APC ClinDoc 038 - Antipsychotic Guidelines · 2019-08-30 · Choosing an Antipsychotic 7 Guide to the relative adverse effects of antipsychotics 8 ... treatment with antipsychotic

Author Unknown Date of production: Sept 2015 Job Title Unknown Review Date Sept 2017 Protocol Lead Unknown Version v.7.0

Berkshire West Integrated Care System Representing

Berkshire West Clinical Commisioning Group Royal Berkshire NHS Foundation Trust

Berkshire Healthcare NHS Foundation Trust Berkshire West Primary Care Alliance

Antipsychotic Guidelines

[APC ClinDoc 038]

For the latest information on interactions and adverse effects, always consult the latest version of the Summary of Product Characteristics (SPC), which

can be found at: http://www.medicines.org.uk/ Approval and Authorisation

Approved by Job Title Date Area Prescribing Committee APC Chair unknown

Change History

Version Date Author Reason v.7 01/10/2018 unknown Updated APC Category

This prescribing guideline remains open to review considering any new evidence

This guideline should only be viewed online and will no longer be valid if printed off or saved locally

Berkshire Healthcare NHS Foundation Trust Edition 7 November 2015 Tel: 0118-960-5075, Monday – Friday 9am – 5pm Antipsychotic Guidelines Email: [email protected] Page 1 of 62

ANTIPSYCHOTIC GUIDELINES

TREATMENT OF SCHIZOPHRENIA AND PSYCHOSIS

Authors (Original Contributor) Ms

Diane Booth former Chief Pharmacist, BHFT

Mrs Kiran Hewitt Lead Clinical Pharmacist, BHFT

Mrs Katie Sims Senior Clinical Pharmacist, BHFT

Mrs Ozma Tahir Lead Medicines Information and Clinical Economy Pharmacist

Version 7.0 Reviewed 09/2015 Document History 6.0 updated in line with recent

references and NICE Guidelines update

Date of Next Review 09/2017

(or sooner if there are changes to national guidelines)

Approved by Drug and Therapeutics Committee, BHFT

13/11/2015


Acknowledgements: The authors would like to thank the members of the pharmacy department, Prospect Park Hospital and the Drugs & Therapeutics Committee representatives of Berkshire Healthcare NHS Foundation Trust who provided help, advice and constructive feed back during the compilation of these guidelines. Any enquiries regarding these guidelines or other medication related queries should be forwarded to the MI service (Medicines Information service), pharmacy department, Prospect Park Hospital, on 0118 960 5075, or your ward/locality pharmacist.

CONTENTS Page Antipsychotic Formulary 4 Cost Implications 5 Schizophrenia Treatment Algorithm 6 Choosing an Antipsychotic 7 Guide to the relative adverse effects of antipsychotics 8 NICE Guidelines – Schizophrenia 9 General Treatment Principles 11 General Prescribing Considerations 12 Prescribing Information – Atypicals 13 Maximum & Equivalent Doses 14 Important Investigations 16 Monitoring 18 Maintenance of Primary Care Patients 20 Use of antipsychotics to treat BPSD 21 Swapping and Stopping 23


Treatment of Special Patient Populations 24 Treatment options in pregnancy 26 Treatment options in breastfeeding 29 Clozapine Important Adverse Effects 31 Initiating Treatment 33 Plasma Level Monitoring 35 Monitoring in the Community 37 Management of Side Effects 38 Augmentation 39 Depot Injections 40 Long-Acting Injection‟s 46 Neuroleptic Malignant Syndrome 53 Extra pyramidal Side Effects 55 Risk of Venous Thromboembolism 58 References 60

Antipsychotic Formulary

With the exception of clozapine, the efficacy of all antipsychotics is very similar and often the choice is governed by the side effect profile of the antipsychotic and its relative importance to the service user (see p.6) First Generation Atypical For Secondary

Care Initiation only

Non-formulary

Benperidol (only licensed to treat deviant antisocial sexual behaviour)

Amisulpride Long Acting Injectables (LAIs)

Paliperidone (oral)

Chlorpromazine Aripiprazole* Flupentixol Pericyazine Flupentixol Olanzapine Fluphenazine Perphenazine Haloperidol Quetiapine Haloperidol Pimozide Levomepromazine Risperidone Zuclopentixol Prochlorperazine

(except to treat emesis)

Promazine Risperidone Olanzapine LA Injection

Sulpiride Paliperidone palmitate

Zotepine

Trifluoperazine Aripiprazole Maintens®

Lurasidone

Zuclopenthixol Clozapine


Sertindole * Aripiprazole liquid is extremely expensive in comparison to tablets and orodispersible tablets (see table overleaf). The need for this must be discussed with pharmacy prior to prescribing. Use of Long Acting Injections The newer atypical LAI antipsychotics are of value in patients who have responded well to antipsychotics but for whom compliance has been a problem and are recommended in:

x Patients who have responded well to oral SGAs but have compliance problems.

x Patients who have responded well to FGA depots but who find the side effects unacceptable There is a shared care Prescribing Arrangement in place, which can be accessed via Team Net following; Clinical>Medicines>Prescribing Arrangements, which explains the different management strategies for patients. Please note there are forms which should be completed and sent to the GP when handing over care.


Cost Implications Antipsychotic costs for 28 days treatment* (from Drug Tariff October 2015) Based on commonly used doses Drug Dose Monthly Cost Amisulpride 600mg/day £20.88 Aripiprazole 15mg/day £43.37

Liquid - £288.12 Haloperidol (tabs) 10mg/day £12.59 Olanzapine 15mg/day £1.77 Quetiapine 600mg/day (XL) £105.56 Quetiapine 600mg/day (IR) £1.56 Risperidone 6mg/day £4.02

Sulpiride 1200mg/day £52.64 Trifluoperazine* 15mg/day £92.40 Zuclopenthixol 25mg/day £4.52 * note increase in price

x All prices are based on standard tablet formulation. x Orodispersible and liquid preparations may cost considerably more and

should only be used when appropriate. The ongoing need should be reviewed regularly.

x Clozapine prices are confidential to BHFT x Clozapine is the only antipsychotic with an evidence base for use in treatment

resistant schizophrenia, hence cost implications are irrelevant. However, clozapine therapy is no longer expensive compared to other atypical antipsychotics.


Schizophrenia Treatment Algorithm

Ineffective

Agree choice of FGA AP with patient/carer. If not possible, start SGA and consider cost.

Titrate to minimum effective dose. Assess over 6-8 weeks.

Change drug and follow above process. Consider a SGA or FGA

Change to clozapine. Titrate according to licensed dosage regime. Optimise treatment. Assess over at least 6 months

Review plasma clozapine level and adjust dosage if necessary. Check compliance. Consider augmentation strategies: clozapine + sulpiride/amisulpride/ risperidone/lamotrigine/ omega-3. Review over 2-3 months

Discuss with patient. Change drug and repeat above process. If poor compliance related to other factors, consider LAI/compliance therapy or compliance aids/liquid or orodispersible preparations.

Continue treatment at established effective dose for at least 2 years (5 years for 2nd or later presentation). Withdraw slowly (after careful consideration) under 2° care advice/supervision.

If clearly measured improvement, C/T and document fully in patient's notes

Review history. Review compliance. Refer to MI for alternatives. E.g. risperidone, high dose olanzapine, augmentation strategies

Poorly tolerated

Ineffective

Not Tolerated / Poor compliance

Ineffective or partially effective

Ineffective

Ineffective

Ineffective

Effective Tolerated

Poor adherence

Effective Tolerated

Effective Tolerated

Effective Tolerated

Effective Tolerated

Effective Tolerated

Change to LAI depot


Choosing an Antipsychotic

With the exception of clozapine, the efficacy of all antipsychotics is broadly similar. NICE(1) recommends oral antipsychotics are prescribed first line for newly diagnosed schizophrenia. The first line drug prescribed should be governed by patient and carer choice, depending on the relative importance to them of experiencing the likely side effects from each agent. The patient decision aid overleaf was originally produced by the NPA(2), and intended to assist healthcare professionals in consultation with patients in whom treatment with antipsychotic drugs is being considered. It has been adapted only in so far as ensuring inclusion of only the antipsychotics available in BHFT. Further information on individual drugs and mental health conditions can be accessed from the website http://www.choiceandmedication.org/berkshirehealthcare/

x If more than one antipsychotic is to be considered, then the least expensive option should be prescribed.

x Where a discussion/agreement on choice of antipsychotic is not possible,

then a second generation antipsychotic (SGA) should usually be chosen. Points for consideration include:

o First generation antipsychotics (FGA) generally have a higher

incidence of movement disorders than SGAs. The possibility of eventual tardive dyskinesia and poorer outcomes should be considered.

o FGAs may be slightly less efficacious than some SGAs with regard to

negative symptoms(3,4,5,6), although the CATIE and CUTLASS studies showed that no difference in psychosocial outcomes were evident (7,8).

o Agents with notable potential for some of the major adverse effects

include:

Initial Sedation: FGAs, olanzapine, quetiapine, risperidone Weight Gain: Chlorpromazine, olanzapine, quetiapine, risperidone Hyperprolactinaemia: FGAs, amisulpride, sulpiride, risperidone Metabolic Adverse effects: SGAs, notably olanzapine (and clozapine) Movements Disorders: FGAs (less so with sulpiride), risperidone at higher doses

x Where there is confirmed treatment resistance (failure to respond to at least 2

antipsychotics), evidence supporting the use of clozapine is overwhelming (9,10,11).

Berkshire H

ealthcare NH

S Foundation Trust

Edition 7 N

ovember 2015

Tel: 0118-960-5075, M

onday – Friday 9am – 5pm

Antipsychotic G

uidelines Em

ail: medicines.inform

[email protected]

P

age 8 of 62

A guide to the relative adverse effects of antipsychotics(2)

EPS

Prolactin Elevation

Weight

Gain

QTc

Prolongation Sedation

Hypotension

Anticholinergic effects

Amisulpride

+ +++

+ +

-/+ -

- Aripiprazole

+/- -

+/- -

-/+ -

- C

hlorpromazine

++ +++

++/+++ ++

+++ +++

++/+++ C

lozapine -

- +++

+ +++

+++ +++

Flupentixol ++

++ ?

- +

- ++

Fluphenazine +++

+++ +

++ ++

+ ++

Haloperidol

+++ +++

+ +++

+ +

+ O

lanzapine +/-

+ +++

+ ++

+ +

Perphenazine +++

+++ ++

-/+ +/++

+ +

Pipotiazine ++

+++ ?

++ +

+ ++

Quetiapine

- -

++ +

++ ++

+ R

isperidone +/++

+++ ++

+ +

+/++ +/-

Sulpiride +

++ +

+ +

- +

Trifluoperazine +++

+++ +/++

++ +

+ +/-

Zuclopenthixol +++

++ ?

