Fluphenazine

Fluphenazine, sold under the brand names Prolixin among others, is an antipsychotic medication.[1] It is used in the treatment of chronic psychoses such as schizophrenia,[1][2] and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine.[3] It is given by mouth, injection into a muscle, or just under the skin.[1] There is also a long acting injectable version that may last for up to four weeks.[1] Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression.[4]

Fluphenazine
Clinical data
Trade namesProlixin, Modecate, Moditen others
AHFS/Drugs.comMonograph
MedlinePlusa682172
License data
Pregnancy
category
  • AU: C
  • US: C (Risk not ruled out)
    Routes of
    administration    		by mouth, IM, depot injection (fluphenazine decanoate)
    ATC code
    Legal status
    Legal status
    Pharmacokinetic data
    Bioavailability2.7% (by mouth)
    Metabolismunclear[1]
    Elimination half-lifeIM 15 hours (HCL), 7-10 days (decanoate)[1]
    ExcretionUrine, faeces
    Identifiers
    CAS Number
    PubChem CID
    IUPHAR/BPS
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    CompTox Dashboard (EPA)
    ECHA InfoCard100.000.639
    Chemical and physical data
    FormulaC22H26F3N3OS
    Molar mass437.53 g·mol−1
    3D model (JSmol)
      (verify)

    Common side effects include movement problems, sleepiness, depression and increased weight.[1] Serious side effects may include neuroleptic malignant syndrome, low white blood cell levels, and the potentially permanent movement disorder tardive dyskinesia.[1] In older people with psychosis as a result of dementia it may increase the risk of dying.[1] It may also increase prolactin levels which may result in milk production, enlarged breasts in males, impotence, and the absence of menstrual periods.[1] It is unclear if it is safe for use in pregnancy.[1] Fluphenazine is a typical antipsychotic of the phenothiazine class.[1] Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors.[1] In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal.[5]

    Fluphenazine came into use in 1959.[6] The injectable form is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] It is available as a generic medication.[1] In the United States the tablets costs between $0.22 and $0.42 per day for a typical dose.[1] The wholesale cost in the developing world of the long acting form is between US$0.20 and US$6.20 per injection as of 2014.[8] It was discontinued in Australia around mid 2017.[9]

    Medical use

    A 2018 Cochrane review found that fluphenazine's was an imperfect treatment and other inexpensive drugs less associated with side effects may be an equally effective choice for people with schizophrenia.[10]

    Side effects

    Discontinuation

    The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[11] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[12] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[12] Less commonly there may be a felling of the world spinning, numbness, or muscle pains.[12] Symptoms generally resolve after a short period of time.[12]

    There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[13] It may also result in reoccurrence of the condition that is being treated.[14] Rarely tardive dyskinesia can occur when the medication is stopped.[12]

    Pharmacology

    Pharmacodynamics
    See also: Antipsychotic § Pharmacodynamics, and Antipsychotic § Comparison of medications

    Fluphenazine acts primarily by blocking post-synaptic D2 receptors in the basal ganglia, cortical and limbic system. It also blocks alpha-1 adrenergic receptors, muscarinic-1 receptors, and histamine-1 receptors.[15][16]

