depot antipsychotic medication: guidelines for … · 2020. 2. 27. · first generation long-acting...
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DEPOT ANTIPSYCHOTIC MEDICATION: GUIDELINES FOR PRESCRIBING
AND ADMINISTERING
FEBRUARY 2020
This policy supersedes all previous policies
I DEPOT ANTIPSYCHOTIC MEDICATION GUIDELINES_PRESCRIBING_ADMINSTRATION_PHA04_FEB 2020
Policy title Depot Antipsychotic Medication: Guidelines for Prescribing and Administration
Policy reference
PHA04
Policy category Clinical
Relevant to All Clinical staff
Date published 2019
Implementation date
February 2020
Date last reviewed
December 2016
Next review date
February 2023
Policy lead Lucy Reeves, Chief Pharmacist
Contact details Email:[email protected]
Accountable director
Dr Vincent Kirchner, Medical Director
Approved by (Group):
Drugs and Therapeutic Committee
February 2020
Approved by (Committee):
Quality Committee
Document history
Date Version Summary of amendments
March 2009 3 Routine review
April 2010 4 Routine review
March 2012 5 Routine review
Nov 2014 6 Routine review
Dec 2016 7
Route of aripiprazole depot updated to include deltoid. Paliperidone three monthly depot is added. Olanzapine depot monitoring advice updated. Administration of depots under restraint added.
Feb 2020 8 High dose antipsychotic monitoring form removed
Membership of the policy development/ review team
Dr Julian Summerfield (Consultant Psychiatrist, Lead Pharmacists, Modern Matrons, Consultant Nurse for Physical Health
Consultation Drug and Therapeutic Committee members
DO NOT AMEND THIS DOCUMENT
Further copies of this document can be found on the Foundation Trust intranet.
II DEPOT ANTIPSYCHOTIC MEDICATION GUIDELINES_PRESCRIBING_ADMINSTRATION_PHA04_FEB 2020
Contents Page
1 Introduction 1
2 Aims and objectives 1
3 Scope of the policy 1
4 Prior to initiation of depot treatment 1
5 Advice on prescribing depot antipsychotics 1
6 Use of unlicensed doses 16
7 Administration of depot antipsychotic medication 16
8 Use of alternative sites or sites which are off-label 18
9 Depots/LAIs administered under restraint 19
10 Generic names/Brand names 19
11 Management of patients on long term depot antipsychotics in relapse
prevention
19
12 Intramuscular anticholinergic medication 21
13 Primary care involvement 22
14 Zuclopenthixol acetate (Clopixol acuphase) 22
15 Related policies 22
16 Dissemination and implementation arrangements 22
17 Training requirements 22
18 Monitoring and audit arrangements 22
19 Review of the policy 23
20 References 24
Appendix 1: Equivalent doses of antipsychotics 28
Appendix 2: Sites Of Administration 29
Appendix 3: Equality Impact Assessment Form 30
1
1 Introduction
1.1.1 Antipsychotic depot / long acting injections (LAI) preparations are used for maintenance therapy in the treatment of schizophrenia, especially when adherence with oral treatment is unreliable.
2 Aims and objectives
2.1.1 To provide guidance on prescribing antipsychotic depot/long-acting injections (LAIs).
3 Scope of the policy
3.1.1 This policy is aimed at all clinical staff who are directly involved in the management of patients who are prescribed depot/LAI antipsychotic preparations.
4 Prior to initiation of depot treatment
4.1.1 Depot preparations should be a treatment option where a service user expresses a preference for such treatment after an acute episode because of its convenience, or as part of a treatment plan in which the avoidance of covert non-adherence (intentional or unintentional) with antipsychotic medication is a clinical priority1.
4.1.2 Following full discussion between the responsible clinician and the service user, the decision to initiate depot antipsychotic injections must take into account the preferences and attitudes of the service user towards the mode of administration and organisational procedures (for example; home visits and location of clinics) related to the delivery of regular intramuscular injections1.
4.1.3 As with oral antipsychotics, service users receiving depots must be maintained under regular clinical review, particularly in relation to the risks and benefits of the medication regimen.
5 Advice on prescribing depot antipsychotics
5.1 Choice of depot antipsychotic
5.1.1 The choice of depot medication is determined by the needs of the individual service user. There are few differences between individual older long-acting antipsychotics. Fluphenazine may be associated with relatively more extrapyramidal side effects but perhaps less weight gain. Flupenthixol, halopepridol and fluphenazine are considered equally effective. Zuclopenthixol may be more effective in preventing relapses than others, although this may be at the expense at the increased burden of side effects. Flupenthixol decanoate can be given in very much higher “neuroleptic equivalent” doses than the other depot antipsychotics and still remain “within BNF limits”, although it is doubtful that this confers any real therapeutic advantage2 . The typical depot antipsychotics should be considered first-line.
2
5.1.2 These medicines are long-acting preparations. Therefore service users should be exposed to the oral form of the medicine (or a test dose of the injection) prior to their first full dose of the injection to minimise the possibility of a long-lasting idiosyncratic reaction. Patients must be offered a patient information leaflet from the Choice and Medication website located on the intranet.
5.2 Dosages - First generation long-acting antipsychotic injections
5.2.1 For first generation long-acting antipsychotics, a test dose must be given. This is a test of the sensitivity or extrapyramidal side effects and any sensitivity of the base oil2. The allergy status for the medicines and base oil (e.g. sesame oil, vegetable oil derived from coconuts) or excipients e.g. benzyl alcohol must be checked and documented in Electronic patient record (Carenotes).
5.2.2 Begin with the lowest therapeutic dose. There is some information that low doses are at least as effective as higher doses. Low doses are likely to be better tolerated2.
5.2.3 See table 1 for when the next dose should be administered.
5.2.4 Oral antipsychotics may also be prescribed initially. These should be gradually reduced and stopped once therapeutic maintenance dose has been established. If the total dosage exceeds BNF limits, the trust High Dose Antipsychotic Therapy guidelines must be implemented (see appendix 1).
5.2.5 The depot should be administered at the longest possible licensed interval, bearing in mind the maximum recommended single dose. There is no evidence to suggest that shortening the dose interval improves efficacy. Injections are painful, so less frequent administration is desirable2.
