Long Acting Antipsychotics

- JEET NADPARA.

• Introduction • Benefits • Methods of improving compliance • Antipsychotic Long Acting Injections (LAI) • Pharmacology • Individual Long Acting Antipsychotics• Advantages & Disadvantages • Conclusion

• Antipsychotic medications can also be administered as long-acting injectable compounds.

• These drugs differ from short-acting compounds in that they are released slowly over a period of several weeks and as a result can take days or weeks to achieve therapeutic serum concentration and weeks to months to achieve steady state.

• Schizophrenia is a major psychiatric disorder, or cluster of disorders, characterized by psychotic symptoms that alter a person's perception, thoughts, mood and behavior.

• Continuous, long-term treatment to minimize relapse and provide clinical benefit to patients.

INTRODUCTION

• Non-compliance to medication is a major risk factor for relapse and re-hospitalization.

• Non-adherence may be both a cause and consequence of worsening of illness

• Long-acting injectable antipsychotic drugs can help to:

Improve complianceReduce relapseLower hospitalization rates

BenefitsConsistent drug delivery.Predictable bioavailability.Eliminates risk of patient deliberately or inadvertently overdosing.Avoidance of covert non-adherence to antipsychotic drugImmediate identification of patients who decline their injection or fail

to receive it through forgetfulness

NICE Guidelines for Schizophrenia. 2009.

Development of Long‐Acting Antipsychotics

Two groups of LAIs: First generation LAIs and Second-generation LAIs.

• FGA 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 , coconut

Antipsychotic Long Acting Injections (LAI)

CLASS DELIVERY AGENT

FGA OIL FLUPHENAZINE DECANOATE

HALOPERIDOL DECANOATE

FLUPENTIXOL/ZUCLOPENTHIXOL

PIPOTIAZINE PALMITATE

PERPHENAZINE DECANOATE

SGA MICROSPHERE RISEPERIDONE,ARPIPRAZOLE

CRYSTAL OLANAZAPINE PAMOATE

PALIPERIDONE PALMITATE

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First-generation LAIs Flupentixol:

◦ Thioxanthine antipsychotic. ◦ LAI is formulated as flupentixol decanoate in a low-viscosity vegetable oil

(fractionated coconut oil). ◦ Peak plasma levels 3–7 days after IM injection◦ Apparent 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.

o It is available as brand name o Inj Fluanxol 20 mg/ml and 40 mg/2mlo Inj Spenzo 20 mg/ml and 40mg/2ml o Cost around 100-200 Rs for 20 mg amp and 200-400 Rs for 40 mg amp.o Initially 20 mg should be given as a test dose. If well tolerated 20-40mg may be given after 1 wk.o Maintenance dose of 20-40 mg can be given every 2-4 wks.o Dose of depot is 8 times of total oral dose o It has mood elevating property, may worsen agitation.

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First-generation LAIs Fluphenazine:

◦ Piperazine phenothiazine compound. ◦ Fluphenazine decanoate is available as an LAI in sesame oil. ◦ Plasma levels peak within 24 h of intramuscular injection◦ Half-life is approximately 7–14 days.◦ Plasma levels obtained vary up to 40-fold in patients receiving the same dose.◦ Smoking significantly reduces plasma fluphenazine levels.◦ Available in brand name : Inj Prolinate 25mg/ml, 50 mg/2ml (amp)◦ Cost around 45 – 50 Rs.

Pros 2-4wk administration Generic formulation

Cons Risk of EPS and tardive dyskinesia No established loading dose option

THERAPEUTIC ACTIONS

Mechanism not fully understood: antipsychotic drugs block postsynaptic dopamine receptors in the brain, depress the RAS, including the parts of the brain involved with wakefulness and emesis; anticholinergic, antihistaminic (H 1), and alpha-adrenergic blocking activity also may contribute to some of its therapeutic (and adverse) actions.

Metabolism: Fluphenazine is extensively metabolized, undergoing "first pass" metabolism by the liver, and is excreted in both the urine and faeces

Distribution: Crosses placenta; enters breast milk

Excretion: Unchanged in the urine

Indication

Fluphenazine decanoate is indicated in the long-term management of psychotic disorders including schizophrenia, mania and organic brain syndrome.

It is of particular value in the treatment of chronic schizophrenia and for patients who are unreliable at taking oral medication.

• The drug often alleviates such target symptoms as hallucinations, delusions, confusion and withdrawal.

• It is not only useful in the hospital milieu but is unparalleled, because of its long duration of action in the long-term maintenance therapy of chronically psychotic patients who are amenable to out-patient therapy.

