Paliperidone

Paliperidone
Names
Trade namesInvega, Xeplion, Trevicta, others
Other names9-hydroxyrisperidone
IUPAC name
  • (RS)-3-[2-[4-(6-fluoro-1,2-benzoxazol-3-yl)piperidin-1-yl]ethyl]-9-hydroxy-2-methyl-6,7,8,9-tetrahydropyrido[1,2-a]pyrimidin-4-one
Clinical data
Drug classAtypical antipsychotic[1]
Main usesSchizophrenia, schizoaffective disorder[1]
Side effectsHeadache, trouble sleepiness, parkinsonism, involuntary muscle movements, dizziness, agitation, depression, weight gain, nausea, dry mouth, QT prolongation, tiredness[1]
WHO AWaReUnlinkedWikibase error: ⧼unlinkedwikibase-error-statements-entity-not-set⧽
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    use    		By mouth (OROS tablets), intramuscular
    Typical dose6 mg PO OD[2]
    External links
    AHFS/Drugs.comMonograph
    MedlinePlusa607005
    Legal
    License data
    Legal status
    Pharmacokinetics
    Bioavailability28% (by mouth)
    Elimination half-life23 hours (by mouth)
    Excretion1% unchanged in urine 18% unchanged in feces
    Chemical and physical data
    FormulaC23H27FN4O3
    Molar mass426.492 g·mol−1
    3D model (JSmol)
    SMILES
    • O=C/1N5/C(=N\C(=C\1CCN4CCC(c3noc2cc(F)ccc23)CC4)C)[C@H](O)CCC5
    InChI
    • InChI=1S/C23H27FN4O3/c1-14-17(23(30)28-9-2-3-19(29)22(28)25-14)8-12-27-10-6-15(7-11-27)21-18-5-4-16(24)13-20(18)31-26-21/h4-5,13,15,19,29H,2-3,6-12H2,1H3/t19-/m1/s1 checkY
    • Key:PMXMIIMHBWHSKN-LJQANCHMSA-N checkY

    Paliperidone, sold under the trade name Invega among others, is an atypical antipsychotic used to treat schizophrenia and schizoaffective disorder.[1] It may be taken by mouth or injected into a muscle.[2] When the unpublished literature is included, benefits are lower and harms are higher than when only the published literature is looked at.[6]

    Common side effects include headache, trouble sleepiness, parkinsonism, involuntary muscle movements, dizziness, agitation, depression, weight gain, nausea, dry mouth, QT prolongation, and tiredness.[1] Other side effects may include neuroleptic malignant syndrome, tardive dyskinesia, diabetes, and high prolactin.[2] In older people with dementia, use increases the risk of death.[2] Use during pregnancy may have negative effects on the baby.[7] Benefits are believed to be due to effects on dopamine and serotonin.[2]

    Paliperidone was approved for medical use in the United States in 2006 and Europe in 2007.[2][1] It is on the World Health Organization's List of Essential Medicines.[8] In the United Kingdom the typical dose by mouth cost the NHS about £105 per month as of 2021.[9] This amount in the United States costs about 400 USD.[10]

    Medical use

    It is used for the treatment of schizophrenia and schizoaffective disorder.[11] When the unpublished literature is included, benefits are lower and harms are higher than when only the published literature is looked at.[6]

    Paliperidone palmitate long-acting injection compared to risperidone for schizophrenia[12]
    When flexibly dosed every four weeks, paliperidone palmitate appears comparable in efficacy and tolerability to risperidone. In short-term studies, paliperidone palmitate – the longer-acting injection – has a similar adverse effect profile to related compounds such as risperidone by mouth. No difference was found in the high rate of reported adverse sexual outcomes and paliperidone palmitate is associated with an increase in serum prolactin.[12]

    Dosage

    The typical dose by mouth is 6 mg once per day; though doses between 3 and 12 mg per day may be used.[2][9]

    The injections into a muscle are typically given at a dose of 25 to 150 mg per month; though there is a special formulation that may be given every three month at a dose of 175 to 525 mg.[9]

    The pills come as an extended release formulation using OROS system to allow for once-daily dosing. Paliperidone palmitate is a long-acting injectable formulation of paliperidone palmitoyl ester indicated for once-every 28 days injection after an initial titration period.

    Side effects

    Sources:[13][14][15][16][17]

    Very common (>10%)
    Common (1–10%)

    Discontinuation

    The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[18] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[19] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[19] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[19] Symptoms generally resolve after a short period of time.[19]

    There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[20] It may also result in reoccurrence of the condition that is being treated.[21] Rarely tardive dyskinesia can occur when the medication is stopped.[19]

    Deaths

    In April 2014, it was reported that 21 Japanese people who had received shots of the long-acting injectable paliperidone to date had died, out of 10,700 individuals prescribed the drug.[22][23][24][25][26][27][28]

