Cochrane review found that fluphenazine was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia. [16] Another 2018 Cochrane review found that there was limited evidence that newer atypical antipsychotics were more tolerable than fluphenazine. [17] Intramuscular depot injection forms are available as both the decanoate and enanthate esters. [18]

Side effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. [19] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. [20] Other symptoms may include restlessness, increased sweating, and trouble sleeping. [20] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. [20] Symptoms generally resolve after a short period of time. [20]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. [21] It may also result in reoccurrence of the condition that is being treated. [22] Rarely tardive dyskinesia can occur when the medication is stopped. [20]

Pharmacology

Pharmacodynamics

Fluphenazine acts primarily by blocking post-synaptic dopaminergic D2 and D1 receptors in the basal ganglia, cortical and limbic system. [5] It also blocks α1 adrenergic receptors, muscarinic M1 receptors, and histaminergic H1 receptors, and like other phenothiazines, it competitively inhibits calmodulin. [23] [24] [25] Fluphenazine depresses both the release of hypothalamic and hypophyseal hormones and the reticular activating system. [5]

Binding Affinities of Fluphenazine [25] [26] [5] [27]
TargetKi (nM)Action
D2 0.89Antagonist
D1 14.45Antagonist
5-HT2A 3.8–98Antagonist
5-HT1B 334Modulator
5-HT2C 174–2,570Antagonist
AR NDAntagonist
α1A 6.4–9Antagonist
H1 7.3–70Antagonist
M1 1,095-3,235.93Antagonist
Calmodulin NDInhibitor
The smaller the Ki, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat). [26]

Pharmacokinetics

Oral fluphenazine rapidly absorbs and plasma levels peak at about 1.0-2.5 ng/mL 2 hours post-ingestion. [28] [29] The volume of distribution is about 298 L due to extensive tissue uptake, and it crosses the blood brain barrier. [29] Bioavailability is low at 2.7% due to first pass metabolism, [30] and the half-life is about 14–16 hours. [28] [31] Steady state concentrations vary considerably across individuals, which indicates variability in absorption, metabolism, or excretion. [28] Additionally, the dose-level relationship is curvilinear with plasma levels of 0.2 - 2.8 ng/mL being optimal for clinical improvement. [28] Fluphenazine is primarily metabolized to fluphenazine sulfoxide by the cytochrome P450 2D6. [5] Benztropine mesylate did not indicate any major drug-drug interactions. [28] Fluphenazine is exreted primarily through urine and feces.

Injectable fluphenazine is dissolved in sesame oil which forms a localized oil depot in the muscle. [32] Due to the lipophilicity of the added decanoate or enanthate group, the drug remains in the oil causing the rate-limiting step for drug being diffusion out, resulting in flip-flop kinetics. [32] Fluphenazine decanoate and enanthate are prodrugs which are hydrolyzed by esterases to fluphenazine. [33] The fluphenazine decanoate acts within 1–3 days, and its effect lasts an average of 2 weeks. [29] The half-life of fluphenazine decanoate is about 6.8-9.6 days, [29] [31] and plasma levels peak at about 2.18 ng/mL about 4–6 hours post injection. [33] Fluphenazine enanthate has a lower half life of about 3.6-3.7 days, reflecting its decreased lipophilicity. [29] [31]