    Fluphenazine[17]
    SiteKi (nM)ActionRef
    5-HT1A145-2829ND[17]
    5-HT1B334ND[17]
    5-HT1D334ND[17]
    5-HT1E540ND[17]
    5-HT2A3.8-98ND[17]
    5-HT2BNDND[17]
    5-HT2C174–2,570ND[17]
    5-HT34,265- > 10,000ND[17]
    5-HT5A145ND[17]
    5-HT67.9 - 38ND[17]
    5-HT78ND[17]
    D114.45ND[17]
    D20.89ND
    D2LND[17]
    D31.412ND[17]
    D489.12ND[17]
    D595–2,590ND[17]
    α1A6.4-9ND[17]
    α1B13ND[17]
    α2A304-314ND[17]
    α2B181.6-320ND[17]
    α2C28.8-122ND[17]
    β1> 10,000ND[17]
    β2> 10,000ND[17]
    H17.3-70ND[17]
    H2560ND[17]
    H31,000ND[17]
    H4> 10,000ND[17]
    M11,095-3,235.93ND[17]
    M22,187.76-7,163ND[17]
    M31441-1445.4ND[17]
    M45,321ND[17]
    M5357ND[17]
    SERTNDND[17]
    NETNDND[17]
    DATNDND[17]
    NMDA
    (PCP)    		NDND[17]
    Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site. All data are for human cloned proteins, except 5-HT3 (rat), D4 (human/rat), H3 (guinea pig), and NMDA/PCP (rat).[17]

    Pharmacokinetics
    Pharmacokinetics of long-acting injectable antipsychotics
    MedicationBrand nameClassVehicleDosageTmaxt1/2 singlet1/2 multiplelogPcRef
    Aripiprazole lauroxilAristadaAtypicalWatera441–1064 mg/4–8 weeks24–35 days?54–57 days7.9–10.0
    Aripiprazole monohydrateAbilify MaintenaAtypicalWatera300–400 mg/4 weeks7 days?30–47 days4.9–5.2
    Bromperidol decanoateImpromen DecanoasTypicalSesame oil40–300 mg/4 weeks3–9 days?21–25 days7.9[18]
    Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days?19 days9.0[19]
    Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[19][20]
    Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[21][22][23]
    Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days?6.4–7.4[22]
    FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days?5.2–5.8[24]
    Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[25][26]
    Olanzapine pamoateZyprexa RelprevvAtypicalWatera150–405 mg/2–4 weeks7 days?30 days–
    Oxyprothepin decanoateMeclopinTypical?????8.5–8.7
    Paliperidone palmitateInvega SustennaAtypicalWatera39–819 mg/4–12 weeks13–33 days25–139 days?8.1–10.1
    Perphenazine decanoateTrilafon DekanoatTypicalSesame oil50–200 mg/2–4 weeks??27 days8.9
    Perphenazine enanthateTrilafon EnanthateTypicalSesame oil25–200 mg/2 weeks2–3 days?4–7 days6.4–7.2[27]
    Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days?14–21 days8.5–11.6[20]
    Pipotiazine undecylenatePiportil MediumTypicalSesame oil100–200 mg/2 weeks???8.4
    RisperidoneRisperdal ConstaAtypicalMicrospheres12.5–75 mg/2 weeks21 days?3–6 days–
    Zuclopentixol acetateClopixol AcuphaseTypicalViscoleob50–200 mg/1–3 days1–2 days1–2 days4.7–4.9
    Zuclopentixol decanoateClopixol DepotTypicalViscoleob50–800 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.

    History

    Fluphenazine came into use in 1959.[6]

    Availability

    The injectable form is on the World Health Organization's List of Essential Medicines, the safest and most effective medicines needed in a health system.[7] It is available as a generic medication.[1] In the United States the tablets costs between 0.22 and 0.42 USD per day for a typical dose.[1] The wholesale cost in the developing world of the long acting form is between 0.20 and 6.20 USD per injection as of 2014.[8] It was discontinued in Australia around mid 2017.[9]

    Other animals

    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.[28]