5.2.6 The observation that some patients deteriorate in the days before the next dose is due is not supported by fact. For some hours to days (with some preparations), plasma levels of antipsychotics continue to fall, albeit slowly after the next injection. Thus patients are most at risk of deterioration immediately after a long-acting injection and not before it. In most trials, relapse occurs only three to six month after withdrawing therapy. This is roughly the time to clear steady state long-acting medicines from the blood2.
5.2.7 Doses should be adjusted after an adequate period of assessment. Attainment of peak plasma levels, therapeutic effect and steady-state plasma levels are delayed with the long-acting injections1. Attainment of steady state usually takes three months for first-generation antipsychotic depots3. Doses may be reduced if adverse effects occur, but should only be increased after careful assessment over at least one month, preferably longer1.
5.2.8 When swapping from one first generation antipsychotic depot to another first generation antipsychotic depot, a direct exchange from one depot to another can usually be made3. If the person has not previously had the new depot, ensure tolerability is checked first with a test dose.
5.2.9 When swapping from a combination of oral antipsychotics plus depot to a depot alone, relapses are more likely in the first three to four months. If the risk of
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relapse is high, consider increasing the depot dose and then reduce the oral doses later3.
5.2.10 When swapping from a first generation antipsychotic depot to another antipsychotic, stop the depot and introduce the new antipsychotic when the next depot date is due, remembering that a slow decay of depot plasma levels may occur. So be aware of adding the new medicine too quickly3.
Table 14-12:
Medicine Test dose Dose range Interval
First generation long-acting antipsychotics
Fluphenazine in
sesame oil
12.5mg (6.25mg in patients
over 60 years)
12.5-100mg every two to five weeks
Reasonable steady state
is achieved at intervals of
two to four weeks
Flupenthixol in thin
vegetable oil
(derived from
coconuts)
20mg (consider 5- 10mg in
elderly patients)
50 every four weeks -400mg/week
Weekly to four weekly
Haloperidol in
sesame oil
50mg every four weeks (12.5
– 25mg every four weeks in
elderly patients)
50-300mg every four weeks
Four weekly
Zuclopenthixol in
thin vegetable oil
(derived from
coconuts)
100mg (consider 25-50mg in
elderly patients)
200-600mg every one to four weeks. Maximum: 600mg every week.
Weekly to four weekly
Second generation long-acting antipsychotics
Aripiprazole (powder
and solvent for
prolonged release
suspension)
None. Response & tolerability
to oral aripiprazole must be
checked prior to initiating the
depot.
300-400mg/month Four weekly
Olanzapine (powder
and solvent for
prolonged release
suspension)
None. Tolerability to oral
olanzapine must be checked
prior to initiating the depot.
150mg every two
weeks to 405mg
every month
Two to four weekly
Paliperidone LA
(prolonged release
suspension)
None. Response and
tolerability to oral risperidone
must be checked prior to
initiating the depot.
25-150mg/month Four weekly
Paliperidone three
monthly (prolonged
release suspension)
(Trevicta)
None. Stabilisation with
paliperidone monthly depot
for at least four months must
have preceded initiation
175-525mg/ three
months
Three monthly
Risperidone (powder
and solvent for
prolonged release
suspension)
None. Response and
tolerability to oral risperidone
must be checked prior to
initiating the depot.
25-50mg/2weeks Two weekly
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5.3 Dosages - second generation long-acting antipsychotic injection
5.3.1 Second generation long-acting antipsychotic injections have a relatively lower propensity for extrapyramidal side effects2.
5.3.2 Second-generation long-acting antipsychotic injections do not require test doses2. Patients to be prescribed risperidone injection or paliperidone monthly depot must be prescribed oral risperidone first to check for tolerability and response to treatment. Patients prescribed paliperidone three monthly depot must be preceded by paliperidone monthly preparation. Patients prescribed aripiprazole or olanzapine depot must be prescribed the respective oral formulation first to check tolerability and response to treatment4.
5.4 Risperidone long acting injection
5.4.1 A test dose is not required, however response and tolerability to oral risperidone must be confirmed before starting the depot formulation. See table 2.
5.4.2 The recommended dose is 25 mg intramuscularly every two weeks. For those patients on a fixed dose of oral risperidone for two weeks or more, the following conversion scheme should be considered. Patients treated with a dosage of 4 mg or less oral risperidone should receive 25 mg, while patients treated with higher oral doses should be considered for the higher dose of 37.5 mg. Sufficient antipsychotic coverage should be ensured during the three-week lag period following the first injection. Where patients are not currently taking oral risperidone, the recommended dose is risperidone injection 25mg every two weeks.
5.4.3 In the elderly, no dose adjustment is required from the recommendation in 5.4.2. However there have been anecdotal cases of reduced mobility.
5.4.4 Deltoid and gluteal intramuscular injections at the same doses are bioequivalent and, therefore, interchangeable12.
5.4.5 After a single intramuscular injection with risperidone injection, the release profile consists of a small initial release of risperidone (<1% of the dose), followed by a lag time of 3 weeks. The main release of risperidone starts from Week 3 onwards, is maintained from 4 to 6 weeks, and subsides by Week 7. Oral antipsychotic coverage should therefore be given during the first 3 weeks of treatment. Oral antipsychotic supplementation on a reducing titration is sometimes required for longer (6-8 weeks)2,12.
5.4.6 The depot must be administered every two weeks as the pharmacokinetic profile does not allow for longer intervals.
5.4.7 Opinions on the dose equivalence vary depending on the reference used. Doses of 25-50mg every 2 weeks m a y equate to oral doses of 1-4mg/day2,3.
5.4.8 It must be stored in the fridge.
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5.4.9 Risperidone injection must be administered every two weeks by deep intramuscular deltoid or gluteal injection. Only needles supplied with the packs should be used. For deltoid administration, use the 1-inch needle alternating injections between the two arms. For gluteal administration, use the 2-inch needle alternating injections between the two buttocks.
5.4.10 Switching to risperidone long-acting injection
Table 2: Switching to or from risperidone long-acting injection2, 3, 12
Switching
from
Recommended method of switching Comments
No treatment
(new patient
or recently
non-
adherent).
Starting
risperidone
injection
Start risperidone oral at 2mg/day and
titrate to effective dose. If tolerated,
prescribe equivalent dose of risperidone
long-acting injection. Oral risperidone
should be continued for at least three
weeks, then taper over one to two weeks.