First-generation LAIs Haloperidol:

◦ Butyrophenone ◦ Haloperidol decanoate is a ester of haloperidol and decanoic acid dissolved in

Sesame seed oil. ◦ After intramuscular injection, haloperidol decanoate is gradually released

from muscle tissue and hydrolysed slowly into free haloperidol which enters the systemic circulation.

◦ Haloperidol decanoate is a potent dopamine antagonist and, therefore, a very incisive neuroleptic.

◦ 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 2–3 months of regular

dosing.◦ Variation in plasma levels is smaller than oral haloperidol.◦ It is available as brand name Inj Senorm LA – 50 mg/mlInj Trancodol LA- 50 mg/ml

o It cost around 180-200 Rs per 1 Amp of 50 ampo While switching from oral to depot dose can be calculated as 15-20 times daily oral dose at every 4 wk interval.o Maximum dose can be given is 300/4wks.

Pros 4wk administration Generic formulation Loading dose options

Cons Risk of EPS and tardive dyskinesia

Distribution Haloperidol crosses the blood-brain barrier easily. Plasma protein binding is 92%

• Metabolism Metabolised by several routes including the cytochrome P450 enzyme system

(particularly CYP 3A4 or CYP 2D6) and glucoronidation.

• Elimination After reaching peak plasma concentrations, levels fall with an apparent half-life of

about 3 weeks. Haloperidol is excreted in the urine (40%) and faeces (60%). About 1% of the dose

is excreted unchanged with the urine.

• Indication For the maintenance therapy of psychoses, particularly for patients requiring prolonged parenteral neuroleptic therapy.

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First-generation LAIs Perphenazine:

◦ Piperazine phenothiazine ◦ Perphenazine decanoate in sesame oil.◦ After intramuscular injection at gluteal region, peak plasma levels are

obtained in 1–7 days◦ Half-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.

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First-generation LAIs Pipotiazine:

◦ Piperidine Phenothiazine Antipsychotic. ◦ The Lai Formulation Contains Pipotiazine Palmitate In Coconut Oil. ◦ Provides Peak Plasma Levels After 1–2 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.

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First-generation LAIs Zuclopenthixol:

◦ 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 19 days.

◦ Dose of 200mg/2 weeks of clopixol depot is equivalent to a daily oral dose of 25 mg clopixol.

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.

It is available as inj. Clopixol depot 200mg/ml amp.

Cost around 300 Rs/amp of 200mg.

It can be given as 200-1200 mg at intervals of 2-4 wks.

It is preferred in agitated and aggressive patients.

First-generation LA’S Drug Injection site Test dose

(mg)Dose range(mg/week)

DosingInterval(weeks)

Comments

Flupentixoldecanoate

Gluteal or thigh 20 12.5-400 2-4 Maximum licenseddose is very highrelative to other LAIs

Fluphenazine decanoate

Gluteal 12.5 6.25-50 2-5 High EPS

Haloperidol Decanoate

Gluteal 25 12.5-75 4 High EPS

Pipothiazine palmitate

Gluteal 25 12.5-50 4 ? Lower incidence of EPS (unproven)

Zuclopenthixol decanoate

Gluteal or thigh 100 100-600 2-4 ? Slightly higher efficacy

Second-generation LAIs Risperidone:

◦ First ‘atypical’ drug to be made available as depot◦ Belongs to benzisoxazole derivative class ◦ Contains risperidone coated in polymer to form microspheres.◦ Have to be suspended in an aqueous base immediately before use.

◦ Available as Risperdal consta in doses of 25, 37.5 and 50 mg◦ Cost around 4000-5000 per 25 mg.◦ Must be stored in fridge.

Absorption:The main release of the drug starts 3 wk after injection, is maintained from 4 to 6 wk, and subsides by 7 wk. Steady state is reached after 4 injections

Disutribution:Volume of distribution: 1-2 L/kg.Risperidone binds to albumin and alpha1-acid glycoprotein.Plasma protein binding:

For risperidone: 90%For 9-hydroxyrisperidone: 77%

MetabolismExtensively metabolized in the liver by CYP2D6 to major active metabolite 9-hydroxyrisperidone. 9-hydroxyrisperidone has similar activity to risperidone.

EliminationEliminated in urine (70%) and feces (14%).

The half-life of risperidone plus 9-hydroxyrisperidone is 3 to 6 days.

ContraindicationsHypersensitivity to risperidone or to any components of the product.

Indications and UsageTreatment of schizophrenia; as monotherapy or as adjunctive therapy to lithium or valproate for the maintenance treatment of bipolar disorder.