Pharmacokinetics of long-acting injectable antipsychotics
MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
Aripiprazole lauroxil Aristada Atypical Water a441–1064 mg/4–8 weeks24–35 days?54–57 days7.9–10.0
Aripiprazole monohydrate Abilify Maintena Atypical Water a300–400 mg/4 weeks7 days?30–47 days4.9–5.2
Bromperidol decanoate Impromen Decanoas Typical Sesame oil 40–300 mg/4 weeks3–9 days?21–25 days7.9 [34]
Clopentixol decanoate Sordinol Depot Typical Viscoleo b50–600 mg/1–4 weeks4–7 days?19 days9.0 [35]
Flupentixol decanoate Depixol Typical Viscoleo b10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2 [35] [36]
Fluphenazine decanoateProlixin Decanoate Typical Sesame oil 12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0 [37] [38] [39]
Fluphenazine enanthateProlixin Enanthate Typical Sesame oil 12.5–100 mg/1–4 weeks2–3 days4 days?6.4–7.4 [38]
Fluspirilene Imap, Redeptin Typical Water a2–12 mg/1 week1–8 days7 days?5.2–5.8 [40]
Haloperidol decanoate Haldol Decanoate Typical Sesame oil 20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9 [41] [42]
Olanzapine pamoate Zyprexa Relprevv Atypical Water a150–405 mg/2–4 weeks7 days?30 days–
Oxyprothepin decanoate Meclopin Typical ?????8.5–8.7
Paliperidone palmitate Invega Sustenna Atypical Water a39–819 mg/4–12 weeks13–33 days25–139 days?8.1–10.1
Perphenazine decanoate Trilafon Dekanoat Typical Sesame oil 50–200 mg/2–4 weeks??27 days8.9
Perphenazine enanthate Trilafon Enanthate Typical Sesame oil 25–200 mg/2 weeks2–3 days?4–7 days6.4–7.2 [43]
Pipotiazine palmitate Piportil Longum Typical Viscoleo b25–400 mg/4 weeks9–10 days?14–21 days8.5–11.6 [36]
Pipotiazine undecylenate Piportil Medium Typical Sesame oil 100–200 mg/2 weeks???8.4
Risperidone Risperdal Consta Atypical Microspheres 12.5–75 mg/2 weeks21 days?3–6 days–
Zuclopentixol acetate Clopixol Acuphase Typical Viscoleo b50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
Zuclopentixol decanoate Clopixol Depot Typical Viscoleo b50–800 mg/2–4 weeks4–9 days?11–21 days7.5–9.0
Note: All by intramuscular injection. Footnotes:a = Microcrystalline or nanocrystalline aqueous suspension. b = Low-viscosity vegetable oil (specifically fractionated coconut oil with medium-chain triglycerides). c = Predicted, from PubChem and DrugBank. Sources:Main: See template.

Availability

The injectable form is on the World Health Organization's List of Essential Medicines. [14] It is available as a generic medication. [2] It was discontinued in Australia in 2017. [15]

Veterinary

In horses, it is sometimes given by injection as an anxiety-relieving medication, though there are many negative common side effects and it is forbidden by many equestrian competition organizations. [44]