Be prepared to continue oral risperidone
for longer.
Use oral risperidone before
giving injection to assure good
tolerability. Those stabilised on
2mg/day should be started on
25mg every two weeks. Those
on higher doses, start on 37.5mg
every 2 weeks. Be prepared to
use 50mg every 2 weeks.
Oral
risperidone to
risperidone
injection
For those patients on a fixed dose of oral risperidone for two weeks or more, the following conversion scheme should be considered. Patients treated with a dosage of 4 mg or less oral risperidone should receive 25 mg risperidone injection, while patients treated with higher oral doses should be considered for the higher dose of 37.5 mg. Where patients are not currently taking oral risperidone, the oral pre-treatment dosage should be considered when choosing the i.m. starting dose.
See above.
Oral
antipsychotics
(not
risperidone) to
risperidone
injection
Either:-
Switch to oral risperidone and titrate to
effective dose. If tolerated, prescribe
equivalent dose of risperidone long-acting
injection. Oral risperidone should be
continued for at least three weeks, then
taper over one to two weeks. Be prepared
to continue oral risperidone for longer.
Or:-
Check tolerability and response to oral
risperidone if possible. Give risperidone
long-acting injection, then the oral
antipsychotics should be slowly tapered
three to four weeks later. Be prepared to
continue oral antipsychotics for longer.
Broadly speaking for those of low
doses, start at 25mg every two
weeks, then adjust as necessary.
If the patient was previously
maintained on doses of middle or
upper range of licensed doses,
start at 37.5mg or 50mg every
two weeks. The continued needs
for oral antipsychotics after three
to four weeks may indicate
higher doses or risperidone long-
acting injection are required.
Depot
antipsychotic
to risperidone
injection
Check tolerability to oral risperidone first
with one dose if possible. Risperidone
long-acting injection should be given one
week before the last dose of the previous
For those of low doses, start at
25mg every two weeks, then
adjust as necessary. If the
patient was previously
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depot injection2. Consider
supplementation with an oral medicine if
the risk of relapse is high3.
Or
Check tolerability to oral risperidone first
with one dose if possible. Switch on the
depot due date, supplementing with oral
risperidone for three to four weeks3.
maintained on doses of middle or
upper range of licensed doses,
start at 37.5mg every two weeks.
Be prepared to increase to 50mg
every two weeks.
Antipsychotic
polypharmacy
with depot to
risperidone
injection
Check tolerability to oral risperidone first
with one dose if possible. Risperidone
long-acting injection should be given one
week before the last dose of the previous
depot injection. The oral antipsychotics
should be slowly tapered three to four
weeks later. Be prepared to continue oral
antipsychotics for longer.
Aim to treat the patient with
risperidone long-acting injection
as the sole antipsychotic. The
dose should be dictated as far as
possible by the total dose or oral
and injectable antipsychotic.
Risperidone
injection to
others
The last dose of risperidone injection will
finally stop releasing risperidone about six
weeks later, so wait until then and
introduce the new antipsychotic gradually
from day 423.
Table 3: Approximate dose equivalence of risperidone to paliperidone2
Risperidone oral
(mg/day)
Paliperidone oral
(mg/day)
Risperidone LAI
(mg/two weeks)
Paliperidone LAI
(mg/month)
2 4 25 50
3 6 37.5 75
4 9 50 100
6 12 - 150
5.5 Paliperidone long acting injection
5.5.1 Paliperidone LAI is restricted to consultant initiation only within the Trust. A non-formulary form must be completed for the specific patient by the consultant before starting treatment (see the trust formulary). Pharmacy will monitor prescribing to ensure it is appropriate and within the Trust formulary specifications.
5.5.2 Tolerability and response to risperidone must be established (oral or LAI) before considering prescribing paliperidone LAI.
5.5.3 There are two methods of initiating paliperidone LAI, depending on if the patient is prescribed risperidone tablets or injection. See Table 4 and 5. It has a
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nanocrystal technology formulation allowing both an early and sustained release3.
5.5.4 Paliperidone LAI should be administered every calender month. Only needles supplied with the pack should be used. It is stored at room temperature4.
5.5.5
Table 411: Switch from oral risperidone Days Dose Day 1 150mg (deltoid muscle) Day 8 100mg (deltoid muscle) Day 36 75mg which may be adjusted thereafter between 25-150mg
once every calender month). (deltoid or gluteal muscles).
Table 511: Switch from risperidone injection Dose of Risperidone LAI Dose of Paliperidone LAI 25mg every two weeks 50mg every month 37.5mg every two weeks 75mg every month 50mg every two weeks 100mg every month
Table 6: Switching to and from paliperidone palmitate2
Switching from
Recommended method of switching
Comments
No treatment, starting paliperidone LAI
Check tolerability and response to oral risperidone first. Give the two initiation doses, 150mg IM deltoid on day 1, 100mg IM deltoid on day 8. Maintenance dose starts one month later (Day 36).
The lowest most effective maintenance dose should be used. The manufacturer recommends a dose of 75mg monthly for the general adult population. This is approximately equivalent to 3mg/day oral risperidone (see table 5).Maintenance dose adjustments should be made monthly. The full effect of the dose adjustment may not be apparent for several months.
Paliperidone /Risperidone to paliperidone LAI
Give the two initiation doses, followed by the maintenance dose (see table 3 and prescribe equivalent dose).
Oral paliperidone/risperidone supplementation during initiation is not necessary.
Oral antipsychotics to paliperidone LAI
Check tolerability to oral risperidone first with one dose if possible. Reduce the dose of the oral antipsychotic over one to two weeks, following the first injection of paliperidone. Give the two initiation doses followed by the maintenance dose.
Depot antipsychotic
Check tolerability to oral risperidone first with one dose if possible. Start paliperidone LAI (at the maintenance dose) when the next injection is due. No initiation doses are required2. Go
The manufacturer recommends a dose of 75mg monthly for the general adult population. If switching from risperidone injection, see table 5 and prescribe the
8
straight to monthly3. equivalent dose. .Maintenance dose adjustments should be made monthly. The full effect of the dose adjustment may not be apparent for several months.
