Anti psychotics : long acting injections

1. Antipsychotic
Long Acting Injections
Presentation by K.Gunesh
Wd 17 20/3/17

2. Outline
 Introduction
 Antipsychotic Long Acting Injections (LAI)
 Pharmacology
 Individual Long Acting Antipsychotics
 Advantages & Disadvantages
 Conclusion
2

3. Introduction - Course of Schizophrenia
4

4. LAI & Adherence
 Non-adherence may be both a cause and consequence of
worsening of illness
 Long-acting injectable antipsychotic drugs can help to:
 Improve adherence
 Reduce relapse
 Lower hospitalization rates
5

5. Antipsychotic Long Acting Injections
(LAI)
 Two groups of LAIs: First generation LAIs and Second-
generation LAIs.
 First LAI – Fluphenazine Enantate- 1966.
 First of the second generation LAI –Risperidone Microspheres
6

6. 1st
Gen LAIs
•Flupentixol Decanoate :
 LAI is formulated as flupentixol decanoate in a low-viscosity vegetable
oil (fractionated coconut oil).
 Peak plasma levels 3–7 days after IM injection
 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.4
7

7. 1st
Gen LAIs
•Fluphenazine Decanoate:
 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.
8

8. 1st
Gen LAIs
•Haloperidol Decanoate:
 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 2–3
months of regular dosing.
 As with fluphenazine, clearance of haloperidol is significantly increased
by smoking.
 Variation in plasma levels is smaller than oral haloperidol.
9

9. 1st
Gen LAIs
 Zuclopenthixol Deconoate:
 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 levels
 Steady-state plasma levels are achieved after around 2 months of regular dosing
10

10. 1st
Gen Antipsychotic long-acting
injections : suggested doses and
frequenciesDrug Licensed
injection site
Test dose
(mg)
Dose range
(mg/week)
Dosing
Interval
(weeks)
Flupentixol
decanoate
Gluteal or thigh 20 12.5-400 2-4
Fluphenazine
decanoate
Gluteal 12.5 6.25-50 2-5
Haloperidol
Decanoate
Gluteal 25 12.5-75 4
Zuclopenthixol
decanoate
Gluteal or thigh 100 100-600 2-4
11

11. 2nd
Gen LAIs
12
Risperidone:

First ‘atypical’ drug to be made available as depot

Contains risperidone coated in polymer to form microspheres.

Have to be suspended in an aqueous base immediately before
use.

Stored in a fridge

Available as doses of 25, 37.5 and 50 mg

12. 13

13. 2nd
Gen LAIs
 Peak release is at about 28 days.
 The long-acting injection 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 reported to be low
14

14. 2nd
Gen LAIs
 Paliperidone Palmitate
 Contains extended release intramuscular
Paliperidone Palmitate( crystalline matrix)
 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
15

15. Paliperidone dosing
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
16
∗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

16. Approximate dose equivalence of
Risperidone and Paliperidone
Risperidone oral
(mg/day)
(bioavailability =
70%)
Paliperidone oral
(mg/day)
(bioavailability =
28%)
Risperidone
LAI (Consta)
(mg/2 weeks)
Paliperidone
palmitate
(mg/month)
2 4 25 50
3 6 37.5 75
4 9 50 100
6 12 - 150
17

17. 2nd
Gen LAIs
 Olanzapine Pamoate
 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
18

18. 2nd
Gen LAIs
 Post Injection Syndrome or Post Injection Delirium Syndrome:
 Sedation, dizziness, slurred speech, agitation, confusion, ataxia, weakness ,
unconsciousness
 Majority occurs in first hr 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 with blood
19

19. 2nd
Gen LAIs
 Aripiprazole:
 First dopamine D2 partial agonist as a once-monthly
injection
 Microsphere long-acting injectable (similar to RLAI)
20

20. 2nd
Gen LAIs
 The most frequently reported adverse events were akathisia, insomnia
and injection-site pain.
 Injection-site reactions were generally mild to moderate in severity and
resolved over time.
 Extrapyramidal symptoms were reported more frequently with
aripiprazole 400 mg or 300 mg prolonged-release injection than oral
aripiprazole
21

