LAMP Modules Presentation

LAIs Available in Canada

First generation

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Second generation

• Paliperidone palmitate
• Risperidone microspheres

Fluphenazine decanoate
Flupenthixol decanoate
Haloperidol decanoate
Pipotiazine palmitate
Zuclopenthixol decanoate

Second Generation LAIs Available in Canada

LAI

Indication

Properties

Mechanism

Paliperidone
palmitate

Schizophrenia

Prolonged-release
injectable suspension for
intramuscular
administration

Due to its extremely low water
solubility, paliperidone
palmitate slowly dissolves at the
injection site and is enzymatically
hydrolyzed to paliperidone, which is
taken up in the systemic circulation

Risperidone
microspheres

Schizophrenia and
related disorders

Powder for injectable
prolonged-release
suspension for
intramuscular
administration

Combination of the release profile
and dosing regimens (IM injections
every 2 weeks) results in sustained
therapeutic concentrations

Bipolar disorder

LAI Evidence

 Davis et al (1994)
• Meta-analysis suggested significant superiority for LAIs
compared to orals

 Cochrane Reviews (1999 - 2007)
• Earlier reviews showed no convincing difference

 Leucht et al (2011)
• Recent review showed significant advantages for LAIs

Manchanda R, Chue P, Malla A, et al. Long-acting injectable antipsychotics: evidence of effectiveness and use. Can J Psychiatry.
2013;58(5 Suppl 1):5S–13S.

Cochrane Review of LAIs

Critiques/criticisms of the Evidence
 Use of inpatient samples
 Short-term trials (few weeks)
 Inappropriate randomization

Abhijnhan A, Adams CE, David A, Ozbilen M. Depot fluspirilene for schizophrenia. Cochrane Database Syst Rev. 2007;1:CD001718.
Da Silva Freire Coutinho E, Fenton M, Quraishi SN. Zuclopenthixol decanoate for schizophrenia and other serious mental illnesses.
Cochrane Database Syst Rev. 1999;3:CD001164.

Recent Meta-Analysis

Leucht et al. (2011)

Kishimoto et al. (2012)

10 RCTs; n = 1700

21 RCTs; n = 5176

> 1 yr; outpatient only

> 6 months; inpatient & outpatient

Inclusion Criteria (narrower)

Inclusion Criteria (broader)

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Schizophrenia or related disorders
Any diagnostic system, any age, and gender
Only long-term studies defined as 1 year or longer
Outpatient studies
Studies with less than 25% inpatients or with an initial
inpatient phase were eligible
Excluded trials with inappropriate randomisation processes

•
•

≥17 years old
Diagnosis of schizophrenia or schizoaffective disorder
Included studies having other diagnoses, such as
schizophreniform disorder
Studies with a duration of at least 24 weeks that provided
information about relapse-related information, such as
study-defined relapse or rehospitalization
Excluded penfluridol, a once-weekly oral antipsychotic,
considering it neither a LAI or oral antipsychotic

Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review
and meta-analysis of randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in
schizophrenia: A meta-analysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

Relapse (Primary Outcome)

 Leucht et al (2011)
• 21.6% LAIs vs 33.3% oral AP (P = 0.0009) - Highly significant

 Kishimoto et al (2013)
• 25.8% LAIs vs 31.4% oral AP (P = 0.41) – Not significant
• Results similar when narrower criteria used
• Fluphenazine LAI 30.6% vs 41.9% oral AP (P = 0.02)
• Not significant for other LAIs (haloperidol, olanzapine,
risperidone, zuclopenthixol) compared to oral APs

Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of
randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A metaanalysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

Secondary Outcomes

 Rehospitalization rates
 Drop out/discontinuation rates
• From all cause
• Adverse events

 Non-adherence
All of the above findings not significant

Leucht C, Heres S, Kane JM, et al. Oral versus depot antipsychotic drugs for schizophrenia – a critical systematic review and meta-analysis of
randomised long-term trials. Schizophr Res. 2011;127(1-3):83–92.
Kishimoto T, Robenzadeh A, Leucht C, et al. Long-acting injectable vs oral antipsychotics for relapse prevention in schizophrenia: A metaanalysis of randomized trials. Schizophr Bull. 2013 Jan 2. Epub ahead of print. P 1-22.

Adherence, Rehospitalization and LAIs

Register based case linked study in Finland
• 2588 patients with schizophrenia discharged after first
hospitalization 2000-2007
• 1406 (54.3%) either did not collect an AP prescription or
used their medication for less than 30 days
• Risk of rehospitalization for patients on LAIs was about onethird of those on oral antipsychotics

.

