Psychotropic Drug Formulary

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MHS

Lead Executive Director: Dr Caroline Allum

Name of originator Dr Elizabeth Francis

Author and job title: Governance Lead Pharmacist, Head of Clinical Audit & NICE

Approved by: Drugs & Therapeutics Group (MHS)

Edition: November 2018

Review date: February 2020

Disclaimer Every attempt has been made to ensure that the information in this Formulary is correct at the time of publication. Where there is doubt, information should be verified against relevant specialist publications

DOCUMENT IS UNCONTROLLED WHEN PRINTED

CONTENTS PAGE Section Document Control Sheet v 1.0 Introduction 1 2.0 Principles 4 3.0 Formulary Management 4 3.1 Formulary Implementation 4 3.2 Requests for Additions/Changes to the Formulary 5 3.3 Funding Issues 6 3.4 Forward Planning 6 3.5 Drug price ranges 8 3.6 Links to relevant Policies and Procedures 8

BNF Section Headings Central Nervous System 10 Hypnotics and Anxiolytics 10 Hypnotics 10 Anxiolytics 12 Benzodiazepines: Approximate equivalent doses to diazepam 13

Drugs used in Psychosis and related disorders 14 Antipsychotic drugs – First Generation 14 Antipsychotic drugs – Second Generation 16 Summary of the Royal College of Psychiatrists recommendation on the use of high dose antipsychotics 17 Antipsychotics: initiative to reduce prescribing to older people with dementia 19 Antipsychotics: risk of venous thromboembolic events 20 Prescribing clozapine – cautions and mandatory monitoring of FBC 22 Clozapine associated gastroinstestinal hypomotility / obstruction 22 White blood cell and Neutrophil count interpretation 24 Missed clozapine dose(s) 24 Smoking and clozapine 24 Caffeine and clozapine 24 Physical health monitoring for all patients prescribed antipsychotics 25 Antipsychotic depot injections 27 Paliperidone palmitate (Xeplion®) – reports of fatalities 28 Licensed route/site of administration for antipsychotic depot injections 29

Antimanic Drugs 30 Prescribing lithium - baseline, on-going monitoring and cautions 31 Prescribing valproate – baseline, on-going monitoring and cautions 33 Prescribing lamotrigine – baseline, on-going monitoring and cautions 34

Antidepressant Drugs 35 Tricyclic and relative antidepressant drugs 35 Monoamine oxidase inhibitors – cautions 37 Selective serotonin reuptake inhibitors 39 Citalopram and escitalopram: QT interval prolongation – new maximum and daily dose restrictions 39 (including in elderly patients)

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CONTENTS PAGE Other antidepressant drugs 42

CNS Stimulants and other drugs used for Attention Deficit Hyperactivity Disorder (ADHD) 43 (CAMHS use only) Differences in extended release methylphenidate for ADHD 45 Methylphenidate: immediate- and modified-release dose equivalents (mg) 45

Antiepileptics in psychiatric disorders 46 Antiepileptic drugs (AEDs): new advice on switching between different manufacturers’ products for a 47 particular drug

Drugs used in Parkinsonism and related disorders 48 Antimuscarinic drugs used in parkinsonism 48 Drugs used in essential tremor, chorea, tics, and related disorders 48

Drugs used in Substance Dependence 49 Alcohol dependence 49 Wernicke’s encephalopathy 50 Nicotine dependence 52 NRT: Patches, lozenges, Inhalator, Nasal Spray – Dosing schedules 52 NICE guidance on smoking cessation 54 NICE guidance on pharmacotherapies for smoking cessation 55 Opioid dependence 56 Methadone and buprenorphine for the management of opioid dependence (TA114) 56

Drugs used in dementia (old age psychiatry only) 57 MHRA Drug Safety Update: Memantine Pump, Rivastigmine transdermal patch 57