    Pharmacology

    Paliperidone[29]
    SiteKi (nM)*
    5-HT1A617
    5-HT2A1.1
    5-HT2C48
    5-HT72.7
    α1A2.5
    α2A3.9
    α2C2.7
    *The smaller the value, the stronger the drug binding.
    Effects of paliperidone treatment (as well as other similar medications) on mitochondrial and cytoskeletal protein phosphorylation -a)Cytoskeletal proteins are phosphorylated/involved in mechanism of anterograde mitochondrial transport b)effects of anterograde mitochondrial movement on synaptic plasticity as well as neurotransmission

    Paliperidone is the primary active metabolite of the older antipsychotic risperidone.[30] While its specific mechanism of action is unknown, it is believed paliperidone and risperidone act via similar, if not identical, pathways.[29] Its efficacy is believed to result from central dopaminergic and serotonergic antagonism. Food is known to increase the absorption of Invega type ER OROS prolonged-release tablets. Food increased exposure of paliperidone by up to 50-60%, however, half-life was not significantly affected. The effect was probably due to a delay in the transit of the ER OROS formulation in the upper part of the GI channel, resulting in increased absorption.[31]

    The half-life is 23 hours.[31]

    Risperidone and its metabolite paliperidone are reduced in efficacy by P-glycoprotein inducers such as St John's wort[32][33]

    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[34]
    Clopentixol decanoateSordinol DepotTypicalViscoleob50–600 mg/1–4 weeks4–7 days ?19 days9.0[35]
    Flupentixol decanoateDepixolTypicalViscoleob10–200 mg/2–4 weeks4–10 days8 days17 days7.2–9.2[35][36]
    Fluphenazine decanoateProlixin DecanoateTypicalSesame oil12.5–100 mg/2–5 weeks1–2 days1–10 days14–100 days7.2–9.0[37][38][39]
    Fluphenazine enanthateProlixin EnanthateTypicalSesame oil12.5–100 mg/1–4 weeks2–3 days4 days ?6.4–7.4[38]
    FluspirileneImap, RedeptinTypicalWatera2–12 mg/1 week1–8 days7 days ?5.2–5.8[40]
    Haloperidol decanoateHaldol DecanoateTypicalSesame oil20–400 mg/2–4 weeks3–9 days18–21 days7.2–7.9[41][42]
    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[43]
    Pipotiazine palmitatePiportil LongumTypicalViscoleob25–400 mg/4 weeks9–10 days ?14–21 days8.5–11.6[36]
    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

    Paliperidone (as Invega) was approved by the Food and Drug Administration (FDA) for the treatment of schizophrenia in 2006. Paliperidone was approved by the FDA for the treatment of schizoaffective disorder in 2009. The long-acting injectable form of paliperidone, marketed as Invega Sustenna in U.S. and Xeplion in Europe, was approved by the FDA on July 31, 2009. It is the only available brand in Bangladesh under the brand name "Palimax ER" manufactured & marketed by ACI Pharmaceuticals.

    It was initially approved in Europe in 2007 for schizophrenia, the extended release form and use for schizoaffective disorder were approved in Europe in 2010, and extension to use in adolescents older than 15 years old was approved in 2014.[44]

    Society and culture

    Names

    On May 18, 2015, a new formulation of paliperidone palmitate was approved by the FDA under the brand name Invega Trinza.[45] A similar 3 -monthly injection of prolonged release suspension was approved in 2016 by the European Medicines Agency originally under the brand name Paliperidone Janssen, later renamed to Trevicta.[46] On September 1, 2021, a newer formulation of paliperidone palmitate, Invega Hafyera, was approved by the US FDA which is available as an injection every six months.

    Cost

    It is marketed by Janssen Pharmaceuticals.