References

  1. ↑ Anvisa (31 March 2023). "RDC Nº 784 - Listas de Substâncias Entorpecentes, Psicotrópicas, Precursoras e Outras sob Controle Especial" [Collegiate Board Resolution No. 784 - Lists of Narcotic, Psychotropic, Precursor, and Other Substances under Special Control] (in Brazilian Portuguese). Diário Oficial da União (published 4 April 2023). Archived from the original on 3 August 2023. Retrieved 16 August 2023.
  2. 1 2 3 4 5 6 7 8 9 10 11 12 13 "fluphenazine decanoate". The American Society of Health-System Pharmacists. Archived from the original on 8 December 2015. Retrieved 1 December 2015.
  3. ↑ "Product Information: Modecate (Fluphenazine Decanoate Oily Injection )" (PDF). TGA eBusiness Services. Bristol-Myers Squibb Australia Pty Ltd. 1 November 2012. Archived from the original on 2 August 2017. Retrieved 9 December 2013.
  4. ↑ Tardy M, Huhn M, Engel RR, Leucht S (August 2014). "Fluphenazine versus low-potency first-generation antipsychotic drugs for schizophrenia". The Cochrane Database of Systematic Reviews. 2014 (8) CD009230. doi:10.1002/14651858.CD009230.pub2. PMC   10898219 . PMID   25087165.
  5. 1 2 3 4 5 6 "Fluphenazine". go.drugbank.com. Retrieved 18 October 2025.
  6. ↑ Davis C (1 January 2007). "Fluphenazine". XPharm: The Comprehensive Pharmacology Reference. pp. 1–7. doi:10.1016/B978-008055232-3.61772-6. ISBN   978-0-08-055232-3.
  7. ↑ Johnson DA (November 2009). "Historical perspective on antipsychotic long-acting injections". The British Journal of Psychiatry. Supplement. 52 (S52): S7-12. doi:10.1192/bjp.195.52.s7. PMID   19880921.
  8. ↑ "Modecate Injection 25mg/ml - Patient Information Leaflet (PIL) - (eMC)". www.medicines.org.uk. Archived from the original on 7 November 2017. Retrieved 6 November 2017.
  9. ↑ Dreher J (28 March 2013). "Depot Neuroleptika: Umrechnung der oralen Dosis in eine Depot-Dosis". Psychiatrie to go (in German). Retrieved 15 July 2025.
  10. ↑ "Fluphenazine". livertox.nih.gov. 2012. PMID   31643176. Archived from the original on 17 February 2013. Retrieved 6 November 2017.
  11. ↑ Baksheeva V, La Rocca R, Allegro D, Derviaux C, Pasquier E, Roche P, et al. (August 2025). "NanoDSF Screening for Anti-tubulin Agents Uncovers New Structure-Activity Insights". Journal of Medicinal Chemistry. 68 (16): 17485–17498. doi:10.1021/acs.jmedchem.5c01008. PMC   12406199 . PMID   40815226.
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  13. ↑ McPherson EM (2007). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Burlington: Elsevier. p. 1680. ISBN   978-0-8155-1856-3.
  14. 1 2 World Health Organization (2019). World Health Organization model list of essential medicines: 21st list 2019. Geneva: World Health Organization. hdl: 10665/325771 . WHO/MVP/EMP/IAU/2019.06. License: CC BY-NC-SA 3.0 IGO.
  15. 1 2 Rossi S, ed. (July 2017). "Fluphenazine - Australian Medicines Handbook". Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 8 August 2017.
  16. ↑ Matar HE, Almerie MQ, Sampson SJ (June 2018). "Fluphenazine (oral) versus placebo for schizophrenia". The Cochrane Database of Systematic Reviews. 6 (6) CD006352. doi:10.1002/14651858.CD006352.pub3. PMC   6513420 . PMID   29893410.
  17. ↑ Sampford JR, Sampson S, Li BG, Zhao S, Xia J, Furtado VA (July 2016). "Fluphenazine (oral) versus atypical antipsychotics for schizophrenia". The Cochrane Database of Systematic Reviews. 2016 (7) CD010832. doi: 10.1002/14651858.CD010832.pub2 . PMC   6474115 . PMID   27370402.
  18. ↑ Maayan N, Quraishi SN, David A, Jayaswal A, Eisenbruch M, Rathbone J, et al. (February 2015). "Fluphenazine decanoate (depot) and enanthate for schizophrenia". The Cochrane Database of Systematic Reviews. 2015 (2) CD000307. doi: 10.1002/14651858.CD000307.pub2 . PMC   10388394 . PMID   25654768.
  19. ↑ Joint Formulary Committee B, ed. (March 2009). "4.2.1". British National Formulary (57 ed.). United Kingdom: Royal Pharmaceutical Society of Great Britain. p. 192. ISBN   978-0-85369-845-6. Withdrawal of antipsychotic drugs after long-term therapy should always be gradual and closely monitored to avoid the risk of acute withdrawal syndromes or rapid relapse.
  20. 1 2 3 4 5 Haddad P, Haddad PM, Dursun S, Deakin B (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. pp. 207–216. ISBN   978-0-19-852748-0.
  21. ↑ Moncrieff J (July 2006). "Does antipsychotic withdrawal provoke psychosis? Review of the literature on rapid onset psychosis (supersensitivity psychosis) and withdrawal-related relapse". Acta Psychiatrica Scandinavica. 114 (1): 3–13. doi:10.1111/j.1600-0447.2006.00787.x. PMID   16774655. S2CID   6267180.
