antipsychotics long acting injections

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Long Acting Antipsychotics

Antipsychotic Long Acting Injections Dr V K SAHUResident Psychiatry1HeadingsIntroduction Methods of improving outcomeAntipsychotic Long Acting Injections (LAI) Pharmacology Individual Long Acting AntipsychoticsAdvantages & Disadvantages Conclusion2IntroductionSchizophrenia is a major psychiatric disorder, or cluster of disorders, characterised by psychotic symptoms that alter a person's perception, thoughts, mood and ehaviourContinuous, long-term treatment to minimize relapse and provide clinical benefit to patients.Non-adherence to medication is a major risk factor for relapse and re-hospitalization.

3Average treatment adherence 13.3 months, adherence is dynamic , missed dose may be silent and may not lead to psychotic relapse even till months laterconsequence of adherence lasts beyond relapsemore time for remission , 3Introduction - Course of Schizophrenia

4Robinson EJ,Birchwood M. Theory of mind skills during an acute episode of psychosis and following recovery. Psychological Medicine 1998 Aug; 28(05): 1101-1112IntroductionWhat constitutes maintenance phase and its treatment in schizophrenia has not yet been established. Discontinuation and intermittent or targeted strategies are not generally recommended.Controversy regarding dose reduction or lower dose therapy, especially with regards to atypical antipsychotics.5Takeuchi H, Suzuki T, Uchida H, Watanabe K, Mimura M. Antipsychotic treatment for schizophrenia in the maintenance phase: a systematic review of the guidelines and algorithms.. Schizophrenia Research 2012 Feb; 134(2-3): 219-256Cognitive behavioural therapyCompliance therapyMore frequent and/or longer visitsPatient/family psycho-educationSymptom/side effect monitoringDose correction to reduce side effectsSimplified medication regimenFirst generation long-acting injectable antipsychoticsSecond-generation long-acting injectable antipsychoticsPharmacological interventionPsychosocial and programmatic interventionsAdherenceLAI & AdherenceNon-adherence may be both a cause and consequence of worsening of illnessLong-acting injectable antipsychotic drugs can help to:Improve adherenceReduce relapseLower hospitalization rates

7Antipsychotic Long Acting Injections (LAI) Two groups of LAIs: First generation LAIs and Second-generation LAIs.First LAI Fluphenazine Enantate- 1966.Second LAI- Fluphenazine decanoate.First of the second generation LAI RisperidoneUnder trial LAI - iloperidone8FGA LAI are esters of parent FGA combined with a long chain fatty acid . Decanoic acid -10 carbon, enthanate -8 , undecylenate -11 , palmitate -16.Once esterified FGA becomes fat soluble dissolved in oily base, such as sesame , coconut8LAI Classification-Delivery mechanism9CLASS DELIVERYAGENTFGAOILFLUPHENAZINE DECANOATEHALOPERIDOL DECANOATEFLUPENTIXOL/ZUCLOPENTHIXOLPIPOTIAZINE PALMITATEPERPHENAZINE DECANOATESGAMICROSPHERERISEPERIDONE,ARPIPRAZOLECRYSTALOLANAZAPINE PAMOATEPALIPERIDONE PALMITATEFirst-generation LAIsFlupentixol: Thioxanthine antipsychotic. LAI is formulated as flupentixol decanoate in a low-viscosity vegetable oil (fractionated coconut oil). Peak plasma levels 37 days after IM injectionApparent half-life of 17 days.Steady-state plasma levels can be expected to be achieved after 2 months or so of regular dosing.In practice, plasma levels may show marked variability independent of dose changes.410First-generation LAIsFluphenazine:Piperazine phenothiazine compound. Fluphenazine decanoate is available as an LAI in sesame oil. Plasma levels peak within 24 h of intramuscular injectionHalf-life is approximately 714 days.Plasma levels obtained vary up to 40-fold in patients receiving the same dose.Smoking significantly reduces plasma fluphenazine levels.11First-generation LAIsHaloperidol:Butyrophenone Haloperidol decanoate in Sesame oil. Peak plasma levels are seen up to 7 days after intramuscular injection Plasma half-life is around 3 weeks.Steady-state plasma levels can be expected to be reached after 23 months of regular dosing.As with fluphenazine, clearance of haloperidol is significantly increased by smoking. Variation in plasma levels is smaller than oral haloperidol.12First-generation LAIsPerphenazine:Piperazine phenothiazine Perphenazine decanoate in sesame oil.Used mainly in northern europe and scandinavia. After intramuscular injection, peak plasma levels are obtained in 17 daysHalf-life is approximately 2 weeks.Steady-state levels are obtained after 3 months.Variations in plasma levels during regular dosing are small.Plasma levels are directly correlated with dose.13First-generation LAIsPipotiazine:Piperidine Phenothiazine Antipsychotic. The Lai Formulation Contains Pipotiazine Palmitate In Coconut Oil. Provides Peak Plasma Levels After 12 Weeks Although No Drug Is Released For At Least 3 Days.Plasma Half-life Is Around 2 Weeks Time To Steady State Is 2 Months.14First-generation LAIsZuclopenthixol:Thioxanthine compound.LAI is formulated as the decanoate ester dissolved in thin vegetable oil (fractionated coconut oil). Peak plasma levels of zuclopenthixol are achieved a week after injection.Plasma half-life has been estimated at 7.4 days and 19 days.Shows moderate inter- and intra-individual differences in plasma levelsMarked differences b/w peak and trough plasma levels when given every 2 weeks (peak levels more than 3 times higher than trough).Steady-state plasma levels are achieved after around 2 months of regular dosing15First Generation Antipsychotic long-acting injections : suggested doses and frequenciesDrugLicensedinjection siteTest dose(mg)Dose range(mg/week)DosingInterval(weeks) Comments

