Flupentixol

Flupentixol
Clinical data
Trade namesDepixol, Fluanxol
AHFS/Drugs.comMicromedex Detailed Consumer Information
Pregnancy
category
  • AU: C
Routes of
administration		Oral, IM (including a depot)
Drug classTypical antipsychotic
ATC code
Legal status
Legal status
  • AU: S4 (Prescription only)
  • CA: ℞-only
  • UK: POM (Prescription only)
  • In general: ℞ (Prescription only)
Pharmacokinetic data
Bioavailability40–55% (oral)[1]
MetabolismGut wall, hepatic[2]
Elimination half-life35 hours[1]
ExcretionRenal (negligible)[3]
Identifiers
IUPAC name
  • (EZ)-2-[4-[3-[2-(trifluoromethyl)thioxanthen-9-ylidene]propyl]piperazin-1-yl]ethanol
CAS Number
PubChem CID
IUPHAR/BPS
DrugBank
ChemSpider
UNII
KEGG
ChEMBL
CompTox Dashboard (EPA)
ECHA InfoCard100.018.459
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Chemical and physical data
FormulaC23H25F3N2OS
Molar mass434.52 g·mol−1
3D model (JSmol)
SMILES
  • FC(F)(F)c2cc1C(\c3c(Sc1cc2)cccc3)=C/CCN4CCN(CCO)CC4
InChI
  • InChI=1S/C23H25F3N2OS/c24-23(25,26)17-7-8-22-20(16-17)18(19-4-1-2-6-21(19)30-22)5-3-9-27-10-12-28(13-11-27)14-15-29/h1-2,4-8,16,29H,3,9-15H2/b18-5- checkY
  • Key:NJMYODHXAKYRHW-DVZOWYKESA-N checkY
 ☒NcheckY (what is this?)  (verify)

Flupentixol (INN), also known as flupenthixol (former BAN), marketed under brand names such as Depixol and Fluanxol is a typical antipsychotic drug of the thioxanthene class. It was introduced in 1965 by Lundbeck. In addition to single drug preparations, it is also available as flupentixol/melitracen—a combination product containing both melitracen (a tricyclic antidepressant) and flupentixol. Flupentixol is not approved for use in the United States. It is, however, approved for use in the UK,[4] Australia,[5] Canada, Russian Federation,[6] South Africa, New Zealand, Philippines and various other countries.

Medical uses

Flupentixol's main use is as a long-acting injection given once in every two or three weeks to individuals with schizophrenia who have poor compliance with medication and suffer frequent relapses of illness, though it is also commonly given as a tablet. There is little formal evidence to support its use for this indication but it has been in use for over fifty years.[4][7]

Flupentixol is also used in low doses as an antidepressant.[4][8][9][10][11][12][13] There is tentative evidence that it reduces the rate of deliberate self-harm, among those who self-harm repeatedly.[14]

Adverse effects

Adverse effect incidence[1][4][5][15][16]