Antipsychotic polypharmacy with depot
Check tolerability to oral risperidone first with one dose if possible. Start paliperidone LAI (at the maintenance dose) when the next injection is due. No initation doses are required. Reduce the dose of the oral antipsychotic cover over one to two weeks, following the first injection of paliperidone.
Aim to treat the patient with paliperidone long-acting injection as the sole antipsychotic. The maintenance dose should be dictated as far as possible by the total dose or oral and injectable antipsychotic
Paliperidone LAI to oral antipsychotic
Start the oral antipsychotic when the next injection is due, but titrate slowly as paliperidone levels can persist for six months.
Paliperidone LAI to risperidone LAI
Start risperidone injection when the next depot dose is due3.
Paliperidone LAI to another depot
Start the new depot slowly to avoid additive ADRs and NMS as paliperidone levels can persist for up to six months3.
Others to paliperidone LAI
Oral antipsychotics can be stopped over one week except olanzapine, quetiapine and clozapine which need to be stopped over four weeks to minimise insomnia and cholinergic rebound3.
5.5.6 Elderly population
Efficacy and safety in elderly > 65 years have not been established. In general, recommended dosing of paliperidone LAI for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. However, because elderly patients may have diminished renal function, dose adjustment may be necessary.
5.5.7 Renal impairment
Paliperidone LAI has not been systematically studied in patients with renal impairment. For patients with mild renal impairment (creatinine clearance ≥ 50 to < 80 ml/min), recommended initiation of paliperidone LAI is with a dose of 100 mg on treatment day 1 and 75 mg one week later, both administered in the deltoid muscle. The recommended monthly maintenance dose is 50 mg with a range of 25 to 100 mg based on patient tolerability and/or efficacy. Paliperidone
9
LAI is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min).
5.5.8 Avoiding missed doses
It is recommended that the second initiation dose of paliperidone LAI be given one week after the first dose. To avoid a missed dose, patients may be given the second dose 4 days before or after the one-week (day 8) time point. Similarly, the third and subsequent injections after the initiation regimen are recommended to be given monthly. To avoid a missed monthly dose, patients may be given the injection up to 7 days before or after the monthly time point. If the target date for the second injection (day 8 ± 4 days) is missed, the recommended reinitiation depends on the length of time which has elapsed since the patient's first injection.
5.5.9 Missed second initiation dose (< 4 weeks from first injection)
If less than 4 weeks have elapsed since the first injection, then the patient should be administered the second injection of 100 mg in the deltoid muscle as soon as possible. A third injection of 75 mg in either the deltoid or gluteal muscles should be administered 5 weeks after the first injection (regardless of the timing of the second injection). The normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy should be followed thereafter.
5.5.10 Missed second initiation dose (4-7 weeks from first injection)
If 4 to 7 weeks have elapsed since the first injection, resume dosing with two injections of 100 mg in the following manner:
a deltoid injection as soon as possible,
another deltoid injection one week later,
resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy.
5.5.11 Missed second initiation dose (> 7 weeks from first injection)
If more than 7 weeks have elapsed since the first injection, initiate dosing as described for the initial recommended initiation of paliperidone LAI above.
5.5.12 Missed monthly maintenance dose (1 month to 6 weeks)
After initiation, the recommended injection cycle of paliperidone depot is monthly. If less than 6 weeks have elapsed since the last injection, then the previously stabilised dose should be administered as soon as possible, followed by injections at monthly intervals.
5.5.13 Missed monthly maintenance dose (> 6 weeks to 6 months)
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If more than 6 weeks have elapsed since the last injection of paliperidone LAI, the recommendation is as follows:
For patients stabilised with doses of 25 to 100 mg:
a deltoid injection as soon as possible at the same dose the patient was previously stabilised on
another deltoid injection (same dose) one week later (day 8)
resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy
For patients stabilised with 150 mg:
a deltoid injection as soon as possible at the 100 mg dose
another deltoid injection one week later (day 8) at the 100 mg dose
resumption of the normal monthly cycle of injections in either the deltoid or gluteal muscle of 25 mg to 150 mg based on individual patient tolerability and/or efficacy
5.5.14 Missed monthly maintenance dose (> 6 months). If more than 6 months have elapsed since the last injection of paliepridone depot, initiate dosing as described for the initial recommended initiation of paliperidone LAI.
5.5.15Sites of administration Deltoid muscle administration The recommended needle size for initial and maintenance administration of the depot into the deltoid muscle is determined by the patient's weight. For those ≥ 90 kg, the 1½ inch, 22 gauge needle (38.1 mm x 0.72 mm) is recommended. For those < 90 kg, the 1-inch, 23 gauge needle (25.4 mm x 0.64 mm) is recommended. Deltoid injections should be alternated between the two deltoid muscles.
Gluteal muscle administration The recommended needle size for maintenance administration of the depot into the gluteal muscle is the 1½-inch, 22 gauge needle (38.1 mm x 0.72 mm). Administration should be made into the upper-outer quadrant of the gluteal area. Gluteal injections should be alternated between the two gluteal muscles.
5.6 Paliperidone three monthly long-acting injection (Trevicta)14
5.6.1 Paliperidone three monthly depot, is indicated for the maintenance treatment of schizophrenia in adults who are clinically stable on one monthly paliperidone LAI. Patients who are adequately treated for four months or more and do not require dose adjustment may be switched to paliperidone three monthly depot. It is restricted in the formulary, to be requested via the non-formulary route, and should be reserved for
11
service users that are non-compliant with monthly administration and susceptible to relapse. 5.6.2 Paliperidone three monthly depot must be initiated in place of the next scheduled dose of 1-monthly paliperidone LAI (± 7 days). The dose equivalence is per table 7.
Table 7: Paliperidone three monthly depot doses for patients adequately treated with one monthly paliperidone palmitate depot
Last dose of one monthly paliperidone palmitate depot
Initiate paliperidone three monthly depot at the following dose
50 mg 175 mg
75 mg 263 mg
100 mg 350 mg
150 mg 525 mg
There is no equivalent dose for the 25 mg dose of paliperidone montlhy depot. 5.6.3 Paliperidone three monthly depot must be administered by intramuscular injection once every 3 months (± 2 weeks). If needed, dose adjustment can be made every 3 months in increments within the licensed range, but onset of action may take several months. 5.6.4 If paliperidone three monthly depot is discontinued, its prolonged activity must be considered.