21. Choice of antipsychotic medication
 The choice of antipsychotic medication should be made ideally as a joint decision
with the consumer and the health care provider.
 Points to be covered:
 Provide information and discuss the likely benefits and possible side effects of
each drug, including:
 Metabolic (including weight gain and diabetes)
 Extrapyramidal (including akathisia, dyskinesia and dystonia)
 Cardiovascular (including prolonging the QT interval)
 Hormonal (including increasing plasma prolactin)
 Other (including unpleasant subjective experiences) 22

22. Combined antipsychotic drugs
 Prescribed in the short term(for example, cross-tapering while switching from one
antipsychotic to another)
 In the longer term (for example, as a strategy to improve symptom control or
reduce side-effects.
 With respect to longer-term use, there is no good objective evidence that combined
antipsychotics (that do not include clozapine) offer any efficacy advantage over
the use of a single antipsychotic.
More harm - increases likely hood of EPS, metabolic side-effects, seizure activity and
prolonged QTc.
23

23. Reducing dose of depots
 If it has not already been done, oral antipsychotic medication should be
discontinued first.
 The interval between injections should be increased to up to 4 weeks before
decreasing the dose given each time. Note: not with risperidone.
 The dose should be reduced by no more than a third at any one time. Note:
special considerations apply to risperidone.
 Decrements should, if possible, be made no more frequently than every 3
months,preferably every 6 months.
 Discontinuation should be seen as the endpoint of the above process
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24. Disadvantages of LAI over oral antipsychotics
1. Understanding the pharmacokinetics & dosing require specific LAI knowledge.
i. Delayed time until steady state is reached
ii. Clinical improvement may be delayed after dose increase
iii. Elimination may take weeks to months
2. Adverse effects may persist after stopping/reducing dose
3. Injection related adverse effects e.g. pain, nodules
4. Some patient regards LAI as indicating a lack of control or autonomy
5. Organised community system to deliver LAIs-LAI storage, reconstitution & administration may
require special precautions, &/or training
6. SGA-LAI have high acquisition costs
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25. Advantages of depot antipsychotics over oral
antipsychotic
1. Improved treatment adherence, overt non-adherence can be addressed
2. Easier early detection of relapse, improved relapse prevention and reduced hospitalization rates
3. Enhanced consistency between the drug prescription and drug delivery
4. More predictable and stable serum concentrations
5. Less variability between patients in steady state blood levels for a given dose
6. Lowest effective dose principle more safely achieved with depots (step-wise reduction)
7. Reduced risk of accidental or deliberate self-poisoning (overdose)
8. Less risk of overdose
9. Bypasses pharmacokinetic hurdles of absorption & first pass hepatic elimination
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26. Conclusion
 When selecting a specific LAI, consider class similarities and individual
antipsychotic differences.
 Individualize the dose and dosing interval based on patient response, peak-
related adverse effects (time to peak is approximately 5 half-lives for most
drugs), and possible reduced symptom control at the end of the dosing
interval
 Although some LAIs are expensive, they potentially reduce the financial
burden of schizophrenia and improve quality of life.
 Do not rule out first-generation LAIs.
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27. Conclusion
 Consider a loading dose strategy to minimize the time a patient
has to take an oral and LAI antipsychotic combination.
 If antipsychotic poly-pharmacy is necessary, document your
rationale.
 Keep other reasons for non-adherence in mind & intervene
accordingly.
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28. References
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Oxford University Press; 2011.
2. Stephen M Stahl. Antipsychotic agents. In: (eds.)Stahl's essential psychopharmacology.
4th ed. Cambridge: Cambridge; 2013. p129-236
3. Thomas R.E. Barnes. Why aren't depot antipsychotics prescribed more often and what
can be done about it?. Advances In Psychiatric Treatment 2005; (11): 211-213.
4. Maxine X. Patel and Anthony S. David. Why aren’t depot antipsychotics prescribed more
often and what can be done about it?. Advances in Psychiatric Treatment 2005; (11): 203-
211.
5. John M. Kane, Carlos Garcia-Ribera. Clinical guideline recommendations for
antipsychotic long-acting injections. The British Journal of Psychiatry.Supplement 2009 Nov;
(195): s63–s67.
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