Common (>1% incidence) adverse effects include
  • Extrapyramidal side effects such as: (which usually become apparent soon after therapy is begun or soon after an increase in dose is made)
- Muscle rigidity
- Hypokinesia
- Hyperkinesia
- Parkinsonism
- Tremor
- Akathisia
- Dystonia
  • Dry mouth
  • Constipation
  • Hypersalivation – excessive salivation
  • Blurred vision
  • Diaphoresis – excessive sweating
  • Nausea
  • Dizziness
  • Somnolence
  • Restlessness
  • Insomnia
  • Overactivity
  • Headache
  • Nervousness
  • Fatigue
  • Myalgia
  • Hyperprolactinemia and its complications such as: (acutely)
- Sexual dysfunction
- Amenorrhea – cessation of menstrual cycles
- Gynecomastia – enlargement of breast tissue in males
- Galactorrhea – the expulsion of breast milk that's not related to breastfeeding or pregnancy
and if the hyperprolactinemia persists chronically, the following adverse effects may be seen:
- Reduced bone mineral density leading to osteoporosis (brittle bones)
- Infertility
  • Dyspepsia – indigestion
  • Abdominal pain
  • Flatulence
  • Nasal congestion
  • Polyuria – passing more urine than usual
Uncommon (0.1–1% incidence) adverse effects include
  • Fainting
  • Palpitations
Rare (<0.1% incidence) adverse effects include
  • Blood dyscrasias (abnormalities in the cell composition of blood), such as:
- Agranulocytosis – a drop in white blood cell counts that leaves one open to potentially life-threatening infections
- Neutropenia – a drop in the number of neutrophils (white blood cells that specifically fight bacteria) in one's blood
- Leucopenia – a less severe drop in white blood cell counts than agranulocytosis
- Thrombocytopenia – a drop in the number of platelets in the blood. Platelets are responsible for blood clotting and hence this leads to an increased risk of bruising and other bleeds
- Hyperthermia
- Muscle rigidity
- Rhabdomyolysis
- Autonomic instability (e.g. tachycardia, diarrhea, diaphoresis, etc.)
- Mental status changes (e.g. coma, agitation, anxiety, confusion, etc.)
Unknown incidence adverse effects include
  • Jaundice
  • Abnormal liver function test results
  • Tardive dyskinesia – an often incurable movement disorder that usually results from years of continuous treatment with antipsychotic drugs, especially typical antipsychotics like flupenthixol. It presents with repetitive, involuntary, purposeless and slow movements; TD can be triggered by a fast dose reduction in any antipsychotic.
  • Hypotension
  • Confusional state
  • Seizures
  • Mania
  • Hypomania
  • Depression
  • Hot flush
  • Anergia
  • Appetite changes
  • Weight changes
  • Hyperglycemia – high blood glucose (sugar) levels
  • Abnormal glucose tolerance
  • Pruritus – itchiness
  • Rash
  • Dermatitis
  • Photosensitivity – sensitivity to light
  • Oculogyric crisis
  • Accommodation disorder
  • Sleep disorder
  • Impaired concentration
  • Tachycardia
  • QTc interval prolongation – an abnormality in the electrical activity of the heart that can lead to potentially fatal changes in heart rhythm (only in overdose or <10 ms increases in QTc)[17][18]
  • Torsades de pointes
  • Miosis – constriction of the pupil of the eye
  • Paralytic ileus – paralysis of the bowel muscles leading to severe constipation, inability to pass wind, etc.
  • Mydriasis
  • Glaucoma

Interactions

It should not be used concomitantly with medications known to prolong the QTc interval (e.g. 5-HT3 antagonists, tricyclic antidepressants, citalopram, etc.) as this may lead to an increased risk of QTc interval prolongation.[16][1] Neither should it be given concurrently with lithium (medication) as it may increase the risk of lithium toxicity and neuroleptic malignant syndrome.[4][5][16] It should not be given concurrently with other antipsychotics due to the potential for this to increase the risk of side effects, especially neurological side effects such as neuroleptic malignant syndrome.[4][5][16] It should be avoided in patients on CNS depressants such as opioids, alcohol and barbiturates.[16]

Contraindications

It should not be given in the following disease states:[1][4][5][16]

Pharmacology

Pharmacodynamics

Binding profile[19]

Proteincis-flupentixoltrans-flupentixol
5-HT1A8028—
5-HT2A87.5 (HFC)—
5-HT2C102.2 (RC)—
mAChRs[20]Neg.Neg.
D13.5474 (MB)
D20.35120
D31.75162.5
D466.3>1000
H10.865.73

Acronyms used:
HFC – Human frontal cortex receptor
MB – Mouse brain receptor
RC – Cloned rat receptor

Its antipsychotic effects are likely caused by D2 and/or 5-HT2A antagonism, whereas its antidepressant effects at lower doses may be mediated by preferential D2/D3 autoreceptor blockade, resulting in increased postsynaptic activation.