Table 8: Doses of one monthly paliperidone palmitate injectable for patients switching from paliperidone three monthly depot
If the last dose of paliperidone palmitate is
Initiate 1-monthly paliperidone palmitate injectable 3 months later at the following dose
175 mg 50 mg
263 mg 75 mg
350 mg 100 mg
525 mg 150 mg
5.6.5 To avoid a missed dose of the depot, patients may be given the injection up to 2 weeks before or after the 3-month time point.
Table 9: Missed doses
If scheduled dose is missed and the time since last injection is
Action
> 3½ months up to 4 months The injection should be administered as soon as possible and then resume the 3-monthly injection schedule.
4 months to 9 months See table 10.
> 9 months Re-initiate treatment with the monthly paliperidone LAI. The three monthly depot can then be resumed after the patient has been adequately treated with 1-monthly paliperidone palmitate depot for at least four months.
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Table 10: Recommended re-initiation regimen after missing 4 months to 9 months of paliperidone palmitate three monthly depot
If the last dose of paliperidone three monthly depot was
Administer 1-monthly paliperidone palmitate injectable, two doses one week apart (into deltoid muscle)
Then administer 3-monthly paliperidone LAI
Day 1 Day 8 1 month after day 8
175 mg 50 mg 50 mg 175 mg
263 mg 75 mg 75 mg 263 mg
350 mg 100 mg 100 mg 350 mg
525 mg 100 mg 100 mg 525 mg
5.6.6 In general, recommended dosing of paliperidone three monthly depot for elderly patients with normal renal function is the same as for younger adult patients with normal renal function. 5.6.7 For patients with mild renal impairment (creatinine clearance ≥ 50 to < 80 ml/min), dose should be adjusted and the patient stabilised using the monthly paliperidone depot, and then changed to the three monthly depot. It is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 ml/min). 5.6.8 No dose adjustment is required in patients with mild or moderate hepatic impairment. Caution is recommended in such patients with severe hepatic impairment.
5.6.9 Paliperidone three montlhy depot must be administered using only the thin wall needles that are provided in the pack. Needles from the monthly paliperidone LAI pack or other needles must not be used.
5.6.10 Sites of administration Deltoid muscle administration • For those ≥ 90 kg, the thin wall 1½ inch, 22 gauge (0.72 mm x 38.1 mm) needle must be used. • For those < 90 kg, the thin wall 1 inch, 22 gauge (0.72 mm x 25.4 mm) needle must be used. It should be administered into the centre of the deltoid muscle. Deltoid injections must be alternated between the two deltoid muscles. Gluteal muscle administration The needle to be used for administration into the gluteal muscle is the thin wall 1½ inch, 22 gauge (0.72 mm x 38.1 mm) needle regardless of body weight. It must be administered into the upper-outer quadrant of the gluteal muscle. Gluteal injections must be alternated between the two gluteal muscles.
5.7 Aripiprazole long acting injection
5.7.1 For patients who have never taken aripiprazole, tolerability and response with oral aripiprazole must occur prior to initiating treatment with aripiprazole depot. The recommended starting and maintenance dose is 400 mg. Titration is not
13
required. It should be administered once monthly as a single injection (no sooner than twenty-six days after the previous injection). After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for fourteen consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy (after which it should be stopped). If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered9.
5.7.2 Aripiprazole depot is restricted in the formulary and can be requested via the non-formulary route (see the trust formulary).
5.7.3 Aripiprazole depot should administered in the gluteal or deltoid muscle.
5.7.4 The safety and efficacy of aripiprazole depot in the treatment of schizophrenia in patients 65 years of age or older has not been established.
5.7.5 Missed doses
Table 119: Missed doses
If 2nd or 3rd dose is missed and time since last injection is:
Action
> 4 weeks and < 5 weeks The injection should be administered as soon as possible and then resume monthly injection schedule.
> 5 weeks Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule.
If 4th or later doses are missed & time since last injection is:
Action
> 4 weeks and < 6 weeks The injection should be administered as soon as possible and then resume monthly injection schedule.
> 6 weeks Concomitant oral aripiprazole should be restarted for 14 days with next administered injection and then resume monthly injection schedule.
5.7.6 Dose adjustments of aripiprazole depot in patients who are taking concomitant strong CYP2D6 inhibitors, strong CYP3A4 inhibitors, and/or CYP3A4 inducers for more than fourteen days.
Table 12: Dose adjustments9
Adjusted dose
Patients taking 400 mg of aripiprazole depot
Strong CYP2D6 or strong CYP3A4 inhibitors 300 mg
Strong CYP2D6 and strong CYP3A4 inhibitors 200 mg
CYP3A4 inducers Avoid use
Patients taking 300 mg of aripiprazole depot
Strong CYP2D6 or strong CYP3A4 inhibitors 200 mg
Strong CYP2D6 and strong CYP3A4 inhibitors 160 mg
CYP3A4 inducers Avoid use
14
Table 13: Examples of interacting medicines9:
Strong CYP2D6
inhibitors
Strong CYP3A4 inhibitors Strong CYP3A4 inducers
Quinidine Ketoconazole Carbamazepine
Fluoxetine Itraconazole Rifampicin
Paroxetine HIV protease inhibitors Rifabutin
Phenytoin
Phenobarbital
Primidone
Efvirenz
Nevirapine
St John‟s Wort
5.7.7 Sites of administration
Gluteal muscle administration
The recommended needle for gluteal administration is a 38 mm (1.5 inch), 22 gauge hypodermic safety needle; for obese patients (Body mass index > 28 kg/m2), a 50 mm (2 inch), 21 gauge hypodermic safety needle must be used. Gluteal injections must be alternated between the two gluteal muscles.
Deltoid muscle administration The recommended needle for deltoid administration is a 25 mm (1 inch), 23 gauge hypodermic safety needle; for obese patients, a 38 mm (1.5 inch), 22 gauge hypodermic safety needle must be used. Deltoid injections must be alternated between the two deltoid muscles.