- ++

+ ++

Notes This is not a com

prehensive list of side effects. Please see the individual S

umm

aries of Product C

haracteristics (ww

w.em

c.medicines.org.uk) for m

ore details and other side effects that m

ay occur. The ranking scores are approximate and refer to relative rather than absolute risks of adverse events occurring, and are based largely on the opinions

provided from six sources [1–6]. They should be used as a rough guide only. B

e aware that side effects are com

monly dose related. Tw

o ranking scores are provided (e.g. ++/+++) to indicate a range of opinion w

here views are divided. N

ot all sources provided an opinion for all side effects. K

ey +++ Frequently causes side effects at therapeutic dose ++ S

ometim

es causes side effect at doses + M

ild or occasionally causes side effects at therapeutic doses –

Little risk or minim

al side effects at usual therapeutic doses R

eferences: 1. The Maudsley P

rescribing Guidelines (2015) 12th Edition. Ed. Taylor D

, et al. Taylor & Francis, London; 2. P

sychotropic Drug D

irectory (2014). Ed. Bazire S

. H

ealthcomm

UK

Ltd. Aberdeen; 3. H

addad PM

, Sharm

a SG

. Adverse effects of atypical antipsychotics. D

ifferential risk and clinical implications. C

NS

Drugs 2007;21:911–36; 4.

British N

ational Formulary N

o. 57. March 2009. B

MJ G

roup and RP

S P

ublishing. London; 5. Am

erican Psychiatric Association G

uideline. Practice guideline for the treatm

ent of patients w

ith schizophrenia. 2nd Edition (2004); 6. C

hoice and Medication. A

handy chart to help you compare the m

edicine treatments to help the sym

ptoms of psychosis and

schizophrenia. ww

w.choiceandm

edication.org.uk/silo/documents/

Page 9 of 62

NICE Guidelines – Psychosis and Schizophrenia There are some important changes to treating schizophrenia detailed in the 2014 NICE Guideline (CG178). With regard to choice of antipsychotic, NICE does not recommend use of any particular drug or group of drugs. Choice should be made between service user and healthcare professional after considering side-effect profiles.

Summary of CG178(1)

o For people with newly diagnosed schizophrenia, offer oral antipsychotic medication. Provide information and discuss the benefits and side-effect profile of each drug with the service user. The choice of drug should be made by the service user and healthcare professional together, considering: - the relative potential of individual antipsychotic drugs to cause extrapyramidal side

effects (including akathisia), metabolic side effects (including weight gain) and other side effects (including unpleasant subjective experiences)

- the views of the carer (if the service user agrees to their being consulted)

o Before starting antipsychotic medication, offer the person with schizophrenia an electrocardiogram (ECG) if: - specified in the SPC - a physical examination has identified specific cardiovascular risk (such as

diagnosis of high blood pressure) - there is personal history of cardiovascular disease, or the service user is being

admitted as an inpatient.

o Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Include the following: - Record the indications and expected benefits and risks of oral antipsychotic

medication, and the expected time for a change in symptoms and appearance of side effects.

- At the start of treatment give a dose at the lower end of the licensed Range and slowly titrate upwards within the dose range given in the BNF or SPC.

- Justify and record reasons for dosages outside the range given in the BNF or SPC. Please refer to BHFT High Dose Antipsychotic Guidance, accessible via Team Net.

o Monitor and record the following regularly and systematically throughout treatment,

but especially during titration: - efficacy, including changes in symptoms and behaviour - side effects of treatment, taking into account overlap between certain side effects

and clinical features of schizophrenia, for example the overlap between akathisia and agitation or anxiety

- adherence - physical health.

Page 10 of 62

- Record the rationale for continuing, changing or stopping medication, and the effects of such changes.

- Carry out a trial of the medication at optimum dosage for 4 to 6 weeks. o Check whether ‘p.r.n.’ prescriptions have led to a dosage above the maximum

specified in the BNF or SPC. o Do not use a loading dose of antipsychotic medication (often referred to as ‘rapid

neuroleptisation’). o Do not initiate regular combined antipsychotic medication, except for short

periods (for example, when changing medication). o If prescribing chlorpromazine, warn of its potential to cause skin photosensitivity.

Advise using sunscreen if necessary o Consider offering depot/long-acting injectable antipsychotic medication to

people with schizophrenia: - who would prefer such treatment after an acute episode - where avoiding covert non-adherence (either intentional or unintentional) to

antipsychotic medication is a clinical priority within the treatment plan. o Offer clozapine to people with schizophrenia whose illness has not

responded adequately to treatment despite the sequential use of adequate doses of at least two different antipsychotic drugs. At least one of the drugs should be a non-clozapine second-generation antipsychotic.

o For people with schizophrenia whose illness has not responded adequately to

clozapine at an optimised dose, healthcare professionals should establish prior compliance with optimised antipsychotic treatment (including measuring therapeutic drug levels) and engagement with psychological treatment before adding a second antipsychotic to augment treatment with clozapine. An adequate trial of such an augmentation may need to be up to 8–10 weeks. Choose a drug that does not compound the common side effects of clozapine.

o Offer people with psychosis or schizophrenia who smoke help to stop smoking, even if previous attempts have been unsuccessful. Be aware of the potential significant impact of reducing cigarette smoking on the metabolism of other drugs, particularly clozapine and olanzapine.

Page 11 of 62

General Treatment Principles

x The lowest effective dose should be used. Initially, titrate the dose to the lowest known to be effective. If there is no response after 2 weeks, increase the dose. An adequate trial (at optimum dosage) should be over 4 to 6 weeks.

x With the exception of clozapine, the efficacy of all antipsychotics is very similar and the initial choice should be governed by the side effect profile and its relative importance to the patient.

x Patients should only be treated with ONE antipsychotic at a time (unless they are swapping treatments or being treated for a refractory illness). Antipsychotic polypharmacy should be avoided due to the risks associated with QT prolongation and sudden cardiac death (12).

x Oral and parenteral doses of the same drug should be prescribed separately because they can vary in bioavailability. o Intramuscular chlorpromazine should not routinely be prescribed. o Antipsychotics should not generally be prescribed on a “prn” basis for their

sedative properties. Benzodiazepines are more appropriate for this indication (for short-term use only). For example, lorazepam may be useful in controlling extreme agitated behaviour and symptoms during the initial weeks (up to four generally) of atypical antipsychotic therapy (13).

x All those receiving antipsychotics should undergo close monitoring of physical health. GPs and primary care healthcare professionals should monitor the physical health of people with schizophrenia at least once a year (people with schizophrenia are at higher risk of cardiovascular disease than the general population).

x Anticholinergic drugs should ideally be prescribed on a “prn” basis if and when EPSE occur. Not all patients experience these side effects. Most patients do not require them long term and withdrawal should be attempted if the patient is no longer experiencing troublesome side effects – refer to anticholinergic guidelines.

x Responses to treatment and side-effects experienced should be assessed using recommended rating scales and recorded in patients‟ notes.

Page 12 of 62

General Prescribing Considerations

x Consider the quantity of antipsychotic medication prescribed. Patients must be able

to obtain their medication easily and maintain regular contact with health care professionals such as their GP or community pharmacist.

x Concordance. Compliance is a key issue in the management of schizophrenic patients. Keep drug regimens as simple as possible and avoid poly-pharmacy.

x Co-prescribing. Many drug combinations worsen side effects or can result in altered blood levels and potential toxicity. Prescribe small quantities initially and review regularly, once a week if need be.

x OTC medication. Examples of problematic over the counter (OTC) or herbal remedies include cold remedies containing pseudoephedrine, sedating preparations and some antihistamines. These can either cause drug interactions, be sedating and/or have an effect on the QTc interval. St John‟s Wort is also a major problem in terms of drug interactions with other medication.

x Side effects. Warn patients and their carers of the main side effects they may experience when taking antipsychotic medication. This may prevent them from discontinuing medication unnecessarily. Reassure patients about milder and transient side effects such as increased appetite, sedation or dizziness and give advice on the management of more severe side effects such as sexual dysfunction, excess weight gain or extreme movement disorders.

x Effects of lifestyle on medication. Alcohol acts centrally, affects dopamine and will interact with antipsychotics. The metabolism of some antipsychotics can be affected by smoking and dose adjustment may be required (usually by secondary care). Recreational abuse of drugs such as cannabis can have extreme effects on mental state and this is particularly pronounced in patients suffering from schizophrenia.

Page 13 of 62

Prescribing Information – Atypicals

Drug Available Forms Available Strengths

Amisulpride Oral tablets 50mg, 100mg, 200mg, 400mg

Oral solution 100mg per 1ml Aripiprazole Oral tablets 5mg, 10mg, 15mg,

30mg Orodispersible tablets 10mg, 15mg

Liquid (not recommended on cost grounds)

1mg per 1ml

Injection 9.75mg Clozapine Oral tablets 25mg, 100mg

Olanzapine Oral tablets 2.5mg, 5mg, 7.5mg, 10mg, 15mg, 20mg

Velotabs® (orodispersible tablets)

5mg, 10mg, 15mg, 20mg

Intramuscular injection 10mg Long acting injection* 210mg,

300mg,405mg Quetiapine

XL can improve compliance, but offers no improvement in side effect profile

Oral immediate release tablets

25mg, 100mg, 150mg, 200mg,

300mg Oral XL® (modified

release) tablets 50mg, 200mg, 300mg, 400mg

Risperidone Oral tablets 0.5mg, 1mg, 2mg, 3mg, 4mg, 6mg

Orodisp. Tabs (Quicklets®)

0.5mg,1mg, 2mg

Oral liquid 1mg per 1ml Long acting injection 25mg, 37.5mg,

50mg *Non-formulary

Page 14 of 62

Antipsychotics – Maximum and Equivalent Doses

Drug

Consensus Equivalent Dose

(mg per day)

Possible Range of Equivalent Values

in Literature (mg per day)

BNF/SPC Maximum Dose

(mg per day)

Oral Chlorpromazine 100 1000 Trifluoperazine 5 2-8 None (see BNF) Flupentixol 3 2-3 18 Zuclopenthixol 25 25-60 150 Haloperidol 3 1-5 PO – 20

(IM – 12) Pimozide 2 1-3 20 Sulpiride 200 200-333 2400

Atypicals *

Clozapine 100 30-150 900 Risperidone 0.5-1 0.5-3 16 Amisulpride - - 1200 Olanzapine - - 20 Quetiapine - - 750(for

schizophrenia) Aripiprazole - - 30

Depots Fluphenazine 5mg per week 1-12.5mg per week 50mg per week Haloperidol 15mg per week 5-25mg per week 75mg per week

(4/52ly recommended)

Flupentixol 10mg per week 8-20mg per week 400mg per week Zuclopenthixol 100mg per week 40-100mg per

week 600mg per week

Risperdal Consta® - - 50mg two weekly (follow manufacturer‟s guidelines)

Xeplion® - Paliperidone palmitate

150mg every 4 weeks**

Abilify Maintena® - Aripiprazole LAI

400mg every four weeks**

(14,15,16,17)

*Equivalent doses for atypical antipsychotics are not particularly useful and so manufacturers‟ guidelines should be followed. Equivalent doses should only be used as a guide, as assessment methods used for determining equivalent doses can produce huge variations in their recommendations(18). It is also important not to confuse antipsychotic equivalence with sedation.