    See also

    References
    1. "fluphenazine decanoate". The American Society of Health-System Pharmacists. Archived from the original on 8 December 2015. Retrieved 1 December 2015.
    2. "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.
    3. 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. 8 (8): CD009230. doi:10.1002/14651858.CD009230.pub2. PMID 25087165.
    4. "Modecate Injection 25mg/ml - Patient Information Leaflet (PIL) - (eMC)". www.medicines.org.uk. Retrieved 6 November 2017.
    5. "Fluphenazine". livertox.nih.gov. Retrieved 6 November 2017.
    6. McPherson EM (2007). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Burlington: Elsevier. p. 1680. ISBN 9780815518563.
    7. 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.
    8. "Fluphenazine Decanoate". International Drug Price Indicator Guide. Archived from the original on 2 August 2017. Retrieved 2 December 2015.
    9. Rossi S, ed. (July 2017). "Fluphenazine - Australian Medicines Handbook". Australian Medicines Handbook. Adelaide, Australia: Australian Medicines Handbook Pty Ltd. Retrieved 8 August 2017.
    10. Matar, Hosam E.; Almerie, Muhammad Qutayba; Sampson, Stephanie J. (12 June 2018). "Fluphenazine (oral) versus placebo for schizophrenia". The Cochrane Database of Systematic Reviews. 6: CD006352. doi:10.1002/14651858.CD006352.pub3. ISSN 1469-493X. PMC 6513420. PMID 29893410.
    11. Joint Formulary Committee, BMJ, 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.
    12. Haddad, Peter; Haddad, Peter M.; Dursun, Serdar; Deakin, Bill (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. p. 207–216. ISBN 9780198527480.
    13. 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.
    14. Sacchetti, Emilio; Vita, Antonio; Siracusano, Alberto; Fleischhacker, Wolfgang (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN 9788847026797.
    15. Siragusa S, Saadabadi A. "Fluphenazine". StatPearls. PMID 29083807.
    16. PubChem. "Fluphenazine". pubchem.ncbi.nlm.nih.gov. Retrieved 30 September 2019.
    17. 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.
    18. 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. https://scholar.google.com/scholar?cites=10379409109713994773
    19. Jørgensen A, Overø KF (1980). "Clopenthixol and flupenthixol depot preparations in outpatient schizophrenics. III. Serum levels". Acta Psychiatr Scand Suppl. 279: 41–54. doi:10.1111/j.1600-0447.1980.tb07082.x. PMID 6931472.
    20. Reynolds, J. E. F. (1993). Anxiolytic sedatives, hypnotics and neuroleptics. Martindale: The Extra Pharmacopoeia, 30th Edition (pp. 364–623). Pharmaceutical Press, London. https://scholar.google.com/scholar?cluster=8335042449033257176
    21. Ereshefsky L, Saklad SR, Jann MW, Davis CM, Richards A, Seidel DR (May 1984). "Future of depot neuroleptic therapy: pharmacokinetic and pharmacodynamic approaches". J Clin Psychiatry. 45 (5 Pt 2): 50–9. PMID 6143748.
    22. 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". Br J Clin Pharmacol. 7 (4): 325–31. doi:10.1111/j.1365-2125.1979.tb00941.x. PMC 1429660. PMID 444352.
    23. Young. D.: Ereshefsky. L.: Saklad. S.R.; Jann. M.W. and Garcia. N.: Explaining the pharmacokinetics of fluphenazine through computer simulations. (Abstract.) Presented at the 19th Annual Midyear Clinical Meeting of the American Society of Hospital Pharmacists. Dallas. Texas (1984).
    24. Janssen PA, Niemegeers CJ, Schellekens KH, Lenaerts FM, Verbruggen FJ, van Nueten JM, Marsboom RH, Hérin VV, Schaper WK (November 1970). "The pharmacology of fluspirilene (R 6218), a potent, long-acting and injectable neuroleptic drug". Arzneimittelforschung. 20 (11): 1689–98. PMID 4992598.
    25. 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.
    26. Reyntigens AJ, Heykants JJ, Woestenborghs RJ, Gelders YG, Aerts TJ (1982). "Pharmacokinetics of haloperidol decanoate. A 2-year follow-up". Int Pharmacopsychiatry. 17 (4): 238–46. doi:10.1159/000468580. PMID 7185768.
    27. 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), 1071–1088. https://scholar.google.com/scholar?cluster=12503004172250709786
    28. 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.
    • "Fluphenazine". Drug Information Portal. U.S. National Library of Medicine.
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