5.8 Olanzapine long acting injection
5.8.1 Olanzapine LAI is non-formulary due to its adverse safety profile and subsequent monitoring requirements. Its use in exceptional cases must be approved via the non-formulary process. Appropriate arrangements must be in place for continued administration and monitoring in the community before the non-formulary request will be approved. Where use has been approved, the sections 5.8.3 & 5.8.4 must be adhered to:
5.8.2 Trust staff may also be required to take over prescribing and administration for patients currently established on olanzapine LAI after transfer from another Trust. Likewise a non-formulary form must be completed and arrangements in place for administration and monitoring. Consideration should also be given to switching the patient to an alternative antipsychotic LAI.
5.8.3 Before prescribing or administering olanzapine LAI, staff must undertake an e- learning package produced by the pharmaceutical company (https://www.zypadhera.co.uk/SignIn.aspx). Certificates must be retained by ward/team manager.
5.8.4 After each injection, patients m u s t be observed in a ward or community team base by appropriately qualified staff for at least three hours for signs and symptoms consistent with olanzapine overdose9. The ward or team base must have resuscitation equipment available. The member of staff undertaking the
15
observation, does not have to be a doctor or nurse, but he/she must report any concerns immediately to a nurse or doctor. At the end of the observation, a nurse must confirm that the patient is alert, oriented, and does not have any signs and symptoms of overdose.
For the remainder of the day after the injection, patients should be advised to be vigilant for signs and symptoms of an overdose secondary to post-injection adverse reactions, be able to obtain assistance if needed, and should not drive or operate machinery10.
If dur ing the observat ion, an overdose is suspected, close medical supervision and monitoring should be initiated and 999 must contacted. Supervision and monitoring must continue until examination indicates that signs and symptoms have resolved or an ambulance team is present.
5.8.5 Service users must initially be treated with oral olanzapine before administering the depot to establish tolerability and response. In line with trial studies, the introduction of long-acting IM olanzapine should be made without recourse of cross-tapering of oral medication5,10.
5.8.6 If oral olanzapine supplementation is clinically indicated, then the combined total dose of olanzapine from both formulations should not exceed the corresponding maximum oral olanzapine dose of 20 mg/day. See table 4.
5.8.7 Olanzapine pamoate releases olanzapine slowly, over six to eight weeks after each injection. The time to steady state is three months3.
5.8.8 Olanzapine pamoate salt provides a slow continuous release of olanzapine that is complete approximately six to eight months after the last injection. Therefore supervision by a clinician, especially during the first 2 months after discontinuation of olanzapine LAI, is needed when switching to another antipsychotic product10.
5.8.9 Olanzapine LAI must be administered in the gluteal muscle only10. It is not licensed for administration in the deltoid muscle.
5.8.10 Olanzapine LAI has not been systematically studied in elderly patients (> 65 years). Olanzapine LAI is not recommended for treatment in the elderly population unless a well-tolerated and effective dose regimen using oral olanzapine has been established. A lower starting dose (150 mg/4 weeks) is not routinely indicated, but should be considered for those 65 and over when clinical factors warrant. Olanzapine depot is not recommended to be started in patients >75 years.
16
Table 14: Recommended Dose Regimen
Oral Olanzapine Recommended starting dose of Olanzapine Depot
Maintenance Dose after 2 months
10mg/day 210mg/2 weeks or 405mg/4 weeks 150mg/2 weeks or 300mg/4 weeks
15mg/day 300mg/2 weeks 210mg/2 weeks or 405mg/4 weeks
20mg/day 300mg/2 weeks 300mg/2 weeks
6 Use of Unlicensed Doses
6.1.1 If for therapeutic reasons clinicians consider a dose of depot medication above the BNF limit is advisable, a full discussion must take place involving the patient, consultant psychiatrist, the prescriber (if the not the consultant) and the nurse who will administer the depot injection. This discussion and its conclusion must be recorded in full in the service user‟s electronic records.
6.1.2 For service users detained under the Mental Health Act, and requiring a second opinion, reference must be made on the T2 or T3 forms specifying the dose prescribed and is above maximum licensed dose.
6.1.3 If the prescribed dose of risperidone injection is above the maximum licensed dose (50mg every two weeks), consideration should be given to prescribing paliperidone LAI as the maximum dose is 150mg every month (see table 3).
7 Administration of depot antipsychotic medication
7.1.1 There is a procedure for the s afer use of injectable medicines which is available on the Trust intranet.
7.1.2 Check the depot is licensed for administration into the preferred muscle site.
7.1.3 The table below details the sites for administration of depot medication. Appendix 3 contains diagrams of the various injection sites referred to below.
Table 154
Depot Licensed Site of Injection Practice Points
Flupenthixol decanoate (Depixol injection, depixol conc. Injection, depixol low volume)
Upper outer quadrant (dorsogluteal region) or lateral thigh (vastus lateralis)
Maximum volume into a single site must not exceed 2ml.
Fluphenazine decanoate (Modecate injection, Modecate conc injection)
Gluteal region
Maximum volume into a single site is not specified in the SPC.
Haloperidol decanoate (Haldol decanoate)
Gluteal region
Maximum volume into a single site must not exceed 3ml.
17
Zuclopenthixol decanoate (Clopixol, clopixol conc injection
Upper outer quadrant (dorsogluteal region) or lateral thigh (vastus lateralis)
Maximum volume into a single site must not exceed 2ml.
Risperidone Gluteal region/deltoid muscle
Fractions of a dose may not be administered.
Paliperidone monthly depot (restricted in the formulary and obtained via a non-formulary form)
Gluteal region/deltoid muscle
Fractions of a dose must not be administered.
Paliperidone three monthly depot (Trevicta) (restricted in the formulary and obtained via a non-formulary form)
Gluteal region/deltoid muscle
Fractions of a dose must not be administered.
Aripiprazole depot (restricted in the formulary and obtained via a non-formulary form)
Gluteal region/deltoid muscle
The suspension must be
injected slowly as a single
injection (doses must not be
divided) into the gluteal
muscle. Olanzapine depot (non-formulary)
Gluteal region
Fractions of a dose must not be administered
18
7.1.4 The gluteal region consists of the dorsogluteal muscle and ventrogluteal muscle. The ventrogluteal muscle has been approved by the Trust to be used as an alternative site to the dorsogluteal, where the BNF states gluteal site. It is acknowledged that this will be administering via an off-label route.
7.1.5 The dorsogluteal site (upper outer quadrant) is perhaps the most popular site. It is close to the sciatic nerve and gluteal artery and is covered by abundant adipose tissue in most people13. This may result in the medicine not reaching the target muscle. This may result in reduced medicine uptake and tissue irritation.