Page 15 of 62

**Can be administered every calendar month (for example, the 1st of every month), which also translates as one less injection per year as compared with four weekly injections.

Page 16 of 62

Important Investigations The healthcare professional carrying out the initial assessment of a patient (whether in primary or secondary care), is responsible for ensuring the following investigations are performed. x Full blood count, including haemoglobin and red blood cell parameters - which may

reveal neutropenia, anaemia, B12 and folate deficiencies.

x B12 and folate - deficiencies may compromise cognitive function and produce confusional states (folate deficiencies are not only implicated in the symptoms of psychosis, but can also reverse the beneficial effects of many antidepressants).

x Metabolic function can be investigated by checking urea and electrolyte plasma levels. Disturbances may arise due to dehydration or physical causes. (antipsychotics can cause water dysregulation including hyponatraemia).

x Thyroid abnormalities often lead to changes in mental state and thyroid function tests should be performed routinely, particularly during the early stages of treatment.

x Liver function tests, although altered by some antipsychotics, may be useful in revealing possible cases of alcohol abuse.

x Blood glucose level to be measured initially to provide a baseline value and because diabetes mellitus has been known to manifest itself as psychosis or delirium. It is important to continue monitoring blood glucose levels due to the increase in use of atypical agents, some of which can cause hyperglycaemia/type 2 diabetes.

x Body weight to be measured initially to provide a baseline value; this is increasingly important due to the increase in use of atypical agents, some of which can cause substantial weight gain. Hence, ongoing monitoring of body weight is also recommended (and can be minimised with careful diet and exercise).

x Waist circumference, to be measured at least once a year and plotted on a chart.

x Blood pressure x Lipids – All patients should receive an initial lipid profile test.

x Prolactin should be checked at baseline in children and adolescents for all antipsychotics. Adult patients about to receive typical antipsychotics or risperidone should receive a baseline test.

x ECG – an initial ECG should be performed if indicated by history or clinical picture (see trust ECG policy).

Page 17 of 62

Ongoing monitoring will really depend on the individual patient‟s circumstances; baseline values of the above, co-morbidity, which antipsychotic has been prescribed and so forth. It may also be indicated when there is a change in the mental or physical health of the patient or when the treatment is modified. x Fasting blood glucose – At start and at 3 months (and at 1 month if taking olanzapine);

more often if there is evidence of elevated levels.

x Body weight – see above

x Prolactin levels should be monitored in patients with suspected hyperprolactinaemia and in patients reporting sexual side effects.

x Illicit drug use can be confirmed by urinary and/or blood drug screen.

x Blood pressure should be monitored during the first two weeks of treatment with antipsychotics, especially clozapine (where the monitoring should be continued if the titration period is longer). Postural hypotension is usually more common in the elderly and can be unpredictable.

x An ECG is essential when treating patients with high dose antipsychotics due to the cardiac side effects of these drugs (notably prolongation of the QTc interval).

x Lipids should be repeated after three months (or sooner if baseline level was elevated). If the levels are normal, then the level should be tested annually only in patients over 40 years old.

An agreement between consultant psychiatrist and GP should be reached regarding the need for an ECG to be performed and any subsequent monitoring requirements.

Page 18 of 62

Monitoring Antipsychotics – except clozapine

Baseline* 1 month 3 months

6 months 12 months Ongoing

Weight (include BMI ideally)

9 Monthly for the first year, then 3-monthly.

Fasting lipids 9 9 Olanzapine Quetiapine

Phenothiazines

Olanzapine Quetiapine

Phenothiazines

Annual

Blood glucose (random/fasting)

9 Olanzapine 9 Olanzapine Annual

Liver Function 9 Annual ECG Baseline and after dose increases and then annually for patients who are

elderly, have cardiac risk factors, are taking other drugs known to prolong the QTc interval or are on high doses. Consider baseline and annual ECG in other patients where indicated.

U&Es 9 Annual FBC 9 Annual

Prolactin 9 Check if symptoms of hyperprolactinaemia occur (menstrual disturbance, galactorrhoea, gynaecomastia, sexual dysfunction)

Annual

Blood pressure and pulse

9 Frequently during titration for FGAs, risperidone and quetiapine.

Annual

Page 19 of 62

Monitoring schedule for clozapine clinics

Baselin

e 1 m

onth 3 m

onths 6 m

onths 12 m

onths O

ngoing

Weight

(include BM

I ideally) 9

At each clinic visit

Blood pressure and

pulse S

itting ● Standing

9

Tw

ice daily during titration, then at every clinic visit.

Blood glucose (random

) 9

M

onthly for the first three months then 3–m

onthly If diabetic or there are concerns over elevated levels, test at every clinic visit

Blood glucose (fasting)

9

A

nnually

Fasting lipids

9

Annually

Liver Function

9

9

A

nnually

EC

G

9

C

lozapine may cause m

yocarditis and cardiomyopathies.

Check E

CG

if any signs or symptom

s develop. Tem

perature

9

Thereafter if any cause for concern

U&

Es

9

A

nnually

FBC

9

As per clozapine protocol – eventually 4-w

eekly.

Prolactin

9

R

are with clozapine. C

heck if symptom

s occur.

Plasm

a level

At request of R

MO

If these tests have been done by the G

P around the scheduled tim

e, do not repeat, just check the result and mark as done

on monitoring sheet

Page 20 of 62

Maintenance of Primary Care Patients

Where possible, patients maintained in the community on continuation therapy should be stable and free from side effects of their medication. These patients should be maintained on treatment for at least two years (five years for second or recurrent episode presentations). Unfortunately, few patients fall into this category and secondary care advice may be required for a number of reasons. Reasons for acute deterioration in mental state should be investigated, such as:- x substance misuse (including alcohol) x non-concordance with medication x drug induced side effects x depression

Secondary care specialists should be consulted when the cause or source of the problem is not obvious and will be happy to give advice concerning their patients

Advice should be sought as soon as possible in the following circumstances: x Patients suffering from rapid weight gain in the first 3 months

(steady weight gain over a long period may be managed with diet and exercise) x Patients suffering from movement disorders such as EPSE, akathisia and tardive

dyskinesia x Patients suffering from sexual dysfunction or hyperprolactinaemia related problems x Patients suffering from significant deterioration in renal or hepatic function or ECG

changes x Patients suffering from excessive and prolonged sedation (lasting more than 4 – 8

weeks) x Patients receiving an unlicensed drug or dose should have all their problems referred x Patients who remain partially resistant to treatment x Patients receiving depot medication. If the patient remains without symptoms for 5 years,

consult with secondary care x Patient receiving poly-pharmacy. Refer those who are unstable and receiving multiple

psychotropics and/or have coexisting medical conditions NB: Clozapine doses must not be altered without secondary care advice.

Page 21 of 62

Use of Antipsychotics to treat behavioural and psychological symptoms of dementia (BPSD)

In March 2004, the Committee on Safety of Medicines (CSM) advised that olanzapine and risperidone should not be used for the treatment of behavioural symptoms of dementia; there was clear evidence of an increased risk of stroke in elderly patients with dementia, and the risk was considered sufficient to outweigh likely benefits(19). A meta-analysis of four placebo-controlled RCTs in elderly patients (n=1,779) with dementia carried out by the MHRA identified a three-fold increase in the risk of stroke or transient ischaemic attack (TIA) with risperidone (OR 3.32, 95%CI 1.43 to 7.70)(19) . The CSM also advised that if risperidone was used for the management of acute psychotic conditions in elderly patients with dementia this should be short-term and under specialist advice. Those patients already being treated with an atypical drug were recommended to have their treatment reviewed.

A meta-analysis of 15 RCTs (n=5,110), generally 10 to 12 weeks in duration, including 16 contrasts of atypical antipsychotic drugs with placebo, found that death occurred more often among patients randomised to drugs (3.5% vs. 2.3%; OR 1.54, 95%CI 1.06 to 2.23; P=0.02)(20).

A review by the European Pharmacovigilance Working Party found that the risk of cerebrovascular events associated with other antipsychotics was not significantly different from that of olanzapine and risperidone, and they advised inclusion of a warning about a possible risk of these events in the SPCs for all typical and atypical antipsychotics(21). Increased mortality with typical antipsychotics has been shown to be similar (22) or even greater than(23) atypical antipsychotics. More recently, a report by the European Medicines Agency (EMEA) concluded that an increase in mortality for FGAs over SGAs could not be confirmed, and that the risk must be assumed to apply to all medicines in the class.

Efficacy

First generation antipsychotics (FGA) have been widely used for decades to treat BPSD. They may well be effective(24) but are not well tolerated.

Second generation antipsychotics were once widely recommended in BPSD as they lacked many of the problems associated with FGA, but their use is now highly controversial. Moreover, effect size is small, and the drugs are also poorly tolerated, as shown in the first CATIE-AD study(25). A Cochrane review of atypical antipsychotics for aggression and psychosis in Alzheimer‟s disease found that olanzapine and risperidone are useful for reducing aggression, and that risperidone reduces psychosis(26). However, the authors also advised that due to modest efficacy and adverse effects, these drugs should not be used routinely, unless there is severe distress or serious risk of physical harm to carers.

The NICE-SCIE guideline recommends that people with dementia who develop non-cognitive symptoms or behaviour that challenges should be offered a pharmacological

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intervention in the first instance only if they are severely distressed or there is an immediate risk of harm to the person or others(27).

Drug treatment with an antipsychotic should only be offered after a full discussion with the patient and/or their carers about the risks and benefits, especially the risk of stroke/TIA and possible adverse effects on cognition. The dose of antipsychotic should be low initially and titrated upwards, and treatment time-limited and regularly reviewed (every three months or according to need). Antipsychotics should not be prescribed to people with mild-to-moderate Lewy Body dementia, as these people are particularly at risk of serious adverse effects (27).

Conclusion and Recommendations

There is a clear increased risk of stroke and a small increased risk of death when antipsychotics (typical or atypical) are used in elderly people with dementia.

The evidence base in this area is insufficient to allow clear recommendations to be made in terms of drug choice, but antipsychotic treatment should be reserved for severe cases, where there is severe distress, or high risk of harm to others.

Risperidone is the only antipsychotic licensed for treating dementia-related behavioural disturbances: and then only for short-term use (up to six weeks) for persistent aggression in Alzheimer‟s-type dementia, unresponsive to non-drug approaches and where there is risk of harm to the patient or others.

In view of all this, the CHM has added risperidone to the list of black triangle medicines. Therefore, all suspected side-effects to risperidone that occur when it is used to treat elderly patients with dementia should be reported via the yellow card system.

Whichever agent is chosen:

x Carry out an individual risk-benefit assessment for each patient, including consideration of previous stroke/TIA and other risk factors for cerebrovascular disease such as hypertension, diabetes, smoking and atrial fibrillation.

x Exclude other factors that could exacerbate BPSD e.g. infection, constipation, pain x Discuss treatment options and risks with the patient (if possible), family/carers and

document x Document the target symptoms requiring treatment x Use a low starting dose and titrate upwards to the lowest effective dose x Monitor closely for adverse effects x Review regularly according to need – at least every 3 months. Discontinue if there is

no evidence of benefit within 3 months.