FlupentixoldecanoateGluteal or thigh 2012.5-400 2-4Maximum licenseddose is very highrelative to other LAIsFluphenazine decanoateGluteal12.56.25-502-5High EPSHaloperidol DecanoateGluteal2512.5-754High EPSPipothiazine palmitateGluteal2512.5-504? Lower incidence of EPS (unproven)Zuclopenthixol decanoateGluteal or thigh100100-6002-4? Slightly higher efficacy16Second-generation LAIsRisperidone:First atypical drug to be made available as depotContains risperidone coated in polymer to form microspheres.Have to be suspended in an aqueous base immediately before use.Stored in a fridgeAvailable as doses of 25, 37.5 and 50 mg17

Unlike FGA-LAIs, Risperidone Long Acting Injections(RLAI) breaks down into completely natural products (CO2 and H2O)


Second-generation LAIsRisperidone injection is not suitable for patients with treatment-refractory schizophrenia.Peak release is at about 28 days.The long-acting injection also seems to be well tolerated: fewer than 10% of patients experience EPS and fewer than 6% withdrew from a long-term trial because of adverse effects.Doses of 2550 mg every 2 weeks appear to be as effective as oral doses of 26 mg/day.Prolactin levels appear to reduce somewhat following a switch from oral to injectable risperidone.Rates of tardive dyskinesia are said to be low

19Second-generation LAIsRLAI may improve the trajectory of myelination in first episode patients and have a beneficial impact on cognitive performance20

Bartzokis G, Lu PH, Amar CP, Raven EP, Detore NR, Altshuler LL "et al". Long Acting Injection Versus Oral Risperidone in First-Episode Schizophrenia: Differential Impact on White Matter Myelination Trajectory. Schizophrenia Reseaarch.Supplement 2011 Oct; 132(1): 35-41.

Second-generation LAIs21PaliperidoneContains extended release intramuscular extended-release intramuscular Paliperidone PalmitateMajor active metabolite of risperidone: 9-hydroxyrisperidoneActive paliperidone plasma levels are seen within a day or so, therefore co- administration of oral paliperidone or risperidone during initiation is not required

Second-generation LAIsPaliperidone palmitate IM does not require cold storage.Prefilled syringes and does not require reconstitutionNo oral supplementation is required on initiation for paliperidone palmitate. No test dose is required for paliperidone palmitate (but patients should ideally be currently stabilised on or have previously responded to oral paliperidone or risperidone).The median time to maximum plasma concentrations is 13 days. Treatment with paliperidone palmitate (100 mg eq.) was efficacious and all doses tested were tolerable.

227. Bartzokis Gopal S1, Hough DW, Xu H, Lull JM, Gassmann-Mayer C, Remmerie BM, "et al". Efficacy and safety of paliperidone palmitate in adult patients with acutely symptomatic schizophrenia: a randomized, double-blind, placebo-controlled, dose-response study. International Clinical Psychopharmacology 2010 Sep; 25(5): 247-56.

Paliperidone dose and administration informationDoseRouteInitiation

Day 1 Day 8 (+/2 days) 150 mg IM Deltoid only100 mg IMDeltoid onlyMaintenance Every month (+/ 7 days) thereafter50150 mg IMDeltoid or gluteal23The second initiation dose may be given 2 days before or after day 8 (after the first initiation dose on day 1).2 Similarly the manufacturer recommends that patients may be given maintenance doses up to 7 days before or after the monthly time point.2 This flexibility should help to minimise the number of missed doses.The maintenance dose is perhaps best judged by consideration of what might be a suitable dose of oral risperidone and then giving paliperidone palmitate in an equivalent dose IM, intramuscularApproximate dose equivalence of risperidone and paliperidoneRisperidone oral(mg/day)(bioavailability = 70%)Paliperidone oral(mg/day)(bioavailability = 28%)RisperidoneLAI (Consta)(mg/2 weeks)Paliperidonepalmitate(mg/month)2425503637.5754950100612-15024Second-generation LAIsILOPERIDONE:Microencapsulated depot formulations of iloperidone and a poly-glycolide polylactide glucose star polymer.Under


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