7.1.6 The ventrogluteal site has few major nerves and blood vessels. The muscle is well defined and large. There can be significant differences in fat depth in obese people. Some authors have argued this is the best site because of notably fewer complications, specifically injuries to the sciatic nerve. Additionally, it can be almost guaranteed that a standard 3cm or 4cm needle will penetrate the muscle. In practice mental health nurses are reluctant to use this area because of problems locating the site and a perceived risk of needle stick injury when injection between the „V‟ of the index and middle fingers13.
7.1.7 The deltoid muscle is rarely used because of the weak evidence it causes more discomfort. Only small volumes (less than 2ml) are recommended at this site. With the exception of risperidone injection, paliperidone monthly depot, paliperidone three monthly depot and aripiprazole monthly depot which are licensed for administration via this route, the deltoid muscle is not routinely used as a site of administration. There is also a risk of injury to the radial nerve and brachial artery13. There is no research in regards to other depots.
7.1.8 The lateral thigh is rarely used. This site is easily accessible, but may result in considerable discomfort14. However it is licensed for administration of flupenthixol and zuclopenthixol depot6,8. It could potentially be used for self-administration under supervision13.
7.1.9 The front of the thigh is not a licensed site of administration. This site may also result in considerable discomfort.
8 Use of alternative sites or sites which are off -label
8.1.1 If there is a good clinical reason for using an off-label site e.g. the amount of subcutaneous (fatty tissue) is too great for the needle to deposit the medication into the muscle or the patient chooses not to have the injection in the clinically preferred site, a full discussion including a risk assessment must take place. The discussion should involve the consultant psychiatrist, the prescriber (if not the consultant) and the administering nurse and patient. This discussion and its conclusion must then be fully recorded in the patient‟s Electronic patient record (Carenotes). The member of staff must have completed the relevant training and supervised practice to equip them to administer in the alternative site safely e.g. the deltoid site. However there is little evidence for other sites in terms of risks and safety.
19
9 Depots/LAIs administered under restraint
9.1.1 Occasionally depot antipsychotic medication may be administered under planned restraint. In keeping with the trust policy, depot antipsychotic medication should be administered with the patient in a prone position.
9.1.2 When considering which depot antipsychotic medication to use, consideration should be given to the licensed site of injection (see table 15) for example flupenthixol decanote and zuclopenthixol decanoate can be administered in the lateral thigh (a licensed site) in a prone restraint rather than in the gluteal region.
9.1.3 If an unlicensed site is considered, the advice of pharmacy must be sought. A discussion involving the consultant, prescriber and nurse must be recorded in the patient‟s electronic patient record (Carenotes) prior to administration.
10 Generic names/Brand names.
10.1.1 Depot / LAI must always be prescribed generically, however paliperidone LAIs must be clearly annotated to distinguish between the different formulations (monthly or three monthly).
Table 16 GENERIC NAME BRAND NAME Flupenthixol Decanoate Depixol
Zuclopenthixol Decanoate Clopixol
Fluphenazine decanoate Modecate
Haloperidol Decanoate Haldol Decanoate
Haloperidol injection Haldol
Aripiprazole long acting injection Abilify Maintena
Risperidone injection Risperdal Consta
Paliperidone monthly depot Xeplion
Paliperidone three monthly depot Trevicta
Olanzapine depot Zypadhera
11 Management of patients on long term depot antipsychotics in relapse prevention
11.1.1 Patients should be reviewed prior to the next injection including an assessment of the previous injection site checking for signs of swelling, pain, inflammation, infection or tissue damage4.
11.1.2 Clinical reviews should be undertaken every six months and should include a shared understanding of relapse plans and any concerns about treatment4.
11.1.3 If a dose reduction is considered, a risk versus benefit analysis should be done taking in the following point2s:
o Is the patient symptom free and if so for how long? Longstanding, non- distressing symptoms, which have previously not responded to medication, may be excluded.
21
o What is the severity of side effects? (GASS tool)
o What is the previous pattern of illness?
o Has dosage reduction been attempted before? If so, what was the outcome?
o What are the current social circumstances?
o What is the potential cost of relapse (e.g. hospital admission, employment)?
11.1.4 If after consideration of the points raised, a decision to reduce medication is made:
Oral antipsychotics should be discontinued first, if concurrently prescribed
The interval between the injections should be increased gradually within licensed limits.
If possible, reduce the dose by no more than a third at a time.
Reduction in dosage should be made no more frequently than every 3 months if possible, preferably every six months.
If the patient becomes symptomatic, this should not be seen as a failure, but as an important step in determining the minimum effective dose that the patient requires.
12 Intramuscular anti-cholinergic medication
12.1.1 Some service users may require anti-cholinergic medication to alleviate the side effects of depot medication. Depot preparations do not produce acute extra pyramidal side effects (EPSEs) at the time of administration. If they do occur this may take hours or days. The administration of i.m. procyclidine with each depot is illogical as its anticholinergic effects will have worn off by the time the depot plasma level peaks2. An anticholinergic is usually prescribed v i a t h e oral or intramuscular routes on an „as required‟ basis.
22
13 Primary Care Involvement
13.1.1 Some service users may have depot medication prescribed and administered at their GP practice. This must always be with prior agreement and after clear communication and liaison between the consultant psychiatrist and the GP. Information such as when to review the medication and how to effectively communicate information or any other information between secondary and primary care should be included in the transfer of care.
14 Zuclopenthixol acetate (Clopixol acuphase)
14.1.1 There is a separate document for Clopixol Acuphase - Guidance for the use of Clopixol Acuphase (zuclopenthixol acetate) in Adult Mental Health Inpatient Settings. Although an oily based preparation, it is not intended as a long-acting depot. Clopixol acuphase must not be used as a test dose for zuclopenthixol decanoate injection.
15 Related policies
Antipsychotic Prescribing Guidelines.
Safer Use of Injectable Medicines procedure.
Medicines Management Policy.
16 Dissemination and implementation arrangements
This document will be circulated to all managers who will be required to cascade the information to members of their teams. It will be available to all staff via the Trust intranet. Managers will ensure that all staff are briefed on its contents and on what it means for them.