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Antipsychotics - Swapping and Stopping

A variety of methods can be used for switching antipsychotics, varying in rate, overlap, gap and complexity. No specific regimes for swapping antipsychotics are available. When selecting an appropriate regimen, a number of factors must be taken into consideration: x speed– how quickly the swap over needs to be carried out (taking into consideration how

„unwell‟ the patient is) x the reason for the switch (e.g. ADR, lack of efficacy) x how long the individual has been on that drug x current dose of the first drug and its half life x how closely the individual can be monitored (e.g. inpatient/outpatient setting) x individual susceptibility and patient tolerability x individual drugs and their effects The safest option is to taper down the dose of the first drug, then leave a drug-free interval before starting the second. However, this does take longer to achieve and risks deterioration during the changeover. “Cross tapering” is usually the preferred option, where the dose of the first drug is slowly reduced (over anything up to 8 weeks), whilst the new agent is being introduced(28). Potential disadvantages should be borne in mind, such as potential for combined side-effects, interactions and potential for drug error. The other preferred option is to taper down the dose of the first drug, and start the second drug as soon as the first one has stopped. When switching from one antipsychotic to another, abrupt withdrawal of the first drug should be avoided, in order to prevent problems such as:

-relapse or destabilisation of illness/symptoms (although true relapses tend to occur 1-6 months after discontinuation of oral antipsychotics, higher rates after abrupt discontinuation have been reported) -cholinergic rebound (nausea, vomiting, restlessness, anxiety, insomnia, fatigue, myalgia, headaches) -withdrawal dyskinesias e.g. EPSE, rebound akathisia, rebound dystonia -withdrawal psychosis (a rapid onset psychosis during the first 24-48 hours which disappears rapidly on reinstitution)

However, where a severe, acute adverse effect has occurred (e.g. clozapine “red” blood result), immediate discontinuation may be necessary. Contact the Medicines Information Service (MI), pharmacy department, Prospect Park Hospital (or your ward pharmacist), on 0118 960 5075, for advice on specific swapping regimes.

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Treatment of Special Patient Populations

Condition/ Population

1st Choice Alternative 2nd Choice

Avoid Comments

Cardio-vascular Disease

amisulpride sulpiride olanzapine aripiprazole

quetiapine risperidone flupentixol

pimozide clozapine haloperidol sertindole

Choice depends on the specific cardiac abnormality – contact MI for specific info

Epilepsy haloperidol sulpiride trifluoperazine

risperidone amisulpride olanzapine

chlorpromazine clozapine depots

Start low and go slow. Consider interactions with epilepsy drugs

Hepatic Impairment

amisulpride sulpiride haloperidol

flupentixol zuclopenthixol (but avoid depots)

phenothiazines clozapine depots

Start low and go slow – contact MI for specific info

Renal Impairment

trifluoperazine aripiprazole

quetiapine risperidone olanzapine haloperidol flupentixol zuclopenthixol

chlorpromazine amisulpride sulpiride

Start low and go slow (doses dependent on GFR). ADRs more frequent – contact MI for specific info

Adolescence atypicals: aripiprazole olanzapine risperidone

haloperidol* chlorpromazine* sulpiride amisulpride clozapine

typicals generally

May reduce cognition. Increased EPSE risk in this group Metabolic adverse effects more common. Monitor carefully.

Old Age** amisulpride risperidone sulpiride aripiprazole

olanzapine quetiapine

phenothiazines Choice is dependent on co-morbidity. Start low, go slow. More susceptible to all side effects so monitor

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Condition/ population

1st Choice Alternative/2nd choice

Avoid Comments

Diabetes amisulpride aripiprazole sulpiride

haloperidol risperidone quetiapine

olanzapine phenothiazines

Clozapine is high risk, but there may be little alternative in treatment resistant schizophrenia

Obesity/weight problems

aripiprazole amisulpride sulpiride

haloperidol trifluoperazine risperidone quetiapine

olanzapine chlorpromazine

Prevention is better than cure. Warn, counsel and monitor. Clozapine is high risk, but there may be little alternative in treatment resistant schizophrenia

Hyperprolactin-aemia (and

related problems)

aripiprazole Quetiapine clozapine

olanzapine Most first-generation antipsychotics Sulpiride Amisulpride risperidone

Olanzapine may cause a transient rise

* widely used despite range of adverse effects, such as extra-pyramidal side effects ** antipsychotics should not be used to treat the behavioural symptoms of dementia

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Treatment options in pregnancy

With any pregnancy, there is a background rate of 2 - 4% for malformations. In women with schizophrenia or bipolar disorder, there is also an increased rate of suicide and potentially significant exacerbation of the disorder if not treated and poorer obstetric outcomes, including increased preterm delivery, low birthweight infants and infants who are small for gestational age(29). The first trimester is generally considered the most sensitive time for abnormalities to occur. The magnitude of risks of malformation associated with most psychotropic medications are not reliably established. The potential harm of treatment must continually be balanced against the risks posed to the woman and infant by the illness. It is the clinician‟s responsibility to support the woman in reaching decisions. In circumstances where this is not possible, the clinician will have to take responsibility for guiding the woman, taking full account of the circumstances and any existing advance decisions she may have made(29). In terms of choice of antipsychotics, the following recommendations from NICE should be noted(29):

x When the limited data available are pooled there appears to be an increased overall risk of malformation with the use of all antipsychotics of 2.4%, although it is not clear if this may relate to the underlying illness.

x Women taking antipsychotics who are planning a pregnancy should be told that the raised prolactin levels associated with some antipsychotics (notably amisulpride, risperidone and sulpiride) reduce the chances of conception. If prolactin levels are raised, an alternative drug should be considered.

x If a pregnant woman is taking clozapine, switching to another drug and careful monitoring should be considered. Clozapine should not be routinely prescribed for women who are pregnant (because of the theoretical risk of agranulocytosis in the foetus) or for women who are breastfeeding (because it reaches high levels in breast milk and there is a risk of agranulocytosis in the infant).

x When deciding whether to prescribe olanzapine to a woman who is pregnant, risk factors for gestational diabetes and weight gain, including family history, existing weight and ethnicity, should be taken into account.

x Depot antipsychotics should not be routinely prescribed to pregnant women because there is relatively little information on their safety, and their infants may show extrapyramidal symptoms several months after administration of the depot. These are usually self-limiting.

x Anticholinergic drugs should not be prescribed for the extrapyramidal side effects of antipsychotic drugs except for acute short-term use. Instead, the dose and timing of the antipsychotic drug should be adjusted, or the drug changed.

x The recommendation on choice of therapy for a lady starting to plan a pregnancy is that: women with schizophrenia who are planning a pregnancy or who are pregnant should be treated according to the NICE clinical guideline on schizophrenia, except that if the woman is taking an atypical antipsychotic consideration should be given to

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switching to a low-dose typical antipsychotic, such as haloperidol, chlorpromazine or trifluoperazine.

Other experts recommend that a pregnant patient who is stable with an antipsychotic with insufficient experience in pregnancy should not be changed to another drug, because this may worsen her health(30). According to Maudsley Prescribing Guidelines73

First Generation Antipsychotics

x Most data originate from studies that included primarily women with hyperemesis gravidarum (a condition associated with an increased risk of congenital malformations) treated with low dose of phenothiazines. The modest increase in risk identified in some of these studies, along with no clear clustering of congenital abnormalities suggest that the condition being treated may be responsible rather than drug treatment.

x There may be an association between haloperidol and limb defects, but if real, the risk is likely to be extremely low.

x A recent prospective study that included 284 women who took an FGA (mostly haloperidol, promethazine or flupentixol) during pregnancy concluded that pre-term birth and low birth weight were more common with FGAs than SGAs (or no antipsychotic exposure). In total, 20% of neonates exposed to an FGA in the last week of gestation experienced early somnolence and jitteriness. The rate of major malformations, at 5%, was double that of controls (no antipsychotic exposure) but there was no clustering of abnormalities.

x Neonatal dyskinesia has been reported with FGAs. x Neonatal jaundice has been reported with phenothiazines.

Second Generation Antipsychotics

x Unlikely to be major teratogens but are associated with some problems. x There are most data for olanzapine which has been associated with both lower birth

weight and increased risk of intensive care admission, a large head circumference and with macrosomia; the last of these is consistent with the reported increase in the risk of gestational diabetes. Olanzapine seems to be relatively safe with respect to congenital malformations; the prevalence being consistent with population norms in a study that reported on 610 prospectively followed pregnancies. Olanzapine has however been associated with a range of problems including hip dysplasia, meningocele, ankyloblepharon, and neural tube defects; (an effect that could be related to pre-pregnancy obesity rather than drug exposure). Importantly there is no clustering of congenital malformations. Further, a recent prospective study that included 561 women who took an SGA (mostly olanzapine, quetiapine, clozapine, risperidone or aripiprazole) during pregnancy concluded that SGA exposure was associated with increased birth weight, a modestly increased risk of cardiac septal defects (possibly due to screening bias or co-exposure to SSRIs), and, as with FGAs, withdrawal effects in 15% neonates.

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x The risk of gestational diabetes may be increased with all SGAs. x The use of clozapine appears to present no increased risk of malformations, although

gestational diabetes and neonatal seizures may be more likely to occur. There is a single case report of maternal overdose resulting in foetal death and there are theoretical concerns about the risk of agranulocytosis in the foetus/neonate. NICE has, in the past, recommended that pregnant women should be switched from clozapine to another antipsychotic. However, for almost all women who are prescribed clozapine, a switch to a different antipsychotic will result in relapse. On the balance of evidence available, clozapine should usually be continued.

x A small prospective case control study reported that babies who were exposed to antipsychotics in utero, had delayed cognitive, motor and social-emotional development at 2 and 6 months old but not at 12 months. The clinical significance of this finding, if any, is unclear.

Recommendations for treatment of Psychosis in Pregnancy:

x Patients with a history of psychosis who are maintained on antipsychotic medication should be advised to discuss a planned pregnancy as early as possible.

x Be aware that drug-induced hyperprolactinaemia may prevent pregnancy. Consider switching to am alternative drug.

x Such patients, particularly if they have suffered repeated relapses, are best maintained on antipsychotics during and after pregnanc. This may minimise foetal exposure by avoiding the need for higher doses, and/or multiple drugs should relapse occur.

x There is most experience with chlorpromazine (constipation and sedation can be a problem), trifluoperazine, haloperidol, olanzapine, quetiapine and clozapine (gestational diabetes may be a problem with all SGAs). If the patient is established on another antipsychotic, the most up-to-date advice should always be obtained; a change in treatment may not be necessary or wise.

x NICE recommends avoiding depot preparations and anticholinergic drugs in pregnancy.

x A few authorities recommend discontinuation of antipsychotics 5-10 days before anticipated delivery to minimise the chances of neonatal effects. This may, however, put mother and infant at risk and needs to be considered carefully. Antipsychotic discontinuation symptoms can occur in the neonate (e.g. crying, agitation, increased suckling). This is thought to be a class effect. When antipsychotics are taken in pregnancy it is recommended that the woman gives birth in a unit that has access to paediatric intensive care facilities. Some centres used mixed feeding (bottle and breast milk) to minimise withdrawal symptoms.

x Find out about alcohol, cigarettes and other drug use, environmental exposures, as well as over the counter remedies and prescribed medication intake and ensure this is documented in notes.

