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to treat schizophrenia and schizoaffective disorder.[1] It may be taken by mouth or injected into a muscle.[2] When the unpublished literature is included, benefits are lower and harms are higher than when only the published literature is looked at.[6]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

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