Bipolar Mania25 mg every 2 wk. Some patients may benefit from a higher dose of 37.5 or 50 mg. Do not make upward dosage adjustments more frequently than every 4 wk.

•Schizophrenia•25 mg every 2 wk (max 50 mg every 2 wk). Do not make upward dosage adjustments more frequently than every 4 wk.

PROS AND CONS

•Risperidone 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 25–50 mg every 2 weeks appear to be as effective as oral doses of 2–6 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

Switching

to risperidone long acting injection (RLAI)‐

Start risperidone oral at 2 mg/day and titrate to effective dose.

If tolerated, prescribe equivalent dose of RLAI Continue with oral risperidone for atleast 3 weeks then taper over 1–2weeks.

Be prepared to continue oral risperidone for longer

Use oral risperidone before giving injection to assure good tolerability

Those stabilised on 2 mg/day start on 25 mg/2 weeksThose on higher doses, start on 37.5 mg/2 weeks and be prepared touse 50 mg/2 weeks

Second-generation LAIs Paliperidone: Contains extended release intramuscular extended-release intramuscular Paliperidone Palmitate

Major active metabolite of risperidone: 9-hydroxyrisperidone Active paliperidone plasma levels are seen within a day or so, therefore co- administration of oral paliperidone or risperidone during initiation is not required

• Paliperidone palmitate IM does not require cold storage.

• Prefilled syringes and does not require reconstitution

• No 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.

Paliperidone Dose Route

Initiation

Day 1 Day 8 (+/−2 days)∗

150 mg IM

Deltoid only

100 mg IM Deltoid only

Maintenance Every month (+/− 7 days)

thereafter 50–150 mg IM∗∗ Deltoid or gluteal

∗The 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, intramuscular

Risperidone oral(mg/day)

(bioavailability = 70%)

Paliperidone oral

(mg/day)(bioavailability =

28%)

RisperidoneLAI (Consta)(mg/2 weeks)

Paliperidonepalmitate

(mg/month)

2 4 25 50

3 6 37.5 75

4 9 50 100

6 12 - 150

Equivalent doses

Olanzapine

• Crystal salt made of Olanzapine & Palmoic acid.

• Each 15 mg of Olanzapine LAI must be dissolved in 0.1 ml of water.

• Max- 3.0 ml or 450 mg Olanzapine

• 3 hr monitoring after giving injection

• Post Injection Syndrome or Post Injection Delirium Syndrome

Parameter Olanzapine LA IMMetabolism Glucuronidation, CYP1A2 and 2D6

Elimination Urine and feces, 7% unchanged

Half-life 30 days

Protein binding 93%

Intramuscular gluteal injection3 vial strengths (210 mg, 300 mg, 405 mg)Once every 2 or 4 week injection24 hour medication stability in vial once reconstituted

Pros2wk or 4wk dosing optionsNew second generation antipsychotic in LAI formulation

ConsCostNeedle sizePost-injection monitoring

Administration

• Olanzapine LA IM should only be administered as a deep intramuscular gluteal injection using a 19-gauge, 1.5 inch needle (2 Hypodermic Needle-Pro needles with protection device are included).

• For obese patients a 2-inch, 19-guage or larger needle can be used for administration (not included).

• Following the needle’s insertion into the muscle, aspiration should take place for several seconds to ensure no blood is drawn into the syringe.

• If any blood is aspirated, the needle and dose should be discarded and a new dose prepared.

• Olanzapine LA IM is not to be administered intravenously or subcutaneously. • Reconstituted olanzapine is a suspension.

Dose Vial Strength Diluent to Add *Final Injection Volume

150 mg 210 mg 1.3 mL 1 mL210 mg 210 mg 1.3 mL 1.4 mL300 mg 300 mg 1.8 mL 2 mL405 mg 405 mg 2.3 mL 2.7 mL

DOSE RECONSTITION

Target Oral Olanzapine Dose

Olanzapine LA IM Dose During the 1st 8 Weeks

Olanzapine LA IM Maintenance Dose After 8

Weeks

10 mg/day 210 mg every 2 weeks or405 mg every 4 weeks

150 mg every 2 weeks or300 mg every 4 weeks

15 mg/day 300 mg every 2 weeks 210 mg every 2 weeks or405 mg every 4 weeks

20 mg/day 300 mg every 2 weeks 300 mg every 2 weeks

Post Injection Syndrome or Post Injection Delirium Syndrome:

• Mimics Olanzapine over dosageSedation, dizziness, slurred speech, agitation, confusion, ataxia, weakness , unconsciousness

• Majority occurs in first hour post-injection, progressing from mild to severe presentations

• Mechanism: Olanzapine LAI is highly soluble in blood compared to muscle.