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Treatment options in breast feeding(15,16,30,31,32)

Another factor would be to consider whether the patient wishes to breastfeed. The benefits of breastfeeding to the mother and infant must be weighed against the risk of drug exposure in the infant. The following principles should be born in mind:

x Premature infants and infants with renal, hepatic, cardiac or neurological impairment are at greater risk from exposure to drugs

x The infants should be monitored for any specific adverse effects of the drugs as well as for feeding patterns and growth and development

x Feeds may be given before taking a dose, to avoid peak drug levels in the milk - or milk could be expressed at this time to give later (although this may be impractical in small infants who may feed every 2-3 hours)

x Any exposure to the drug that has already occurred during pregnancy is likely to be more than the exposure during breast feeding

x Continuing a drug during breastfeeding can allow the small quantity contained in the breast milk to help offset any neonatal withdrawal symptoms

x Use the lowest effective dose

x Avoid polypharmacy Phenothiazines: Phenothiazines (chlorpromazine, flupentixol, levopromazine, perphenazine, and zuclopenthixol) given to the mother result in only very limited concentration found in mothers‟ milk samples due to the high plasma protein binding(30). When neuroleptic or phenothiazine therapy is urgently needed, levomepromazine (among those neuroleptics with weak action) and perphenazine or trifluopromazine (among those with moderately strong action) are preferable. The appearance of acute toxic symptoms as a result of phenothiazine in the milk is unlikely. Monotherapy should be the goal. In cases of symptoms potentially associated with the drug therapy, a paediatrician and a teratology information centre should be contacted to decide individually upon measuring drug values in the infant‟s serum, supplementary formula feeding, weaning, and/or changing therapy. As with all psychoactive drugs, there is insufficient experience of the long-term effects on breastfed children as a result of ongoing therapy to their mothers. Haloperidol

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If indicated, haloperidol may be used during lactation. Monotherapy is the goal. In cases of symptoms potentially associated with the drug therapy, a paediatrician and a teratology information centre should be contacted to decide individually upon measuring drug values in the infant‟s serum, supplementary formula feeding, weaning, and/or changing therapy. As with all psychoactive drugs, there is insufficient experience on the long-term effects on breastfed children as a result of ongoing therapy to their mothers. Atypical antipsychotics Olanzapine, quetiapine, and risperidone are acceptable during lactation. The other atypical neuroleptics should, if possible, not be used, due to lack of data or to higher drug transfer into the milk. Because of the risk of neutropenia and seizures, it is advisable to avoid breastfeeding on clozapine until more data become available. Monotherapy is the goal. In cases of symptoms potentially associated with the drug therapy, a paediatrician and a teratology information centre should be contacted to decide individually upon measuring drug values in the infant‟s serum, supplementary formula feeding, weaning, and/or changing therapy. As with all psychoactive drugs, there is insufficient experience on the long-term effects on breastfed children as a result of ongoing therapy to their mothers. For further information about these agents, or to discuss patients who are currently taking other medication please contact Medicines Information on 0118 960 5075 or [email protected].

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Clozapine Background Clozapine is indicated for treatment-resistant schizophrenia (TRS) and unresponsive psychotic disorders in Parkinson‟s disease. Clozapine has been shown to be effective in up to 30 – 50% of people with TRS(9). This may rise to 60% if effective doses are continued for 12 months (33). Here, peak responses were demonstrated to occur at 12-24 weeks. Clozapine also reduces suicide rates in schizophrenia, which may be as high as 10%.

Important Adverse Effects Neutropenia/agranulocytosis are very well-known adverse effects of clozapine, but due to the effective haematological monitoring programme, fatalities are minimal. Less well known but potentially fatal adverse effects include myocarditis and gastrointestinal hypomotility. Blood dyscrasias Clozapine can cause a usually reversible neutropenia in 3-4% of patients, which may progress to agranulocytosis in 0.8% of patients over one year. The risk is higher in older people, in Asian races and those with lower baseline leucocyte counts(34). Interestingly, there is no dose-relationship to this (35).The onset peaks at around 8-10 weeks and lasts between 12 and 20 days. However, the incidence after 3 years is minimal. Myocarditis Clozapine is associated with an increased risk of myocarditis which has, in rare cases, been fatal. Risk of myocarditis or cardiomyopathy may be as high as 1 in 1000.The increased risk of myocarditis is greatest in the first 2 months of treatment; cardiomyopathy may occur later in treatment, but both may occur at any time. Fatal cases of cardiomyopathy have also been reported rarely. Myocarditis or cardiomyopathy should be suspected in patients who experience persistent tachycardia at rest, especially in the first few months of treatment, and/or palpitations, arrhythmias, flu-like symptoms, chest pain and other symptoms of heart failure (e.g. fatigue, dyspnoea, tachypnoea) or symptoms that mimic myocardial infarction(36). Signs include ECG changes (ST depression), enlarged heart and eosinophilia. If suspected, clozapine should be stopped and the patient referred to a cardiologist. Patients who develop clozapine-induced myocarditis or cardiomyopathy should not be re-exposed to clozapine.

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Gastrointestinal hypomotility Some 30-60% of patients report constipation as a side effect of clozapine(37).The effect has been attributed to the peripheral anticholinergic and antiserotonergic properties of clozapine(38). Gastrointestinal hypomotility may lead to obstruction, impaction, paralytic ileus, aspiration of vomit, necrotizing colitis and intestinal perforation. There have been a number of fatalities, some of which have occurred without any history of abdominal symptoms (39). Particular care is necessary in patients who are receiving concomitant medications known to cause constipation (especially those with anticholinergic properties such as some antipsychotics, antidepressants and antiparkinsonian treatments), have a history of colonic disease or a history of lower abdominal surgery as these may exacerbate the situation. It is vital that constipation is recognised and actively treated. Thromboembolism In common with other antipsychotics, clozapine has been associated with thromboembolism. Risk has been estimated to be 1 in 2000 to 1 in 6000 (40). It seems most likely to occur during the first 3 months of treatment but can occur at any time. Whilst causes are probably multifactorial, precautionary measures such as encouraging exercise and good hydration are recommended, as is staff education.

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Initiating Treatment x Clozapine can only be initiated under a consultant psychiatrist‟s supervision/advice.

x Before starting, patients should have a physical examination and cardiac disease excluded.

x Each patient, doctor prescribing and pharmacist dispensing, has to be registered with the manufacturing company and blood testing is a mandatory part of treatment. This takes place weekly for the first 18 weeks, then fortnightly between weeks 18 and 52. After 1 year of treatment with stable neutrophil counts, patients may be monitored at least at 4 week intervals. Monitoring must continue throughout treatment and for at least 4 weeks after discontinuation.

x Slow initiation of clozapine is essential to minimise common side-effects such as hypotension and sedation, which are dose-dependent and more frequent at the beginning of treatment.

x Blood pressure (lying and standing) and pulse checks should be carried out twice a day during the titration period.

x The initial dose should be 12.5mg, given at night (to avoid the need for blood pressure checks over the first few hours).

x Doses are increased slowly (see table below), given twice daily, until the initial target dose is achieved (see below). Response should be observed over several weeks at this dose and ideally a plasma level taken, before considering increasing further, in increments of 50-100mg/week.

x If a dose is not tolerated, decrease to a dose which was tolerated and increase more slowly if need be. Most side-effects of clozapine are dose-dependent, and can be minimised by careful dose escalation.

x If the patient has not taken clozapine for more than 48 hours, it should be re-commenced at the starting dose but the increasing regime can be done more quickly.

x Some patients can be initiated with clozapine in the community, for which there is a BHFT guideline available. Community initiations would need support from the Crisis Resolution Home Treatment Team or CMHTs with monitoring blood pressure, pulse and temperature in such cases.

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Clozapine Titration

Day Morning Dose (mg) Evening Dose (mg) 1 12.5 - 2 12.5 12.5 3 25 25 4 25 25 5 25 50 6 25 50 7 50 50 8 50 75 9 75 75 10 75 100 11 100 100 12 100 125 13 100 150 * 14 100 200 If required, daily doses can be further increased in increments of 50mg, preferably at weekly intervals. Initial target doses

x Female patients attain, on average, higher plasma clozapine concentrations at a given dose than men.

x Smoking has a major effect on clozapine dose requirement due to lowering of plasma clozapine levels by induction of one of the major metabolising enzymes. The effect may be dose-related – heavy smokers can require a substantially higher clozapine dose than non-smokers.

x Targets should be increased in obesity and younger patients (<40) and decreased for the elderly and smaller/thinner patients. Assuming average weight and age, suggested targets to aim for are as follows:

*Female non-smoker: 250mg/day Female smoker: 450mg/day Male non-smoker:350mg/day Male smoker: 450 – 550mg/day For further advice, contact MI.

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Clozapine Plasma Level Monitoring Whilst clozapine dosage is normally adjusted according to clinical response and tolerability, plasma level monitoring can sometimes help in management, e.g.

x Monitoring adherence x Optimising dosage x Minimising the risk/severity of side-effects x Investigating suspected drug-drug interactions

Studies suggest that efficacy in treatment-resistant schizophrenia may be associated with “trough” clozapine concentrations of 0.35mg/L or above(41-44). However, a minority of patients appear to respond to concentrations lower than this. Equally, a small percentage of patients appear to require much higher levels for response. There is no clearly established upper limit for plasma clozapine, although levels above 0.6mg/l suggest increases risk of adverse effects such as seizures, and in practice the incidence of other side-effects may be dose-limiting. A possible confounding factor in the interpretation of plasma clozapine results is the presence of gastrointestinal hypomotility. Constipated patients may not absorb clozapine as expected, and continued dosing without addressing the constipation may make matters worse. Similarly, when a patient is severely constipated and this is finally resolved, a sudden rise in clozapine absorption and resulting levels, may ensue.

Suggested Situations in which a plasma clozapine level may be useful x Assessing adherence. Total or erratic non-concordance is predictable from clozapine

plasma levels. However, it should be noted that occasionally some patients (often young, male, smokers) may metabolise clozapine so quickly that they have very low levels, even though they are taking it as prescribed.

x Identifying slow metabolisers. Occasionally, a level for a patient complaining of side-effects reveals a plasma level that is much higher than predicted. To identify these patients before this happens, it may be worth considering a plasma level in the very early stages of treatment, before the target dose has been reached.

x Identifying ultra-rapid metabolisers. If there has been no clinical response at the target dose for several weeks, a plasma level may be useful to guide further dose increases to reach the suggested threshold concentration for response (0.35mg/l).

x Changes in smoking habit. Smoking has a big effect on clozapine dose requirement. Plasma clozapine may rise substantially within 3-5 days of smoking cessation at constant clozapine dose, and vice versa. Careful monitoring is thus essential if there is a change in smoking habit. Nicotine replacement therapy per se does not affect plasma clozapine levels.