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CONTENTS PAGE Appendix 1 Prescribing in Children and Adolescent Mental Health Services (CAMHS) 60 Appendix 2 2a Drugs used outside of the UK Marketing Authorisation 62 2b List of NELFT approved unlicensed medicines [Unlicensed indication] 65 2c Medicines available as a Special-order (‘Specials’) 67 Appendix 3 Clozaril Patient Monitoring Service (CPMS) Registration Forms – links 68 Appendix 4 4a Example clozapine dosing schedule for in-patients with Schizophrenia – 69 CPMS 4b Example clozapine dosing schedule for in-patients with Schizophrenia – 70 Maudsley (12th Edition, 2015) Appendix 5 Plasma Clozapine and Olanzapine Assay Request Forms – links 71 Appendix 6 Calculating total daily prescribed antipsychotic dose (Adults) 72 Appendix 7 Maximum recommended/licensed antipsychotic doses (Adults) 73 Appendix 8 Haloperidol: Oral and Intramuscular equivalent doses for rapid control of 74 Severe Acute Psychomotor Agitations associated with Psychotic Disorder or manic episodes of Bipolar 1 Disorder Appendix 9 9a Psychotropic drugs and cytochrome P450 (CYP) interactions 75 9b Major cytochrome based drug and food interactions 76 Appendix 10 Smoking and psychotropic drugs 78 Appendix 11 Caffeine and psychotropic drugs 79  Caffeine and psychotropic drug interactions  Caffeine content of drinks Appendix 12 New Drug Request Form 80 Appendix 13 1-monthly Paliperidone palmitate LAI (Xeplion®): Initiation or switching from 82 other depot preparations Appendix 14 Aripiprazole LAI (Abilify Maintena®): Initiation or switching from oral or other 83 depot antipsychotic preparations Appendix 15 Blank 84 Appendix 16 Olanzapine Embonate (ZypAdhera®) Long Acting Injection cautions and 85 administration guidelines Olanzapine LAI physical health observation chart 87 Appendix 17 Controlled Drugs Schedules 89 Appendix 18 Non-formulary drugs 91 Appendix 19 NELFT NICE Technology Appraisal Guidance (TAG) Adherence Check List – 93 Mental Health Services Appendix 20 NELFT Approved Psychotropic Drugs 94 Appendix 21 List of abbreviations 95 Appendix 22 22a Potential intervention to support the implementation of the MHRA safety alert 96 on the use of valproate in women of child-bearing age 22b Required safety precautions when prescribing valproate for women of child- 97 bearing age Appendix 23 Antipsychotic Dosage Ready Reckoner [Adults] 98

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Document Control Sheet Date Amendment Details Amended / Updated By

January 2013 First Edition Authored by Approved: 18th November 2014 – MHS DTG Dr Elizabeth Francis January 2014 Reviewed Dr Elizabeth Francis August 2014  Haloperidol* – new (lower) maximum dose for oral and intramuscular Dr Elizabeth administration (see Appendix 8) Francis (*Refer to the BNF/eBNF for children for dosing guidance in children and adolescents)  Nalmefene approved for initiation by substance misuse consultant  Topiramate approved for third line use in alcohol dependency, initiation by substance misuse consultant; prescribing responsibility retained within NELFT [Off-Label/unlicensed use]  Quetiapine XL status changed to “Non-formulary”  New legal status of: o Zaleplon – POM to Schedule 4 Part 1 Controlled Drug (CD Benz POM) o Zopiclone – POM to Schedule 4 Part 1 Controlled Drug (CD Benz POM) o Tramadol – POM to Schedule 3 Controlled Drug (CD No Register POM); but exempt from Safe Custody Regulations  Aripiprazole IM Depot injection (Abilify Maintena®) – Named-patient use only  Intranet links updated for new/updated NELFT Intranet website

October 2014 New NICE Clinical Guideline: Psychosis and Schizophrenia in adults: Dr Elizabeth treatment and management (CG178 March 2014): Francis  Monitoring and cautions for all patients prescribed antipsychotic drugs, including cautions in hepatic and renal impairment