    References

    1. 1 2 3 4 5 6 "Invega". Archived from the original on 9 January 2021. Retrieved 25 October 2021.
    2. 1 2 3 4 5 6 7 "Paliperidone Monograph for Professionals". Drugs.com. Archived from the original on 25 February 2021. Retrieved 25 October 2021.
    3. ↑ "Invega- paliperidone tablet, extended release". DailyMed. Archived from the original on 24 January 2016. Retrieved 19 August 2020.
    4. ↑ "Invega Sustenna- paliperidone palmitate injection". DailyMed. 31 January 2019. Archived from the original on 13 May 2021. Retrieved 19 August 2020.
    5. ↑ "Invega Trinza- paliperidone palmitate injection, suspension, extended release". DailyMed. 31 January 2019. Archived from the original on 17 June 2021. Retrieved 19 August 2020.
    6. 1 2 Hodkinson, A; Heneghan, C; Mahtani, KR; Kontopantelis, E; Panagioti, M (25 August 2021). "Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports". BMC medicine. 19 (1): 195. doi:10.1186/s12916-021-02062-w. PMID 34429113.
    7. ↑ "Paliperidone Use During Pregnancy". Drugs.com. Archived from the original on 4 December 2020. Retrieved 25 October 2021.
    8. ↑ World Health Organization (2021). World Health Organization model list of essential medicines: 22nd list (2021). Geneva: World Health Organization. hdl:10665/345533. WHO/MHP/HPS/EML/2021.02.
    9. 1 2 3 BNF 81: March-September 2021. BMJ Group and the Pharmaceutical Press. 2021. p. 422. ISBN 978-0857114105.
    10. ↑ "Invega Prices, Coupons & Patient Assistance Programs". Drugs.com. Archived from the original on 25 January 2021. Retrieved 25 October 2021.
    11. 1 2 3 4 5 Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, Samara M, Barbui C, Engel RR, Geddes JR, Kissling W, Stapf MP, Lässig B, Salanti G, Davis JM (September 2013). "Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments meta-analysis". Lancet. 382 (9896): 951–62. doi:10.1016/S0140-6736(13)60733-3. PMID 23810019. S2CID 32085212.
    12. 1 2 Nussbaum AM, Stroup TS (June 2012). "Paliperidone palmitate for schizophrenia". The Cochrane Database of Systematic Reviews. 6 (6): CD008296. doi:10.1002/14651858.CD008296.pub2. PMC 3494051. PMID 22696377. Archived from the original on 2018-02-05. Retrieved 2021-09-01.
    13. ↑ "DrugPoint® System". Truven Health Analytics, Inc. Greenwood Village, CO: Thomsen Healthcare. 2013. Archived from the original on 2018-01-27. Retrieved 2021-09-01.
    14. ↑ "INVEGA® PRODUCT INFORMATION". Janssen Pharmaceuticals. 2013. Archived from the original on 2018-12-15. Retrieved 2021-09-01.
    15. ↑ Park YW, Kim Y, Lee JH (December 2012). "Antipsychotic-induced sexual dysfunction and its management". The World Journal of Men's Health. 30 (3): 153–9. doi:10.5534/wjmh.2012.30.3.153. PMC 3623530. PMID 23596605.
    16. ↑ Joint Formulary Committee. British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.
    17. ↑ "paliperidone (Rx) - Invega, Invega Sustenna". Medscape Reference. Archived from the original on 2015-05-12. Retrieved 2021-09-01.
    18. ↑ 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.
    19. 1 2 3 4 5 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. Archived from the original on 2021-04-14. Retrieved 2021-09-01.
    20. ↑ 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.
    21. ↑ Sacchetti, Emilio; Vita, Antonio; Siracusano, Alberto; Fleischhacker, Wolfgang (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN 9788847026797. Archived from the original on 2021-04-14. Retrieved 2021-09-01.
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    24. ↑ "20 minutes - Un médicament anti-schizophrénie tue". Monde. Archived from the original on 2014-04-23. Retrieved 2021-09-01.
    25. ↑ "Deaths reported after Xeplion injections". Life & Style. NZ Herald News. Archived from the original on 2016-03-04. Retrieved 2021-09-01.
    26. ↑ "17 deaths reported after schizophrenia drug injections". Japan Today: Japan News and Discussion. Archived from the original on 2014-04-23. Retrieved 2021-09-01.
    27. ↑ "21 Dead in Japan From New Johnson & Johnson Antipsychotic". Mad In America. 2014-04-18. Archived from the original on 2014-04-22. Retrieved 2021-09-01.
    28. ↑ "Schizophrenia drug blamed for 17 deaths". Sky News Australia. Archived from the original on 2014-04-13. Retrieved 2021-09-01.
    29. 1 2 Corena-McLeod M (2015). "Comparative Pharmacology of Risperidone and Paliperidone". Drugs in R&D. 15 (2): 163–74. doi:10.1007/s40268-015-0092-x. PMC 4488186. PMID 25943458.
    30. ↑ "Paliperidone". The DrugBank database. Archived from the original on 2011-11-17. Retrieved 2021-09-01.
    31. 1 2 "Paliperidone extended release: Scientific Discussion" (PDF). EMA. 16 July 2007. Archived (PDF) from the original on 19 May 2012. Retrieved 1 September 2021.
    32. ↑ Wang, J. S.; Ruan, Y.; Taylor, R. M.; Donovan, J. L.; Markowitz, J. S.; Devane, C. L. (2004). "The Brain Entry of Risperidone and 9-hydroxyrisperidone Is Greatly Limited by P-glycoprotein". The International Journal of Neuropsychopharmacology. 7 (4): 415–9. doi:10.1017/S1461145704004390. PMID 15683552.
    33. ↑ Gurley BJ, Swain A, Williams DK, Barone G, Battu SK (2008). "Gauging the clinical significance of P-glycoprotein-mediated herb-drug interactions: comparative effects of St. John's wort, Echinacea, clarithromycin, and rifampin on digoxin pharmacokinetics". Mol Nutr Food Res. 52 (7): 772–9. doi:10.1002/mnfr.200700081. PMC 2562898. PMID 18214850.
    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.
    44. ↑ "Procedural steps taken and scientific information after the authorisation" (PDF). EMA. 16 July 2015. Archived (PDF) from the original on 18 June 2018. Retrieved 1 September 2021.
    45. ↑ "Invega Trinza (paliperidone palmitate) NDA approval letter" (PDF). U.S. Food and Drug Administration. Archived (PDF) from the original on 22 December 2015. Retrieved 10 December 2015.
    46. ↑ "Trevicta (previously Paliperidone Janssen)". Summary of the European public assessment report (EPAR) for Trevicta. EMC. 2018-09-17. Archived from the original on 2018-06-20. Retrieved 2022-03-14.
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