Tiihonen J. et al. A Nationwide Cohort Study of Oral and Depot Antipsychotics After First Hospitalization for Schizophrenia. American
Journal of Psychiatry. 2011;168(6):603

Poor Adherence is Not Reflected in
Clinical Trials
 Patients are:
• Highly selected,
• Motivated, and
• Closely monitored

 Patients participating in RCTs are more likely to be
willing to take treatment and to be cooperative, thereby
obscuring any observable differences

Second Generation LAIs Available in Canada

Paliperidone Palmitate (PP)

SG LAIs

Availability

Initiation

Kit contains
• 1 Pre-filled syringe
• 2 needles
• 1” 23G or 1.5” 22G (depending on patient weight and
injection site)

Day 1: 150 mg by deep IM deltoid injection
Day 8: 100 mg by deep IM deltoid injection

• 50, 75, 100 & 150 mg

• For patients who have never taken oral paliperidone or
oral/injectable risperidone, it is recommended to establish
tolerability with oral paliperidone or oral risperidone prior
to initiating treatment

• Store at room temperature

• Absorption better from the deltoid injection especially during
initial doses

Oral Supplement

Dosing & Adjustments

• Oral supplementation is not required at initiation
(as per PM)

• Monthly dosing (50-150 mg) IM Gluteal or Deltoid
• First episode patients may require lower doses

• Clinically some patients (ie. acutely ill, previously on high
dose medication, those showing breakthrough symptoms)
may require oral supplementation at initiation

• Adjustment of the maintenance dose may be made monthly
• When making dose adjustments, the prolonged-release
characteristics should be considered, as the full effect of
the dose may not be evident for several months

INVEGA SUSTENNA® Product Monograph, Dec 30, 2013.

Second Generation LAIs Available in Canada (cont’d)
Availability

Initiation

Kit contains:
• 1 vial of Risperidone microspheres
• 1 prefilled syringe containing diluent
• 2 needles
• 2” 20G (gluteal)
• 1” 21G (deltoid)

Risperidone Microspheres (RLAI)

SG LAIs

• 25 mg every 2 weeks by deep IM injection; gluteal
or deltoid

• 12.5, 25, 37.5 & 50 mg
• Keep refrigerated (2-8 degrees Celsius). Bring to room
temperature before injection
• Use within 6 hours of reconstituting the preparation

• Can stay up to 7 days outside of the refrigerator at
temperatures no greater than 25 degrees Celsius

Oral Supplement

Dosing & Adjustments

• Oral supplementation should be continued for 3 weeks
after the first injection

• Dose can be adjusted monthly [dose range: 25, 37.5, 50 mg
(maximum)]

• Some experts advocate gradual tapering after 3 weeks.
Patients showing breakthrough symptoms may require
longer period of oral supplementation until the effective
dose of LAI has been established

• In clinical practice, doses of 75 mg have been used for
patients who have shown good tolerability but require
higher dose for full clinical response

• Patient should be continued on lowest dose needed
• Upward dose adjustment should not be made more
frequently than every 4 weeks. The clinical effects of this
dose adjustment should not be anticipated earlier than 3
weeks after the 1st injection with the higher dose.

RISPERDAL® CONSTA® Product Monograph, August 13, 2013

Switching to SG LAIs from an Oral
Antipsychotic
Paliperidone Palmitate (PP)
Paliperidone
Palmitate 150 mg (deltoid)
Stop Oral
Paliperidone
Palmitate 100 mg (deltoid)

Patient
on oral

DAY 1

Flexible
50 - 150 mg
(deltoid or gluteal)

Flexible
50 - 150 mg

DAY 8
(+/- 2 to 4 days)*

4 WEEKS
LATER

MONTHLY
(+/- 7 days)*

*To avoid a missed dose

Risperidone Microspheres (RLAI)
Risperidone Microspheres 25 mg
Risperidone Microspheres 25 mg
Stop Oral

Patient
on oral

DAY 1

DAY 14
(WEEK 2)

DAY 21

Flexible 25-50 mg

Flexible 25-50 mg

Flexible 25-50 mg

DAY 28
WEEK 4

EVERY 2
WEEKS

EVERY 2
WEEKS

Approximate conversion: Risperidone oral 2-3 mg (25 mg RLAI), Risperidone oral 4-5 mg (37.5mg RLAI), Risperidone oral 6 mg and over (50 mg RLAI)
These ratios are approximate and may not work for some patients.

