Fluphenazine

Fluphenazine

Clinical data
Trade names	Prolixin, Modecate, Moditen others
AHFS/Drugs.com	Monograph
MedlinePlus	a682172
License data	US  DailyMed:  Fluphenazine
Pregnancy category	AU:C
Routes of administration	By mouth, Intramuscular injection, depot injection (fluphenazine decanoate)
Drug class	Typical antipsychotic
ATC code	N05AB02 ( WHO )
Legal status
Legal status	BR: Class C1 (Other controlled substances) [1] CA: ℞-only UK: POM (Prescription only) US: ℞-only
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
IUPAC name 2-[4-[3-[2-(trifluoromethyl)-10H-phenothiazin-10-yl]propyl]piperazin-1-yl]ethanol
CAS Number	69-23-8  Y
PubChem CID	3372
IUPHAR/BPS	204
DrugBank	DB00623  Y
ChemSpider	3255  Y
UNII	S79426A41Z
KEGG	D07977  Y
ChEBI	CHEBI:5123  Y
ChEMBL	ChEMBL726  Y
CompTox Dashboard (EPA)	DTXSID2023068
ECHA InfoCard	100.000.639
Chemical and physical data
Formula	C22H26F3N3OS
Molar mass	437.53 g·mol−1
3D model (JSmol)	Interactive image
SMILES FC(F)(F)c2cc1N(c3c(Sc1cc2)cccc3)CCCN4CCN(CCO)CC4
InChI 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 Y Key:PLDUPXSUYLZYBN-UHFFFAOYSA-N Y
(verify)

Fluphenazine, sold under the brand name Prolixin among others, is a high-potency typical antipsychotic medication. ^[2] It is used in the treatment of chronic psychoses such as schizophrenia, ^{[2] [3]} and appears to be about equal in effectiveness to low-potency antipsychotics like chlorpromazine. ^[4] It is given by mouth, injection into a muscle, or just under the skin. ^[2] There is also a long acting injectable version that may last for up to four weeks. ^[2] Fluphenazine decanoate, the depot injection form of fluphenazine, should not be used by people with severe depression. ^[5]

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 is a typical antipsychotic of the phenothiazine class. ^[2] Its mechanism of action is not entirely clear but believed to be related to its ability to block dopamine receptors. ^[2] In up to 40% of those on long term phenothiazines, liver function tests become mildly abnormal. ^[6]

Fluphenazine came into use in 1959. ^[7] The injectable form is on the World Health Organization's List of Essential Medicines. ^[8] It is available as a generic medication. ^[2] It was discontinued in Australia in 2017. ^[9]

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. ^[10] Another 2018 Cochrane review found that there was limited evidence that newer atypical antipsychotics were more tolerable than fluphenazine. ^[11] Intramuscular depot injection forms are available as both the decanoate and enanthate esters. ^[12]

Side effects

Discontinuation

The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse. ^[13] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite. ^[14] Other symptoms may include restlessness, increased sweating, and trouble sleeping. ^[14] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains. ^[14] Symptoms generally resolve after a short period of time. ^[14]

There is tentative evidence that discontinuation of antipsychotics can result in psychosis. ^[15] It may also result in reoccurrence of the condition that is being treated. ^[16] Rarely tardive dyskinesia can occur when the medication is stopped. ^[14]

Pharmacology

Pharmacodynamics

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

Fluphenazine acts primarily by blocking post-synaptic dopaminergic D₂ receptors in the basal ganglia, cortical and limbic system. It also blocks α₁ adrenergic receptors, muscarinic M₁ receptors, and histaminergic H₁ receptors. ^{[17] [18]}

Fluphenazine ^[19]

Site	Ki (nM)	Action	Ref
5-HT1A	145–2829	ND	[19]
5-HT1B	334	ND	[19]
5-HT1D	334	ND	[19]
5-HT1E	540	ND	[19]
5-HT2A	3.8–98	ND	[19]
5-HT2B	ND	ND	[19]
5-HT2C	174–2,570	ND	[19]
5-HT3	4,265– >10,000	ND	[19]
5-HT5A	145	ND	[19]
5-HT6	7.9–38	ND	[19]
5-HT7	8	ND	[19]
D1	14.45	ND	[19]
D2	0.89	ND
D2L		ND	[19]
D3	1.412	ND	[19]
D4	89.12	ND	[19]
D5	95–2,590	ND	[19]
α1A	6.4–9	ND	[19]
α1B	13	ND	[19]
α2A	304–314	ND	[19]
α2B	181.6–320	ND	[19]
α2C	28.8–122	ND	[19]
β1	>10,000	ND	[19]
β2	>10,000	ND	[19]
H1	7.3–70	ND	[19]
H2	560	ND	[19]
H3	1,000	ND	[19]
H4	>10,000	ND	[19]
M1	1,095-3,235.93	ND	[19]
M2	2,187.76–7,163	ND	[19]
M3	1441–1445.4	ND	[19]
M4	5,321	ND	[19]
M5	357	ND	[19]
SERT Tooltip Serotonin transporter	ND	ND	[19]
NET Tooltip Norepinephrine transporter	ND	ND	[19]
DAT Tooltip Dopamine transporter	ND	ND	[19]
NMDA (PCP)	ND	ND	[19]
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). [19]