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x When adding an interacting drug. Levels may increase significantly with an enzyme-inhibiting drug such as SSRIs (especially fluvoxamine), cimetidine, ciprofloxacin and erythromycin. Enzyme inducers such as carbamazepine, phenytoin and rifampicin can lower levels.

x In clinical situations that may result in a high clozapine plasma level, such as liver disease and serious chest infections.

x Investigating clozapine overdose. Practical considerations at BHFT A level is generally only useful after the titration period has elapsed and if the clozapine dose has been stable within the last week. The blood sample should ideally be taken immediately before the normal morning dose. Or, if dosage is once-daily, 10-12h post-dose. Samples taken less than 6 hours post-dose may make the result difficult to interpret. For urgent clozapine levels, please telephone the clozapine service on 0118-960-5296. Otherwise, requests for plasma levels should be emailed to the clozapine service staff prior to the patient‟s next routine blood test, so that blood for a plasma level can be taken at the same time (thus avoiding patients having to have additional blood tests). The pharmacy clozapine service will arrange samples to be sent to the Medical Toxicology Unit, Kings College Hospital, London. Do not send blood samples yourself.

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Clozapine Monitoring in the Community Once a patient has been receiving clozapine for 52 weeks with no haematological problems, blood sampling is carried out every four weeks and prescriptions can be dispensed monthly. If appropriate, prescribing and management of the sampling can theoretically be transferred to the patient‟s GP. Transfer of prescribing responsibility needs to be agreed between the consultant, the GP, the pharmacy supplying the clozapine (which needs to be registered with the company) and the pharmaceutical company. However, at present, shared care arrangements do not exist for clozapine in Berkshire. The patient must be advised that the timings for blood sampling and supply of medication differ in the community. The patient must visit the GP for a blood test two weeks prior to the next supply of clozapine being due. If the result is green, a supply of clozapine can be prescribed and collected from the nominated pharmacy in two weeks time. For further advice please contact the pharmacy clozapine service, Prospect Park Hospital on 0118 960 5296.

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Management of Clozapine-Induced Side-Effects

Side-Effect Likely Time Frame Management Suggestions Sedation First few months. May

be persistent, but tolerance should develop

Give larger proportion at night. May need single night-time dose. Decrease dose if necessary. Check plasma level.

Hypersalivation First few months, but may persist. Common at night

Use a towel to cover pillow. If distressing, try an anti-muscarinic agent - hyoscine hydrobromide 300mcg (Kwells®) sucked and swallowed at night. Second line treatment choice is pirenzepine 25-50mg up to TDS (unlicensed in the UK). Discuss alternative agents with pharmacy if these are not effective.

Tachycardia First 4 weeks. May persist. Often dose-related

Common and usually benign. Slow down dose escalation. Reduce dose. Consider small dose of beta-blocker if benign sinus tachycardia. Be alert to signs of myocarditis e.g. fever, hypotension, chest pain (see previous section).

Constipation Any time. Usually persists

High fibre diet. Bulk forming/stimulant laxatives. Check for/encourage adequate fluid intake. Effective treatment is essential to avoid serious consequences.

Hypotension First 4 weeks Take care when standing up. Reduce dose or slow down rate of increase. Give largest dose at bedtime. Consult pharmacy if severe.

Hypertension First 4 weeks, sometimes longer

Monitor closely and slow down dose increases if necessary. Hypotensive therapy is sometimes necessary.

Weight Gain First year – or at anytime.

Dietary counselling before and during treatment. Monitor weight. Exercise.

Fever First 3 weeks Give antipyretic but check FBC. Reduce rate of titration. Beware myocarditis. Not usually related to blood dyscrasias.

Seizures Any time. More frequent at doses over 600mg/day (and/or plasma levels above 0.6mg/l)

Avoid rapid dose increases. After a fit, withhold dose for 1 day & resume at half dose. Consider EEG/neurology referral and valproate prophylaxis.

Nausea First 6 weeks. Try an anti-emetic e.g. domperidone. Avoid metoclopramide and prochlorperazine (which can cause EPSE)

Nocturnal Enuresis

Any time Avoid night-time doses (last dose before 6pm) and fluids before bedtime. Can resolve without intervention. Consider desmopressin in severe cases, but risk of hyponatraemia.

Neutropenia/ag First 18 weeks usually Stop clozapine. Admit

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ranulocytosis

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Clozapine Augmentation For TRS that has proved to be unresponsive to clozapine alone, adding a second antipsychotic has become a common strategy. However, the evidence base supporting it is weak. It has been hypothesised that that any pharmcodynamic synergy might be related to an increased level of D2 dopamine receptor occupancy (45,46). However, such an increase might also be expected to result in an increased risk of EPS. An alteration of the interaction between serotonin and D2 activity has also been suggested as a relevant mechanism (47). Pharmacokinetic interactions may also play a part. In practice, the results are often disappointing, and only achieve small changes in symptoms. However, RCTs and open studies have reported clozapine augmentation to be relatively well tolerated. The main treatment-emergent side effects have been predictable from the pharmacology of the augmenting drug, with EPS and prolactin elevation among the most common problems. Augmentation should only be attempted after 6 months of optimised clozapine alone has failed to provide clinical benefit. Any trial should be carefully monitored for evidence of benefit and increased side-effects. If there is no clear benefit, then the augmenting drug should be withdrawn within 6 months. The table below shows some common treatment options.

Augmenting Drug Comments

Amisulpride 400-800mg/day (48,49)

Only one small RCT, but widely used. Increased prolactin levels potentially problematic.

Sulpiride 400mg/day(47)

Supported by a randomized controlled trial in partial responders (the first RCT for clozapine –antipsychotic augmentation). Prolactin increases potentially problematic.

Aripiprazole 15-30mg/day(50)

Limited evidence but may improve metabolic parameters. Reports of nausea, vomiting, insomnia, headache and agitation in the first 2 weeks (51) and also modest weight loss (52)

Haloperidol 2mg/day Modest evidence of benefit (53) Risperidone 2-6mg/day (54,55)

Mixed results. Reports of increases in clozapine levels. Isolated problems such as agranulocytosis, atrial ectopics and possible NMS reported (56,57,58)

Lamotrigine 25-300mg/day (59)

May be useful in partial or non-responders. Some negative reports but a meta-analysis suggests moderate effect size (60)

Page 41 of 62

FGA Depot Injections

The main advantage and general indication for giving antipsychotic medication in depot form is that compliance with therapy can be assured. Disadvantages include a suspected higher incidence of extra-pyramidal side effects (EPSE), local complications due to the administration of an intramuscular injection and other side effects associated with antipsychotic medication (see previous). These are more common in elderly patients and when using high doses. There are few differences between first-generation antipsychotic (FGA) depots, with the possible exception of zuclopenthixol. Cochrane reviews concluded that they are equally effective, although there is some evidence that zuclopenthixol may be more effective at preventing relapses (61). Flupentixol can be given within license at much higher “neuroleptic equivalent” doses than other depots. However, standard doses are as effective as high doses (15). For full guidance on all aspects of depot administration, including different sites of administration, z-tracking techniques etc, please see guide in Appendix Prescribing Advice for FGA x always give a test dose when initiating treatment

- to minimise potential side effects of the drug and adverse reactions to the oil. It should be noted that some EPSE occur only after several doses of the depot (see BNF or contact MI for manufacturers recommended test doses). For risperidone, a test dose is not required (the aqueous base is not allergenic).

x continue with the lowest therapeutic dose

- low doses are better tolerated, less expensive and may also be at least as effective as higher doses(15). There are few data showing clear dose-response effects for depot preparations.

x administer at the longest possible licensed interval

- all depots can be safely administered at their maximum licensed dosing interval - there is no evidence to suggest shortening the dose interval improves efficacy and less frequent administration is less stressful (injections are painful).

x administer the smallest volume of depot possible (the bigger the volume injected, the

more painful it is). x adjust doses only after an adequate period of assessment

- peak plasma levels and achievement of steady state are delayed with depot injections. Doses may be reduced if adverse effects occur, but should only be increased after careful assessment once the drug has achieved steady state.

Page 42 of 62

Points to Remember x at the start of therapy, plasma levels of antipsychotic released from a depot increase

over several weeks, without increasing the given dose. This is due to accumulation; steady state is only achieved after 6-8 weeks.

x depot preparations take at least two months to achieve steady plasma levels x true relapse seems only to occur three to six months after withdrawing depot therapy

x administering anticholinergics IM. IM procyclidine injections should NOT be routinely

administered with each depot dose. This is because the depots do not produce acute EPSE s at the time of administration. This may take hours or days, by which time the anticholinergic drug will have worn off.

x injections should be given into the buttock as a large muscle is needed for steady

absorption of the drug For full guidance on the administration of depots, please refer to the following guide:

Guidance on the Administration to Adults of Oil-based Depot and other Long-Acting Intramuscular Antipsychotic Injections

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SGA Long Acting Injections

LAI Indications

Dose Range/ frequency Route

Cost/month

(calendar)

Paliperidone

palmitate

(Xeplion®

maintenance

treatment of

schizophrenia in adult patients stabilised w

ith paliperidone or risperidone

Start w

ith 150mg on day

one, then 100mg on day

eight (both via deltoid m

uscle). The third injection should be given one m

onth after the second initiation dose.

Maintenance dose range:

75mg to 150m

g every m

onth.

Intramuscular

First two initiation doses

by deltoid muscle then can

be administered by either

deltoid or gluteal muscle.

150mg - £392.59

100mg - £314.07

75mg - £244.90

Aripiprazole

LAI (A

bilify M

aintena®

Abilify M

aintena is indicated for m

aintenance treatm

ent of schizophrenia in adult patients stabilised w

ith oral aripiprazole.

The recomm

ended starting and m

aintenance dose of A

bilify Maintena

is 400 mg.

After the first injection,

treatment w

ith 10 mg to

20 mg oral aripiprazole

should be continued for 14 consecutive days to m

aintain therapeutic

Intramuscular

Deltoid or gluteal m

uscle.

400mg - £220.41

Page 44 of 62

aripiprazole concentrations during initiation of therapy.

If there are adverse reactions w

ith the 400 m

g dosage, reduction of the dose to 300 m

g once m

onthly should be considered.

Risperidone

Consta

(Risperdal

Consta®

)

RIS

PE

RD

AL

CO

NS

TA®

is indicated for the m

aintenance treatm

ent of schizophrenia in patients currently stabilised w

ith oral antipsychotics

Recom

mended dose 25

mg intram

uscular every tw

o weeks.

Som

e patients may

benefit from the higher

doses of 37.5 mg or 50

mg. D

oses higher than 50 m

g every 2 weeks are

not recomm

ended.

RIS

PE

RD

AL C

ON

STA

should be adm

inistered every tw

o weeks by deep

intramuscular deltoid or

gluteal injection using the appropriate safety needle. For deltoid adm

inistration, use the 1-inch needle alternating injections betw

een the two arm

s. For gluteal adm

inistration, use the 2-inch needle alternating injections betw

een the two buttocks.