INVEGA SUSTENNA® Product Monograph, Dec 30, 2013. RISPERDAL® CONSTA® Product Monograph, Aug 13, 2013

Switching Between LAI’s

 Tolerability should be established with oral paliperidone
or oral risperidone for patients who have never taken
these agents
 When switching patients who are on a stable dose of a
long-acting injectable, initiate paliperidone palmitate
therapy in place of the next scheduled injection then
continue at monthly intervals
 The one-week initiation dosing regimen is not required


Switching Between LAI’s (cont’d)
Approximate dose equivalence between risperidone microspheres
and paliperidone palmitate (as per PM)
Previous Risperidone
Microspheres Dose

Paliperidone Palmitate
Dose

25 mg every 2 weeks

50 mg eq. monthly

37.5 mg every 2 weeks

75 mg eq. monthly

50 mg every 2 weeks

100 mg eq. monthly

Switching early psychosis patients from risperidone microspheres to paliperidone palmitate may require more careful
dose adjustment

For patients on FG LAIs being switched to SG LAIs it is recommended that they have the injection
on the next scheduled injection day and follow the dosing regimen of SG LAI. Dose is dependent on
whether the patient is on low, average or high dose of FG LAI


Patient Acceptance of LAIs

 Important for physicians and patients to;
• Share knowledge about LAIs
• Reflect on their respective bias and attitude about injections

 Collaborative discussions are essential to gaining
acceptance to any treatment plan
 Motivational Interviewing techniques may help to foster
collaborative discussions

Motivational Interviewing: Definition

 Motivational interviewing has been applied to improve
treatment adherence
 Motivational interviewing matches patients’ level of
problem recognition and motivation to change, with
specific strategies and goals.

Kisely S, Ligate L, Roy MA, Lavery T. Applying Motivational Interviewing to the initiation of long-acting injectable atypical
antipsychotics. Australasian Psychiatry. 2012; 20(2); 138-142.

Motivational Interviewing: Principles

 Motivational interviewing has four principles:
1. Expressing empathy through reflective listening;
2. Developing discrepancy by increasing the perceived
discrepancy between the patient’s present behaviour and his or
her core values;
3. Supporting self-efficacy to bolster patients’ confidence in their
ability to achieve their desired change; and
4. Rolling with resistance by avoiding arguments


Motivational Interviewing: Stages of Change

 Change, as conceptualized in motivational interviewing,
has the following five stages:
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Pre-contemplation
Contemplation
Preparation
Action
Maintenance


Motivational Interviewing Skills

Simple
Reflection

Shift
Focus

Roll with
Resistance

Side with
the Negative

Open-Ended
Questions

Listen
Reflectively

Express
Empathy

Develop
Discrepancy

Reframing

Avoid
Arguments

Affirm


Simple Reflection
Respond to resistance with
nonresistance by repeating the patient's
statement in a neutral form


Shift Focus
Help the patient shift focus away from
obstacles and barriers


Roll with Resistance
Actively involve the person in the
process of problem solving


Side with the Negative
Take up the negative voice in the discussion


Open-Ended Questions
Solicit additional information in a neutral way


Listen Reflectively
Check rather than assume that you know
what is meant


Express Empathy
Empathy communicates acceptance


Develop Discrepancy
Encourage the patient to see the difference
between their current situation and their
hopes for the future


Reframing
Use a new and positive interpretation of
negative information from the patient


Avoid Arguments
They are counterproductive
and breed defensiveness


Affirm
Support and promote self-efficacy

Motivational Interviewing Steps:
A Practical Approach


Establish Rapport and Build a Therapeutic Alliance


Set a Collaborative Agenda for Remission and Recovery


Assess Importance

Examine the good things and the not-so-good
things about the current situation
(e.g., patient not taking oral medication regularly)

Assess Importance


Explore Personal Importance as it Pertains to the Individual
Assess Importance

Compare good vs not-so-good
(ownership of problems)

Assess Importance


Discuss Short-Term and Long-Term Goals as
Defined by the Patient
Assess Importance


Discuss Discrepancies with Desired and Achievable
Goals in Short and Long-term
Assess Importance

Openly discuss discrepancies between
physician and patient perspectives

Assess Importance


Summarize and Review Periodically
Assess Importance


Ask for Decision

Assess Importance

Assist patient in making a decision
that reflects his/her perspectives,
goals and knowledge

Ask for Decision

Assess Importance

Review Goals and Provide
Continuous Support for Self Efficacy

Ask for Decision

Assess Importance

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