Pharmacokinetics

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Pharmacokinetics of long-acting injectable antipsychotics

Medication	Brand name	Class	Vehicle	Dosage	Tmax	t1/2 single	t1/2 multiple	logPc	Ref
Aripiprazole lauroxil	Aristada	Atypical	Water a	441–1064 mg/4–8 weeks	24–35 days	?	54–57 days	7.9–10.0
Aripiprazole monohydrate	Abilify Maintena	Atypical	Water a	300–400 mg/4 weeks	7 days	?	30–47 days	4.9–5.2
Bromperidol decanoate	Impromen Decanoas	Typical	Sesame oil	40–300 mg/4 weeks	3–9 days	?	21–25 days	7.9	[20]
Clopentixol decanoate	Sordinol Depot	Typical	Viscoleo b	50–600 mg/1–4 weeks	4–7 days	?	19 days	9.0	[21]
Flupentixol decanoate	Depixol	Typical	Viscoleo b	10–200 mg/2–4 weeks	4–10 days	8 days	17 days	7.2–9.2	[21] [22]
Fluphenazine decanoate	Prolixin Decanoate	Typical	Sesame oil	12.5–100 mg/2–5 weeks	1–2 days	1–10 days	14–100 days	7.2–9.0	[23] [24] [25]
Fluphenazine enanthate	Prolixin Enanthate	Typical	Sesame oil	12.5–100 mg/1–4 weeks	2–3 days	4 days	?	6.4–7.4	[24]
Fluspirilene	Imap, Redeptin	Typical	Water a	2–12 mg/1 week	1–8 days	7 days	?	5.2–5.8	[26]
Haloperidol decanoate	Haldol Decanoate	Typical	Sesame oil	20–400 mg/2–4 weeks	3–9 days	18–21 days		7.2–7.9	[27] [28]
Olanzapine pamoate	Zyprexa Relprevv	Atypical	Water a	150–405 mg/2–4 weeks	7 days	?	30 days	–
Oxyprothepin decanoate	Meclopin	Typical	?	?	?	?	?	8.5–8.7
Paliperidone palmitate	Invega Sustenna	Atypical	Water a	39–819 mg/4–12 weeks	13–33 days	25–139 days	?	8.1–10.1
Perphenazine decanoate	Trilafon Dekanoat	Typical	Sesame oil	50–200 mg/2–4 weeks	?	?	27 days	8.9
Perphenazine enanthate	Trilafon Enanthate	Typical	Sesame oil	25–200 mg/2 weeks	2–3 days	?	4–7 days	6.4–7.2	[29]
Pipotiazine palmitate	Piportil Longum	Typical	Viscoleo b	25–400 mg/4 weeks	9–10 days	?	14–21 days	8.5–11.6	[22]
Pipotiazine undecylenate	Piportil Medium	Typical	Sesame oil	100–200 mg/2 weeks	?	?	?	8.4
Risperidone	Risperdal Consta	Atypical	Microspheres	12.5–75 mg/2 weeks	21 days	?	3–6 days	–
Zuclopentixol acetate	Clopixol Acuphase	Typical	Viscoleo b	50–200 mg/1–3 days	1–2 days	1–2 days		4.7–4.9
Zuclopentixol decanoate	Clopixol Depot	Typical	Viscoleo b	50–800 mg/2–4 weeks	4–9 days	?	11–21 days	7.5–9.0
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. ^[7]

Availability

The injectable form is on the World Health Organization's List of Essential Medicines. ^[8] It is available as a generic medication. ^[2] It was discontinued in Australia in 2017. ^[9]

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. ^[30]

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. "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. "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.
6. "Fluphenazine". livertox.nih.gov. 2012. PMID   31643176 . Retrieved 6 November 2017.
7. McPherson EM (2007). Pharmaceutical Manufacturing Encyclopedia (3rd ed.). Burlington: Elsevier. p. 1680. ISBN   9780815518563.
8. 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.
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 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.
11. 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. 7 (7): CD010832. doi: 10.1002/14651858.CD010832.pub2 . PMC   6474115 . PMID   27370402.
12. 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.
13. 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.
14. Haddad P, Haddad PM, Dursun S, Deakin B (2004). Adverse Syndromes and Psychiatric Drugs: A Clinical Guide. OUP Oxford. pp. 207–216. ISBN   9780198527480.
15. 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.
16. Sacchetti E, Vita A, Siracusano A, Fleischhacker W (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN   9788847026797.
17. Siragusa S, Saadabadi A (2020). "Fluphenazine". StatPearls. PMID   29083807.
18. "Fluphenazine". PubChem. U.S. National Library of Medicine. Retrieved 30 September 2019.
19. Roth BL, Driscol J. "PDSP K_i 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.
20. 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.
21. 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.
22. Reynolds JE (1993). "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
23. 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.
24. 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.
25. 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.
26. 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.
27. 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.
28. 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.
29. 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.
30. 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.