• hypothesized that direct or partial injection into vasculature or bleeding around injection site leading to direct contact of Olanzapine

SwitchingDirect switching to olanzapine LAI, ideally following an oral trial, is usually possible.

So, when switching from another LAI (but not risperidone) olanzapine oral or LAI can be started on the day the last LAI was due.

Likewise for switching from oral treatment – a direct switch is possible but prior antipsychotics are probably best reduced slowly after starting olanzapine (either oral or LAI).

When switching from risperidone RLAI, olanzapine should be started, we suggest, 3–4 weeks after the last injection was due (e.g. 5–6 weeks after the last injection).

Aripiprazole LAI

It is an extended-release injectable suspension available in 400 mg or 300 mg strength vials.

its monohydrate polymorphic form

Mechanism of ActionAtypical antipsychotic; partial agonist at dopamine D2 and serotonin type 1 (5-HT1A) receptors; antagonist at serotonin type 2 (5-HT2A) receptor; also has alpha-blocking activity

AbsorptionBioavailability: 87% (tablet); 100% (IM)Peak plasma time: 1-3 hr (IR); 5-7 hr (ER); 3-5 hr (tablet)

DistributionProtein bound: 99%

MetabolismMetabolized by CYP2D6 and CYP3A4Metabolites: Dehydroaripiprazole (40%)

EliminationHalf-life: 75 hr (parent drug); 94 hr (metabolite); 30-47 days (IM); 146 hr (poor metabolizers)

Excretion: Feces (55%), urine (25%)

Schizophrenia10-15 mg/day PO initially; may be increased to 30 mg/day PO after 2 weeks

Maintenance with once-monthly IM injectionAbilify Maintena: 400 mg IM once monthly; continue treatment with aripiprazole PO (10-20 mg/day) or other oral antipsychotic for 14 consecutive days following first injectionOnly to be administered by deep IM injection into gluteal muscle Establish tolerability with oral aripiprazole prior to initiating if patient has never taken aripiprazoleAdminister monthly dose no sooner than 26 days after previous injection Consider dose reduction to 300 mg/month if adverse reaction occurs

Bipolar Mania Acute and maintenance treatment of manic or mixed episodes associated with

bipolar I disorder, either as monotherapy or as adjunct to lithium or valproate Monotherapy: 15 mg/day PO initially; may be increased gradually; not to exceed

30 mg/day Adjunct to lithium or valproate: 10-15 mg/day PO initially; recommended daily

dose is 15 mg/day; may be gradually increased; not to exceed 30 mg/day Continue stabilization dose for up to 6 weeks; treatment >6 weeks not studied

Switching

Switching to aripiprazole LAIOral antipsychotics Cross taper antipsychotic with oral aripiprazole* over 2 weeks.Start LAI, continue aripiprazole oral for 2 weeks then stopDepot antipsychotics(not risperidone LAI)Start oral aripiprazole* on day last depot injection was due. Startaripiprazole LAI after 2 weeks then stop oral aripiprazole 2 weeks laterRisperidone LAI Start oral aripiprazole* 5–6 weeks** after the last risperidone injection.Start aripiprazole LAI 2 weeks later; discontinue oral aripiprazole2 weeks after that

Iloperidone Iloperidone is an atypical antipsychotic that recently received marketing approval from the Food and Drug Administration for the acute treatment of schizophrenia.

Iloperidone is a pure antagonist and the first antipsychotic to have pharmacogenomic studies indicate predictive response based on six identified polymorphisms.

Iloperidone has been studied for nearly 20 years. In May 2009, the Food and Drug Administration approved the marketing of iloperidone for the acute treatment of schizophrenia in adults.

The three phases of the study included an open-label predepot phase, in which all patients with schizophrenia received 21 days of oral iloperidone (target dosage, ≤24 mg daily).

In the second phase, patients received single intramuscular injections of iloperidone (12–750 mg) or placebo for 28-day cycles.

In the final phase, patients received oral iloperidone for 364 days. Iloperidone demonstrated sustained release over 28 days, with the depot injections of 360 and 750 mg having comparable AUC values to oral iloperidone 12 and 24 mg/day, respectively.

Moreover, the tolerability of the depot formulation was similar to that of the oral tablets, regardless of patient age, sex, or weight.

Conclusion Iloperidone may be a viable and safe option for the treatment of schizophrenia in adult patients, especially for patients who cannot tolerate other antipsychotic agents.

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