50mg dose, 4w

ks = £285.52

37.5mg dose, 4w

ks = £222.64

25mg, 4w

ks = £159.38

Page 45 of 62

Page 46 of 62

Risperidone Long-Acting Injection (RLAI) (Risperdal Consta®) RLAI is indicated for the treatment of schizophrenia and other psychotic conditions in which positive symptoms and/or negative symptoms are prominent. It should be considered for: 1. Patients who have responded to treatment with an oral atypical antipsychotic, but

who are non-compliant, or 2. Patients who have responded well to a depot preparation of a typical antipsychotic,

but are suffering from side effects. RLAI should not be used as first line treatment or for patients who have a history of treatment resistance to atypical antipsychotic agents. Treatment Guidelines RLAI releases risperidone via sustained release biospheres. Only small amounts of risperidone are released during the first three weeks. The main drug release starts in week three and peaks in weeks 5-6. As a result, alternative antipsychotic cover (ideally oral risperidone) will be needed for the first three weeks of treatment. x RLAI should only be initiated by or following consultation with a consultant psychiatrist

x Risperidone naive patients should undergo a trial of oral risperidone to identify intolerance to the drug. This should be given at least several days before using the injection.

Oral risperidone (or other current oral antipsychotic) must be continued for at least three weeks from the first injection (therapeutic levels are not reached until approx. Four weeks following injection). x Patients taking 4mg of risperidone orally or less (or equivalent dose of another

antipsychotic) should be started on the 25mg dose administered every two weeks. Treatment continues with fortnightly injections.

x Patients taking higher doses of oral antipsychotic can be stared on 37.5mg every two weeks.

x The dose of RLAI should not be increased for at least six weeks (i.e. until the fourth injection), as steady state will not be reached before this. At this point it may be increased by 12.5mg and a further six weeks should elapse before changes.

x The maximum dose for working age adults is 50mg every two weeks. However, clinical trials did not demonstrate any increased efficacy at this dose over lower doses.

x Any existing antipsychotic medication should ideally be reduced and discontinued three weeks after the first RLAI injection

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x where necessary, (e.g. patients receiving the equivalent or more than 4mg per day of risperidone), the dose of RLAI may then be increased to 50mg

x if oral supplementation is deemed necessary, consider low dose benzodiazepines (short term)

Storage and General Information

x Each pack of RLAI contains one vial containing the risperidone microspheres, one solvent syringe, one Alaris Smartsite needle-free vial access device for reconstitution and two needles:

For GLUTEAL injection, select the 20G TW 2-inch (0.9 mm x 50 mm) needle (longer needle with yellow coloured hub).

For DELTOID injection, select the 21G UTW 1-inch (0.8 mm x 25 mm) needle (shorter needle with green coloured hub).

x The entire box must be kept refrigerated. Storage at temperatures in excess of 80C

reduces the shelf life to 7 days. Thus the product must be used within seven days of dispensing; this will be indicated on the pharmacy dispensing label.

x Once reconstituted, the suspension must be used within six hours. Risperidone LAI

must only be prepared for immediate use, never in advance.

x Reconstitute following the manufacturer‟s instructions and give the whole contents of the vial.

NB: Inappropriate storage of RLAI has lead to much wastage and hence cost pressures within the Trust. Please help to avoid wastage by ensuring the cold chain is maintained and that only those injections that are due to be administered within the next seven days are ordered from pharmacy.

x Some clinical waste is produced when administering the injection. Staff must carry sharps boxes and be prepared for the safe disposal of waste products - refer to the most current Berkshire Healthcare NHS Trust Care and Control of Medicines Policy for full guidelines.

Training for Staff Nurses should familiarise themselves with the method of reconstitution and injection before administering. Nurses who have not been trained on giving the injection via the deltoid route should not do so. Each member of staff is personally responsible for their own competency to do this, and should ensure that they maintain this level of training. Janssen-Cilag are

Page 48 of 62

happy to organise training sessions for staff and may be contacted by the ward or the CMHT lead. Patient care may be managed by primary care teams/workers when: - the patient was initiated on RLAI in primary care - OR the patient has been stabilised on a maintenance dose of RLAI - OR there has been discussion between primary and secondary care to agree the

transfer of responsibility before the patient is stabilised.

Switching to RLAI

Existing treatment Recommended method of switching

Comments

No treatment Start oral risperidone at 2mg day, and titrate to at least 4mg/day. If tolerated, prescribe recommended dose of RLAI. Continue with oral risperidone for at least three weeks, then taper over at least a further week. It may be necessary to continue oral risperidone for longer.

Use oral risperidone first to ensure tolerability. Patients taking 4mg or less oral risperidone should start at 25mg. Those on higher doses should start on 37.5mg.

Oral risperidone Prescribe equivalent RLAI dose

As above.

Oral antipsychotics. Ideally, switch to oral risperidone and titrate dose to at least 4mg/day. If tolerated, prescribe RLAI. Continue with oral risperidone as above. OR Give RLAI and continue oral antipsychotic for three weeks. Gradually discontinue over at least one further week (and be prepared to continue for longer).

Those on lower oral antipsychotic doses should start on 25mg RLAI. Those on the higher end of the licensed range should start on 37.5mg.

Depot antipsychotic. Give RLAI one week BEFORE the last depot injection is given.

For those on lower doses, start RLAI at 25mg. For those on the middle to upper range of licensed doses, start at 37.5mg.

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Depot and oral antipsychotics.

Give RLAI one week BEFORE the last depot injection is given. Slowly taper oral antipsychotics 3-4 weeks later. It may be necessary to continue them for longer.

Aim to use RLAI as the sole antipsychotic. Choose starting RLAI dose according to the total dose of oral and depot antipsychotic. This will often need to be 37.5mg.

Aripiprazole or Abilify Maintena® For patients who have never taken aripiprazole, tolerability with oral aripiprazole must occur prior to initiating treatment with Abilify Maintena. The recommended starting and maintenance dose of Abilify Maintena is 400 mg. Titration of the dose of this medicinal product is not required. It should be administered once monthly as a single injection (no sooner than 26 days after the previous injection). After the first injection, treatment with 10 mg to 20 mg oral aripiprazole should be continued for 14 consecutive days to maintain therapeutic aripiprazole concentrations during initiation of therapy. If there are adverse reactions with the 400 mg dosage, reduction of the dose to 300 mg once monthly should be considered. Missed dose information 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 subsequent doses are missed (i.e., after attainment of steady state) and 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.

Method of administration Abilify Maintena is only intended for intramuscular use and should not be administered intravenously or subcutaneously. It should only be administered by a healthcare professional. The suspension should be injected immediately after reconstitution but can be stored below 25 °C for up to 4 hours in the vial. The suspension should be injected slowly as a single injection (doses must not be divided) into the gluteal or

Page 50 of 62

deltoid muscle. Care should be taken to avoid inadvertent injection into a blood vessel. Sites of injections should be rotated between the two gluteal or deltoid muscles. 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 should be used. 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 should be used (see section 6.6). The powder and solvent vials are for single-use only. Xeplion (paliperidone palmitate) Posology Recommended initiation of XEPLION is with a dose of 150 mg on treatment day 1 and 100 mg one week later (day 8), both administered in the deltoid muscle in order to attain therapeutic concentrations rapidly (see section 5.2). The third dose should be administered one month after the second initiation dose. The recommended monthly maintenance dose is 75 mg; some patients may benefit from lower or higher doses within the recommended range of 25 to 150 mg based on individual patient tolerability and/or efficacy. Patients who are overweight or obese may require doses in the upper range (see section 5.2). Following the second initiation dose, monthly maintenance doses can be administered in either the deltoid or gluteal muscle. Adjustment of the maintenance dose may be made monthly. When making dose adjustments, the prolonged release characteristics of XEPLION should be considered (see section 5.2), as the full effect of maintenance doses may not be evident for several months. Switching from oral paliperidone or oral risperidone Previous oral paliperidone or oral risperidone can be discontinued at the time of initiation of treatment with XEPLION. Some patients may benefit from gradual withdrawal. XEPLION should be initiated as described at the beginning of section 4.2 above. Switching from risperidone long acting injection When switching patients from risperidone long acting injection, initiate XEPLION therapy in place of the next scheduled injection. XEPLION should then be continued at monthly intervals. The one-week initiation dosing regimen including the intramuscular injections (day 1 and 8, respectively) as described in section 4.2 above is not required. Patients previously stabilised on different doses of risperidone long acting injection can attain similar paliperidone steady-state exposure during maintenance treatment with XEPLION monthly doses according to the following: Doses of risperidone long acting injection and XEPLION needed to attain similar paliperidone exposure at steady-state Previous risperidone long acting injection dose XEPLION injection 25 mg every 2 weeks 50 mg monthly 37.5 mg every 2 weeks 75 mg monthly 50 mg every 2 weeks 100 mg monthly Discontinuation of antipsychotic medicinal products should be made in accordance with appropriate prescribing information. If XEPLION is discontinued, its prolonged release characteristics must be considered. As recommended with other antipsychotic medicinal products, the need for continuing existing extrapyramidal symptoms (EPS) medicine should be re-evaluated periodically. Missed doses Avoiding missed doses

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It is recommended that the second initiation dose of XEPLION 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 XEPLION 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. 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 XEPLION 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. Missed second initiation dose (4-7 weeks from first injection) If 4 to 7 weeks have elapsed since the first injection of XEPLION, resume dosing with two injections of 100 mg in the following manner: 1. a deltoid injection as soon as possible, 2. another deltoid injection one week later, 3. 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. Missed second initiation dose (> 7 weeks from first injection) If more than 7 weeks have elapsed since the first injection of XEPLION, initiate dosing as described for the initial recommended initiation of XEPLION above. Missed monthly maintenance dose (1 month to 6 weeks) After initiation, the recommended injection cycle of XEPLION 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. Missed monthly maintenance dose (> 6 weeks to 6 months) If more than 6 weeks have elapsed since the last injection of XEPLION, the recommendation is as follows: For patients stabilised with doses of 25 to 100 mg 1. a deltoid injection as soon as possible at the same dose the patient was previously stabilised on 2. another deltoid injection (same dose) one week later (day 8) 3. 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 1. a deltoid injection as soon as possible at the 100 mg dose 2. another deltoid injection one week later (day 8) at the 100 mg dose 3. 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 Missed monthly maintenance dose (> 6 months) If more than 6 months have elapsed since the last injection of XEPLION, initiate dosing as described for the initial recommended initiation of XEPLION above. Switching regimes may vary depending on the individual patient and current drug regime. Contact the Medicines Information Service, pharmacy department, Prospect Park Hospital, on 0118 960 5075 for specific information.