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[21]
Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days ?19 days9.0[22]
Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[22][23]
Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[24][25][26]
Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days ?6.4–7.4[25]
FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days ?5.2–5.8[27]
Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[28][29]
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[30]
Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days ?14–21 days8.5–11.6[23]
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

In March 1963 the Danish pharmaceutical company Lundbeck began research into further agents for schizophrenia, having already developed the thioxanthene derivatives clopenthixol and chlorprothixene. By 1965 the promising agent flupenthixol had been developed and trialled in two hospitals in Vienna by Austrian psychiatrist Heinrich Gross.[31] The long- acting decanoate preparation was synthesised in 1967 and introduced into hospital practice in Sweden in 1968, with a reduction in relapses among patients who were put on the depot.[32]

References

  1. 1 2 3 4 5 "Depixol Tablets 3mg - Summary of Product Characteristics (SPC)". electronic Medicines Compendium. Lundbeck Ltd. 27 December 2012. Retrieved 20 October 2013.
  2. ↑ Jann, MW; Ereshefsky, L; Saklad, SR (July–August 1985). "Clinical pharmacokinetics of the depot antipsychotics". Clinical Pharmacokinetics. 10 (4): 315–333. doi:10.2165/00003088-198510040-00003. PMID 2864156. S2CID 12848774.
  3. ↑ Balant-Gorgia, A. E.; Balant, L. (Aug 1987). "Antipsychotic drugs: clinical pharmacokinetics of potential candidates for plasma concentration monitoring". Clinical Pharmacokinetics. 13 (2): 65–90. doi:10.2165/00003088-198713020-00001. PMID 2887326. S2CID 24707620.
  4. 1 2 3 4 5 6 7 Joint Formulary Committee (2013). British National Formulary (BNF) (65 ed.). London, UK: Pharmaceutical Press. ISBN 978-0-85711-084-8.
  5. 1 2 3 4 5 Rossi, S, ed. (2013). Australian Medicines Handbook (2013 ed.). Adelaide: The Australian Medicines Handbook Unit Trust. ISBN 978-0-9805790-9-3.
  6. ↑ "Fluanxol® (flupentixol) Tablets Registration Certificate". Russian State Register of Medicinal Products. Retrieved 29 July 2014.
  7. ↑ Shen, X; Xia, J; Adams, CE (Nov 14, 2012). Shen, Xiaohong (ed.). "Flupenthixol versus placebo for schizophrenia". Cochrane Database of Systematic Reviews. 11: CD009777. doi:10.1002/14651858.CD009777.pub2. PMID 23152280.
  8. ↑ Robertson MM, Trimble MR (May 1981). "The antidepressant action of flupenthixol". The Practitioner. 225 (1355): 761–3. PMID 7291129.
  9. ↑ Pöldinger W, Sieberns S (1983). "Depression-inducing and antidepressive effects of neuroleptics. Experiences with flupenthixol and flupenthixol decanoate". Neuropsychobiology. 10 (2–3): 131–6. doi:10.1159/000117999. PMID 6674820.
  10. ↑ Johnson DA (January 1979). "A double-blind comparison of flupenthixol, nortriptyline and diazepam in neurotic depression". Acta Psychiatrica Scandinavica. 59 (1): 1–8. doi:10.1111/j.1600-0447.1979.tb06940.x. PMID 369298. S2CID 144717662.
  11. ↑ Young JP, Hughes WC, Lader MH (May 1976). "A controlled comparison of flupenthixol and amitriptyline in depressed outpatients". British Medical Journal. 1 (6018): 1116–8. doi:10.1136/bmj.1.6018.1116. PMC 1639983. PMID 773506.
  12. ↑ Fujiwara J, Ishino H, Baba O, Hanaoka M, Sasaki K (August 1976). "Effect of flupenthixol on depression with special reference to combination use with tricyclic antidepressants. An uncontrolled pilot study with 45 patients". Acta Psychiatrica Scandinavica. 54 (2): 99–105. doi:10.1111/j.1600-0447.1976.tb00101.x. PMID 961463. S2CID 25364795.