17 Training requirements
Staff administering depot/LAI must be suitably qualified and competent to administer depot injections. Supplementary training for specific LAI preparation must be completed where applicable. For further training requirements please refer to the Trust‟s Mandatory Training Policy and Learning and Development Guide.
18 Monitoring and audit arrangements
23
19 Review of the policy
The next review date for this policy is February 2023.
Elements to be
monitored
Lead How trust will monitor compliance
Frequency
Reporting arrangemen ts
Acting on recommendations and Lead(s)
Change in practice and lessons to be shared
Process for prescribing medicines
Chief Pharmacist (CP)
Clinical pharmacy review of medicine charts.
ongoing
Divisional Leads
DTC
Required actions will be identified and completed in a specified time frame.
Required changes to practice will be identified and actioned within a specific time frame. A lead member of the team will be identified to take each change forward where appropriate. Lessons will be learned with all relevant stakeholders
Process for medicine administration
Nursing Director
ongoing
DTC
24
20 References
1 National Institute for Health and Clinical Excellence (2014). Psychosis and schizophrenia in
adults. Treatment and management. NICE Clinical Guidance 178. 2 Taylor D. Paton C., Kapur S. The South London and Maudsley NHS Foundation Trust.
Oxleas NHS Foundation Trust. Prescribing Guidelines. 13th Edition. London. Informa Healthcare. 2018.
3 Bazire S. Psychotropic drug directory. The professionals‟ pocket handbook and aide
memoire. 2018. 4 Guidance on the Administration to Adults of Oil-based Depot and Other Long-acting
Intramuscular Antipsychotic Injections. Fourth edition. PHGB/NPR/1113/0021 February 2014. 5 Sanofi. The specification of product characteristics. Modecate concentrate 100mg per ml (21
March 2015) (online). Available: https://www.medicines.org.uk/emc/medicine/6955 (accessed February 2020).
6 Lundbeck Ltd. The specification of product characteristics . Depixol injection and conc.
Injection (February 2017). (online). Available: https://www.medicines.org.uk/emc/medicine/1074 (accessed February 2020)
7 Janseen Cilag Ltd. The specification of product characteristics. Haldol decanoate. (March
2019). (online). Available: https://www.medicines.org.uk/emc/medicine/904 (accessed February 2020)
8 Lundbeck Ltd. The specification of product characteristics. Depixol injection and conc.
Injection (December 2016). (online). Available: https://www.medicines.org.uk/emc/medicine/21319(accessed February 2020)
9 Otsuka Pharmaceuticals. The specification of product characteristics. Abilify maintena (April
2019). (online). Available: https://www.medicines.org.uk/emc/medicine/28494. (accessed February 2020)
10 Eli Lilly and Company Ltd. The specification of product characteristics. Zypadhera powder
and solvent for prolonged release suspension for injection (November 2018). (online). Available: https://www.medicines.org.uk/emc/medicine/21361 (accessed February 2020)
11 Janseen Cilag Ltd. The specification of product characteristics. Xeplion 50 mg, 75 mg, 100
mg and 150 mg prolonged release suspension for injection. (September 2018). (online). Available: https://www.medicines.org.uk/emc/medicine/24403 (accessed February 2020)
12 Janseen Cilag Ltd. The specification of product characteristics. Risperdal Consta 25, 37.5 and
50 mg powder and solvent for prolonged-release suspension for intramuscular injection. (September 2018). (online). Available: https://www.medicines.org.uk/emc/medicine/9939 (accessed February 2020)
13 Gray R. et al (2009). Antipsychotic long-acting injections in clinical practice: medication
management and patient choice. Br. J. of Psych. 195, s51 – s56. 14. Janseen Cilag Ltd. The specification of product characteristics. Trevicta prolonged-release
suspension for intramuscular injection. (November 2019). (online). Availablehttps://www.medicines.org.uk/emc/medicine/32050 (accessed February 2020).
28
Appendix 1
Table 10: Equivalent doses of antipsychotics2,3
Antipsychotic Equivalent dose (consensus)
Range of values in literature
Amisulpride 100mg per day 40-150mg per day
Benperidol 2mg per day
Chlorpromazine 100mg per day -
Clozapine 100mg per day 30-150mg per day
Flupenthixol 2-3mg per day 2-3mg per day
Flupenthixol depot 10mg per week 10-20mg per week
Fluphenazine 2mg per day 2-5mg per day
Fluphenazine depot 5mg per week 1-12.5mg per week
Haloperidol 2-3mg per day 1.5-5mg per day
Haloperidol depot 15mg per week 5-25mg per week
Paliperidone LAI 12.5mg every week or 50mg every month
Pericyazine 24mg
Perphenazine 10mg per day 10mg per day
Pimozide 2mg per day 2mg per day
Pipothiazine depot 10mg per week 10-12.5mg per week
Promazine 100mg 50-200mg per day
Risperideone 500micrograms – 1mg per day
500micrograms –3mg per day
Risperidone long-acting injection
12.5mg per week or25mg every two weeks
Sulpiride 200mg per day 200-270mg per day
Trifluoperazine 5mg per day 2.5-5mg per day
Zuclopenthixol 25mg per day 25-60mg per day
Zuclopenthixol depot 100mg per week 40-100mg per week
NB: Check the maximum licensed dose for each preparation when using this table.
29
Appendix 2
Buttock (Gluteus Medius) Site for IM Injection Leg (Vastus Lateralis) Site For IM Injection
Hip (Ventrogluteal) Site for IM Injection Arm (Deltoid) Site for IM
Injection
30
Appendix 3
Equality Impact Assessment Tool
Yes/No Comments
1 Does the policy/guidance affect one group less or more favourably than another on the basis of:
Race
No
Ethnic origins (including gypsies and travellers)
No
Nationality
No
Gender
No
Culture
No
Religion or belief
No
Sexual Orientation including lesbian, gay and bisexual people
No
Age
No
Disability- learning disability, physical disability, sensory impairment and mental health problems
No
2
Is there any evidence that some groups are affected differently?
No
3
If you have identified potential discrimination, are any exceptions valid, legal and/or justifiable?
N/A
4
Is the impact of the policy/guidance likely to be negative?
No
5
If so can the impact be avoided?
N/A
6
What alternatives are there to achieving the policy/guidance without the impact?
N/A
7
Can we reduce the impact by taking different action?
N/A