Paliperidone

Paliperidone, sold under the brand name Invega among others, is an atypical antipsychotic. It is marketed by Janssen Pharmaceutica. Invega is an extended release formulation of paliperidone that uses the OROS extended release system to allow for once-daily dosing. Paliperidone is mainly used to treat schizophrenia and schizoaffective disorder.

Paliperidone
Clinical data
Trade namesInvega, Xeplion, others
Other names9-hydroxyrisperidone
AHFS/Drugs.comMonograph
MedlinePlusa607005
License data
Pregnancy
category
  • AU: B3
  • US: C (Risk not ruled out)
    Routes of
    administration    		Oral (OROS tablets), IM depot injection
    ATC code
    Legal status
    Legal status
    • AU: S4 (Prescription only)
    • US: ℞-only
    Pharmacokinetic data
    Bioavailability28% (oral)
    Elimination half-life23 hours (by mouth)
    Excretion1% unchanged in urine 18% unchanged in feces
    Identifiers
    CAS Number
    PubChem CID
    DrugBank
    ChemSpider
    UNII
    KEGG
    ChEBI
    ChEMBL
    ECHA InfoCard100.117.604
    Chemical and physical data
    FormulaC23H27FN4O3
    Molar mass426.484 g/mol g·mol−1
    3D model (JSmol)
     NY (what is this?)  (verify)

    Paliperidone palmitate is a long-acting injectable formulation of paliperidone palmitoyl ester indicated for once-every 28 days injection after an initial titration period.

    Medical use

    It is used for the treatment of schizophrenia and schizoaffective disorder. In a 2013 study in a comparison of 15 antipsychotic drugs in effectiveness in treating schizophrenic symptoms, paliperidone was ranked fifth and demonstrated standard-high effectiveness. 10-14% more effective than haloperidol, quetiapine, and aripiprazole, 11% less effective than risperidone (4th), and 43% less effective than clozapine (1st).[1]

    Paliperidone palmitate long-acting injection compared to risperidone for schizophrenia[2]
    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.[2]

    Adverse effects

    Sources:[3][4][5][6][7]

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

    Discontinuation

    The British National Formulary recommends a gradual withdrawal when discontinuing antipsychotics to avoid acute withdrawal syndrome or rapid relapse.[8] Symptoms of withdrawal commonly include nausea, vomiting, and loss of appetite.[9] Other symptoms may include restlessness, increased sweating, and trouble sleeping.[9] Less commonly there may be a feeling of the world spinning, numbness, or muscle pains.[9] Symptoms generally resolve after a short period of time.[9]

    There is tentative evidence that discontinuation of antipsychotics can result in psychosis.[10] It may also result in reoccurrence of the condition that is being treated.[11] Rarely tardive dyskinesia can occur when the medication is stopped.[9]

    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.[12][13][14][15][16][17][18]

    Pharmacology
    Paliperidone[19]
    SiteKi (nM)
    5-HT1A617
    5-HT2A1.1
    5-HT2C48
    5-HT62414
    5-HT72.7
    α1A2.5
    α2A3.9
    α2B4.0
    α2C2.7
    D21.6
    D2L6.6
    D33.5
    H119
    mACh>10,000
    Values are Ki (nM). The smaller the value, the more strongly the drug binds to the site.

    Paliperidone is the primary active metabolite of the older antipsychotic risperidone.[20] While its specific mechanism of action is unknown, it is believed paliperidone and risperidone act via similar, if not identical, pathways.[21] 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.[22]

    The half-life is 23 hours.[22]

    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.[23]

    Brand names

    On May 18, 2015, a new formulation of paliperidone palmitate was approved by the FDA under the brand name Invega Trinza.[24] 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.[25]

    References
    1. 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.
    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. PMID 22696377.
    3. "DrugPoint® System". Truven Health Analytics, Inc. Greenwood Village, CO: Thomsen Healthcare. 2013.
    4. "INVEGA® PRODUCT INFORMATION". Janssen Pharmaceuticals. 2013.
    5. 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.
    6. Joint Formulary Committee. British National Formulary (BNF) 65. Pharmaceutical Pr; 2013.
    7. "paliperidone (Rx) - Invega, Invega Sustenna". Medscape Reference.
    8. 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.
    9. 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.
    10. 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.
    11. Sacchetti, Emilio; Vita, Antonio; Siracusano, Alberto; Fleischhacker, Wolfgang (2013). Adherence to Antipsychotics in Schizophrenia. Springer Science & Business Media. p. 85. ISBN 9788847026797.
    12. "21 users of schizophrenia drug dead". The Japan Times.
    13. "Schizophrénie: controverse autour d'un médicament au Japon". Médecine.
    14. "20 minutes - Un médicament anti-schizophrénie tue". Monde.
    15. "Deaths reported after Xeplion injections". Life & Style. NZ Herald News.
    16. "17 deaths reported after schizophrenia drug injections". Japan Today: Japan News and Discussion.
    17. "21 Dead in Japan From New Johnson & Johnson Antipsychotic". Mad In America.
    18. "Schizophrenia drug blamed for 17 deaths". Sky News Australia.
    19. Corena-McLeod M (June 2015). "Comparative Pharmacology of Risperidone and Paliperidone - Table 1". Drugs in R&D. 15 (2): 163–74. doi:10.1007/s40268-015-0092-x. PMC 4488186. PMID 25943458.
    20. "Paliperidone". The DrugBank database.
    21. 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.
    22. "Paliperidone extended release: Scientific Discussion" (PDF). EMA. 16 July 2007.
    23. "Procedural steps taken and scientific information after the authorisation" (PDF). EMA. 16 July 2015.
    24. "Invega Trinza™ (paliperidone palmitate) NDA approval letter" (PDF). U.S. Food and Drug Administration. Retrieved 10 December 2015.
    25. "Trevicta (previously Paliperidone Janssen)". Summary of the European public assessment report (EPAR) for Trevicta. EMC.
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