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Neuroleptic Malignant Syndrome Neuroleptic Malignant Syndrome (NMS) is a rare and potentially fatal idiosyncratic adverse drug reaction resulting in a sudden loss in control of body temperature. It has been estimated to occur in up to 1% of patients receiving conventional antipsychotic medication (although can also occur with atypicals) and has also been seen in patients treated with antidepressants, lithium, carbamazepine, metoclopramide and on sudden discontinuation of levodopa therapy. This syndrome of sympathetic hyperactivity may be due to sudden changes in dopaminergic function upsetting thermoregulatory centres in the brain. NMS can be fatal due to renal and respiratory failure. The incidence of fatalities is around 20% although higher figures have been quoted in patients receiving depot antipsychotics(16,62). In contrast, some cases have few signs and symptoms, and asymptomatic rises in plasma creatine kinase are common. Onset of NMS is variable; it may be as early as 45 minutes or as late as 65 days after initiation of the antipsychotic(63). Main Symptoms/Signs • hyperthermia or fever within 24–72 hours (not always seen e.g. if concomitant

carbamazepine is being given) usually to over 38.50c • severe muscle rigidity and tremor • mental state changes - confusion, agitation, altered (reduced) level of consciousness,

irritability, mutism • sweating, dehydration • dysphagia • hypertension, fluctuating blood pressure and tachycardia • incontinence, urinary retention, obstruction • raised creatinine phosphokinase (CPK) levels - over 1000iu in 1L • raised white cell count Risk Factors • History – previous NMS, organic brain disease, Parkinson‟s disease, alcoholism,

hyperthyroidism, mental retardation, previous ECT • Mental state – psychosis, psychomotor agitation, overactivity, catatonia, affective

disorder • Physical state – dehydration, postpartum, being young and male • Medication – high potency typical antipsychotics, IM therapy, concurrent MAOIs or

carbamazepine, rapid dose reduction or escalation, high doses, abrupt withdrawal of anticholinergics

General Treatment

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• immediate withdrawal of all antipsychotic, antidepressant and lithium treatment • transfer to medical or ICU ward, for general supportive medical intervention – ice

packs, rehydration, bromocriptine, dantrolene • use diazepam for sedation and as a muscle relaxant • monitor blood pressure, pulse, rigidity and muscle tone, and temperature every four

hours • monitor white cell count, U&E, and liver function tests daily. Rechallenge with antipsychotics Rechallenge with antipsychotics may show a high rate of recurrence but is associated with an acceptable risk - most patients are eventually able to tolerate antipsychotics again if the necessary monitoring and checks are undertaken. In particular: • review diagnosis of NMS to ensure key features were present and review diagnosis

to confirm the need for antipsychotic medication • consider alternative strategies where possible, e.g. ECT, benzodiazepines etc • a minimum of 5–14 days should elapse post recovery before restarting an

antipsychotic • depot medication must never be used • for rechallenge, choose a drug from a different class from the one which caused

NMS, or select a low potency drug (e.g. chlorpromazine) or an agent with low D2 receptor blockade (e.g. quetiapine, clozapine), or one used before without problems

• use low starting dose and increase slowly • perform alternate day CPK levels and monitor pulse, temperature and muscle tone

daily until stable. Check white blood cell count weekly and ensure adequate hydration and nutrition

• inform patients and carers of the risks and how to recognise the syndrome in the future

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Extra Pyramidal Side Effects (EPSE) Akathisia, pseudoparkinsonism, dyskinesias and dystonias have all been associated either acutely or chronically with antipsychotic drugs and are thought to be due to non-selective dopamine (D2) receptor blockade(64). Acute reactions are usually at the start of treatment or after a dose increase and are usually reversible. Tardive forms are not invariably reversible on discontinuation of the drug or on dose reduction and can be aggravated by anticholinergics. They are generally dose related, more likely to occur with typical antipsychotics (especially high potency ones) and are less common with most atypicals(15). Pseudoparkinsonism Pseudoparkinsonism has been estimated to occur in 15-50% of patients and can be mistaken for depression or the negative symptoms of schizophrenia. It is more common in elderly females(65). Symptoms usually appear within days to weeks of onset of treatment or dose increase. Characteristics • muscle rigidity • tremor • akinesia • excess salivation • decreased/slow physical and/or mental activity • shuffling gait • lack of facial expression • slow monotonous speech Treatment • reduce dose of antipsychotic • prescribe antimuscarinic drug - e.g. procyclidine 5mg when required, up to three

times a day (see antimuscarinic prescribing guidelines) • switch to an antipsychotic less likely to produce parkinsonian symptoms e.g. atypicals

or sulpiride The condition should resolve itself upon termination of treatment with the antipsychotic, but may take several weeks to disappear depending on the individual patient.

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Acute Dystonia and Dyskinesia

Dystonic reactions have been estimated to affect 2-10% of patients(64). It is more common in young males (especially if antipsychotic naïve) given high potency drugs, and is rare in the elderly. Acute dystonia can occur within hours of commencing treatment with oral antipsychotics. Characteristics • uncontrolled muscle spasms in any part of the body • torticollis • involuntary tongue protrusion • oculogyric crisis The patient may be unable to swallow or speak clearly. In extreme cases the back may arch or the jaw dislocate. The experience can be frightening and painful. Treatment • prescribe antimuscarinic drug orally or IM depending on the severity of symptoms e.g.

procyclidine 5mg – see antimuscarinic prescribing guidelines. Response to IM administration takes around 20 minutes

• switch to an antipsychotic less likely to produce parkinsonian symptoms e.g. atypicals or sulpiride or lower the dose.

Akathisia Akathisia is a subjectively unpleasant state of inner restlessness where there is a strong desire or compulsion to move. It is estimated to be a problem in 20-30% of patients taking antipsychotics and can occur within hours to weeks of commencing treatment with antipsychotics or increasing the dose. Tardive akathisia takes longer to develop and can persist after antipsychotics have been withdrawn. Akathisia is especially implicated with high potency antipsychotics, and is less common with atypicals. Characteristics • rocking from foot to foot, foot stamping when seated, foot tapping, constant pacing,

constantly crossing/uncrossing legs • mental unease • irritability, agitation and aggression (often mistaken for worsening of the patient‟s

symptoms or behavioural problems) Akathisia can be mistaken for psychotic agitation and has been linked with suicide and aggression towards others. Treatment • reduce dose of antipsychotic • switch to an atypical antipsychotic • prescribe propranolol (30 - 80mg/day in divided doses) – unlicensed indication

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• prescribe clonazepam (up to 1.5mg daily in divided doses) – unlicensed indication • Anticholinergic drugs e.g. procyclidine may be effective if parkinsonism is also

present, but are generally unhelpful for the relief of akathisia Upon discontinuation of the antipsychotic, akathisia symptoms generally resolve within 7 days, but may take several weeks to disappear. Tardive Dyskinesia Tardive dyskinesia is an involuntary hyperkinesia, which increases with anxiety, goes away during sleep and in some cases may be irreversible. The prevalence of tardive dyskinesia (TD) has been estimated at around 10-20% (may be up to 40% in long term patients). It is more common in elderly females, those with an affective illness, and those who have had acute EPSE earlier in treatment(66). It usually occurs after months to years of treatment. Characteristics It is generally seen as repetitive, involuntary and purposeless movements. A wide variety can occur: • orofacial movements – lip smacking, chewing, tongue protrusion • choreiform hand movements - pill rolling or piano playing • pelvic thrusting • tics TD is potentially irreversible in 50% of cases. After antipsychotic withdrawal, symptoms may improve or worsen within several weeks, but this is usually followed by a long slow recovery over the next months or years. Treatment • withdraw all antimuscarinics (which can exacerbate symptoms) • reduce dose of, or discontinue, antipsychotic • consider change to clozapine or quetiapine or olanzapine(67). Clozapine is the

antipsychotic most likely to be associated with resolution of symptoms. • Consider withdrawal of other drugs which may exacerbate TD e.g. metoclopramide,

antidepressants, antimuscarinics, and antiparkinson drugs • consider use of tetrabenazine titrate to 25-200mg/day * • consider other treatments clonazepam (1-4mg/day in divided doses) ** diazepam (6-25mg/day) buspirone ** vitamin E (400iu increasing to 1600 iu/day) **

* only licensed treatment of TD in the UK ** unlicensed treatment options – contact MI for specific information

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Risk of Venous Thromboembolism (VTE) Although VTE is treatable, it has a three month mortality rate of 15-18%(68) and evidence is accumulating that the use of antipsychotics is an established risk factor for VTE. An MHRA drug safety update in June 2009(69) concluded that an increased risk of VTE could not be excluded, following a Europe-wide review of Yellow card data and published epidemiological studies. It stated that a possible relationship between use of antipsychotic medicines and venous thromboembolic events (VTE) was first suggested about five decades ago, after the introduction of phenothiazines. Since then, case reports of VTE have been received periodically through the Yellow Card Scheme and further studies have been completed that investigated this issue(70,71). Yellow Card data Many of the cases reported via the Yellow Card Scheme were potentially confounded by other risk factors or contained limited information to allow a clear causal relation to be established for antipsychotics and risk of VTE. Some of the known side effects of antipsychotics (e.g. sedation, weight gain) are known risk factors for VTE, and a direct or indirect causal association between antipsychotic use and VTE could not be excluded. Published epidemiological data Information from the literature is limited by a lack of randomised controlled trial data and by heterogeneity among the available observational studies. However, despite these limitations, all of the published studies to June 2008 conclude that there is an increased risk of VTE with exposure to antipsychotics(70,71). MHRA General Advice • Antipsychotic use may be associated with an increased risk of VTE • At present there are insufficient data available to determine any difference in risk

between atypical and conventional antipsychotics, or between individual drugs • All possible risk factors for VTE should be identified before and during antipsychotic

treatment and preventative measures undertaken In 2010, Parker and colleagues published a population based nested case-control study using the UK Qresearch primary care database(72). They aimed to determine whether antipsychotic drugs were associated with an increased risk of VTE, and to examine risks by type of antipsychotic, potency and dose. The study included primary care patients aged over 16 who were taking antipsychotics, mostly conventional agents with prochlorperazine accounting for 80% of all prescriptions. The authors found that the use of antipsychotics was associated with a significantly increased risk of VTE (odds ratio 1.32).There were 25532 eligible cases and 89491 matched controls.

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• Individuals prescribed antipsychotic drugs in the previous 24 months had a 32%

greater risk of VTE than non-users, after risk-factor adjustment. • Patients who had started a new drug in the previous 3 months had about twice the

risk. • The risk was greater for individuals prescribed atypical rather than conventional

drugs. It also tended to be greater for patients prescribed low rather than high potency drugs.

• However, consistent with previous estimates, they found a low absolute risk of antipsychotic-related VTE (4 extra cases of VTE per 10,000 patients over one year).

• The rarity of such adverse events does not justify antithrombotic prophylaxis without other medical conditions for which such preventative treatment is indicated.

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References 1. NICE guidelines [CG178] Published date: February 2014, Psychosis and schizophrenia in

adults: prevention and management 2. NPC. Patient decision aid: Antipsychotic drugs. December 2009. Accessed from

www.npci.org.uk/pda 3. Leucht S et al. Second-generation versus first-generation antipsychotic drugs for

schizophrenia: a meta-analysis. Lancet 2009;373:31-41. 4. Erhart SM, Marder SR, Carpenter WT. Treatment of schizophrenia negative symptoms:

future prospects. Schizophr Bull. 2006; 32:234-7. 5. Danion JM, Rein W, Fleurot O. Improvement of schizophrenic patients with primary negative

symptoms treated with amisulpride. Amisulpride study group. Am J Psychiatry. 1999; 156: 610-16.

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