  22. ↑ Sacchetti E, Vita A, Siracusano A, Fleischhacker W (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN   978-88-470-2679-7.
  23. ↑ Siragusa S, Bistas KG, Saadabadi A (2020). "Fluphenazine". StatPearls. PMID   29083807.
  24. ↑ "Fluphenazine". PubChem. U.S. National Library of Medicine. Retrieved 30 September 2019.
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  26. 1 2 Roth BL, Driscol J. "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Retrieved 14 August 2017.
  27. ↑ Siragusa S, Bistas KG, Saadabadi A (2025). "Fluphenazine". StatPearls. Treasure Island (FL): StatPearls Publishing. PMID   29083807 . Retrieved 18 October 2025.
  28. 1 2 3 4 5 Dysken MW, Javaid JI, Chang SS, Schaffer C, Shahid A, Davis JM (1 May 1981). "Fluphenazine pharmacokinetics and therapeutic response". Psychopharmacology. 73 (3): 205–210. doi:10.1007/BF00422403. PMID   6787637.
  29. 1 2 3 4 5 "Hazardous Substances Data Bank (HSDB) : 3334". PubChem. U.S. National Library of Medicine. Retrieved 12 December 2025.
  30. ↑ Koytchev R, Alken RG, McKay G, Katzarov T (1 October 1996). "Absolute bioavailability of oral immediate and slow release fluphenazine in healthy volunteers". European Journal of Clinical Pharmacology. 51 (2): 183–187. doi:10.1007/s002280050182. PMID   8911886.
  31. 1 2 3 Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). "Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man". British Journal of Clinical Pharmacology. 7 (4): 325–331. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC   1429660 . PMID   444352.
  32. 1 2 Luo JP, Hubbard JW, Midha KK (August 1997). "Studies on the mechanism of absorption of depot neuroleptics: fluphenazine decanoate in sesame oil". Pharmaceutical Research. 14 (8): 1079–1084. doi:10.1023/a:1012165731390. PMID   9279892.
  33. 1 2 Luo JP (March 1999). Pharmacokinetic studies of fluphenazine and four ester prodrugs (Ph.D. thesis). University of Saskatchewan.
  34. ↑ Parent M, Toussaint C, Gilson H (1983). "Long-term treatment of chronic psychotics with bromperidol decanoate: clinical and pharmacokinetic evaluation". Current Therapeutic Research. 34 (1): 1–6.
  35. 1 2 Jørgensen A, Overø KF (1980). "Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels". Acta Psychiatrica Scandinavica. Supplementum. 279: 41–54. doi:10.1111/j.1600-0447.1980.tb07082.x. PMID   6931472.
  36. 1 2 Reynolds JE (1993). "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
  37. ↑ Ereshefsky L, Saklad SR, Jann MW, Davis CM, Richards A, Seidel DR (May 1984). "Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches". The Journal of Clinical Psychiatry. 45 (5 Pt 2): 50–9. PMID   6143748.
  38. 1 2 Curry SH, Whelpton R, de Schepper PJ, Vranckx S, Schiff AA (April 1979). "Kinetics of fluphenazine after fluphenazine dihydrochloride, enanthate and decanoate administration to man". British Journal of Clinical Pharmacology. 7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC   1429660 . PMID   444352.
  39. ↑ Young D, Ereshefsky L, Saklad SR, Jann MW, Garcia N (1984). Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.). 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas, Texas.
  40. ↑ Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, et al. (November 1970). "The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug". Arzneimittel-Forschung. 20 (11): 1689–98. PMID   4992598.
  41. ↑ Beresford R, Ward A (January 1987). "Haloperidol decanoate. A preliminary review of its pharmacodynamic and pharmacokinetic properties and therapeutic use in psychosis". Drugs. 33 (1): 31–49. doi:10.2165/00003495-198733010-00002. PMID   3545764.
  42. ↑ Reyntigens AJ, Heykants JJ, Woestenborghs RJ, Gelders YG, Aerts TJ (1982). "Pharmacokinetics of haloperidol decanoate. A 2-year follow-up". International Pharmacopsychiatry. 17 (4): 238–46. doi:10.1159/000468580. PMID   7185768.
  43. ↑ Larsson M, Axelsson R, Forsman A (1984). "On the pharmacokinetics of perphenazine: a clinical study of perphenazine enanthate and decanoate". Current Therapeutic Research. 36 (6): 1071–88. INIST   8951670.
  44. ↑ Loving NS (31 March 2012). "Effects of Behavior-Modifying Drug Investigated (AAEP 2011)". The Horse Media Group. Archived from the original on 6 January 2017. Retrieved 13 December 2016.
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