  13. ↑ Tam W, Young JP, John G, Lader MH (March 1982). "A controlled comparison of flupenthixol decanoate injections and oral amitriptyline in depressed out-patients". The British Journal of Psychiatry. 140 (3): 287–91. doi:10.1192/bjp.140.3.287. PMID 7093597.
  14. ↑ Hawton, K; Witt, KG; Taylor Salisbury, TL; Arensman, E; Gunnell, D; Hazell, P; Townsend, E; van Heeringen, K (6 July 2015). "Pharmacological interventions for self-harm in adults" (PDF). The Cochrane Database of Systematic Reviews. 7 (7): CD011777. doi:10.1002/14651858.CD011777. hdl:10536/DRO/DU:30080508. PMC 8637297. PMID 26147958.
  15. ↑ Bostwick, JR; Guthrie, SK; Ellingrod, VL (January 2009). "ntipsychotic-induced hyperprolactinemia" (PDF). Pharmacotherapy. 29 (1): 64–73. doi:10.1592/phco.29.1.64. hdl:2027.42/90238. PMID 19113797. S2CID 25981099.
  16. 1 2 3 4 5 6 "FLUANXOL® DEPOT FLUANXOL® CONCENTRATED DEPOT". TGA eBusiness Services. Lundbeck Australia Pty Ltd. 28 June 2013. Retrieved 20 October 2013.
  17. ↑ "Guidelines for the Management of QTc Prolongation in Adults Prescribed Antipsychotics" (PDF). nhs.uk.{{cite web}}: CS1 maint: url-status (link)
  18. ↑ Lambiase, Pier D; de Bono, Joseph Paul; Schilling, Richard J; Lowe, Martin; Turley, Andrew; Slade, Alistair; Collinson, Jason; Rajappan, Kim; Harris, Stuart; Collison, Jason; Carpenter, Viki (July 2019). "British Heart Rhythm Society Clinical Practice Guidelines on the Management of Patients Developing QT Prolongation on Antipsychotic Medication". Arrhythmia & Electrophysiology Review. 8 (3): 161–165. doi:10.15420/aer.2019.8.3.G1. ISSN 2050-3369. PMC 6702465. PMID 31463053.
  19. ↑ Roth, BL; Driscol, J (12 January 2011). "PDSP Ki Database". Psychoactive Drug Screening Program (PDSP). University of North Carolina at Chapel Hill and the United States National Institute of Mental Health. Archived from the original on 8 November 2013. Retrieved 20 October 2013.
  20. ↑ Golds PR, Przyslo FR, Strange PG (March 1980). "The binding of some antidepressant drugs to brain muscarinic acetylcholine receptors". British Journal of Pharmacology. 68 (3): 541–9. doi:10.1111/j.1476-5381.1980.tb14570.x. PMC 2044199. PMID 7052344.
  21. ↑ 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.
  22. 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.
  23. 1 2 Reynolds JE (1993). "Anxiolytic sedatives, hypnotics and neuroleptics.". Martindale: The Extra Pharmacopoeia (30th ed.). London: Pharmaceutical Press. pp. 364–623.
  24. ↑ 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.
  25. 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.
  26. ↑ 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.
  27. ↑ 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.
  28. ↑ 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.
  29. ↑ 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.
  30. ↑ 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.
  31. ↑ Gross, H.; Kaltenbäck, Elfriede (1965). "Flupenthixol (Fluanxol®), ein Neues Neuroleptikum aus der Thiaxanthenreihe (Klinische Erfahrungen bei Einem Psychiatrischen Krankengut)". Acta Psychiatrica Scandinavica. 41: 42–56. doi:10.1111/j.1600-0447.1965.tb04969.x. S2CID 145021607.
  32. ↑ c.g. Gottfries m.d; Green, L. (1974). "Flupenthixol Decanoate -In Treatment of Out-Patients". Acta Psychiatrica Scandinavica. 50: 15–24. doi:10.1111/j.1600-0447.1974.tb08890.x. PMID 4533707. S2CID 42657501.
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