October 2014 New NICE Clinical Guideline: Bipolar disorder: the assessment and Dr Elizabeth management of bipolar disorder in adults, children and young people in Francis primary and secondary care (CG185 September 2014) & new BNF updates (electronic BNF October 2014):  Lithium monitoring  Valproate monitoring and cautions, including stopping valproate if there is abnormal liver function  Lamotrigine monitoring and cautions

November  Summary table for antipsychotic physical health monitoring added Dr Elizabeth 2014  Updated NICE Technology Appraisals and Clinical Guidelines integrated Francis into relevant sections  Discontinued drugs removed from document: o Clopixol Acuphase 100mg/2mL o Depixol Depot 100mg/mL, 0.5mL ampoule  Forms in appendices updated – New Chair of the DTG  Lisdexamfetamine (Elvanse®) included for ADHD [Schedule 2 CD POM]

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December  Aripiprazole depot approved for inclusion in the formulary Dr Elizabeth 2014  Paliperidone depot (Xeplion®) Initiation/Switching Form updated (Appendix Francis 13)  Aripiprazole depot (Abilify Maintena®) Initiation/Switching Form added (Appendix 14) January 2015  Updated guidance on the prescribing of high dose combination Dr Elizabeth antipsychotics (Summary of The Royal College of Psychiatrists Francis recommendations on the use of high dose antipsychotics, 2014)  Paliperidone palmitate (Xeplion®) – additional safety information included for the prescribing of paliperidone depot and risk of death  Citalopram and escitalopram: QT interval prolongation (p39) – new sections included: o Drug interactions o Guidance on monitoring o Link to full MHRA guidance  Updated guidance reference added: Guidance on the Administration to Adults of Oil-based Depot and other Long-Acting Intramuscular Antipsychotic Injections (February 2014, 4th Edition)  Appendix 6 – Calculating total daily prescribed antipsychotic doses – updated with new Haloperidol maximum daily dose March 2015  Forms in appendices updated – New Chair of the DTG Dr Elizabeth  Registration forms in the appendices updated Francis  Pipotiazine Palmitate (Piportil Depot®) removed from formulary due to national unavailability August 2015  Items added following DTG approval – Nicotine Replacement Therapy: Dr Elizabeth o Nicorette® Inhalator* Francis o Nicorette® Nasal Spray* *There must be service user engagement with the NELFT smoking cessation nurse/team before prescribing the inhalator or nasal spray  Forms in appendices updated  Prices updated  Hyperlinks to NICE clinical guidelines updated  Hyperlinks to new CPMS documents added  New NELFT logo added September  Links for the following medicines guidance and Patient Information Leaflets Dr Elizabeth 2015 added: Francis o Switching patients from Quetiapine XL to Quetiapine IR o Switching patients from Piportil (Pipotiazine Palmitate) depot to 15/09/15: alternative oral or depot preparation Presented to the  Paliperidone LAI Initiation/Switching Form amended MHS D & T Group  Link to the MHRA Yellow Card reporting scheme added for approval of  Link to a publicly available web calculator implementing a Qthrombosis amendments to algorithm* added date – APPROVED

December  Reference to BNF chapters amended to state “eBNF” to reflect changes in Dr Elizabeth 2015 the new printed copy of the BNF (September 2015 – March 2016, BNF 70). Francis The printed copy of the BNF no longer has numeric categories for the

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chapters. The electronic BNF continues to indicate numeric categories  Shared care guidelines updated – references updated: o Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents: Methylphenidate (Ritalin TM, Equasym TM, Equasym XL TM, Medikinet TM, Medikinet XL TM, Concerta XL TM), Dexamphetamine (Dexedrine TM) and Atomoxetine (Strattera TM). Shared Care Guideline by Dr Manas Sarkar. July 2015 version o Shared care guidelines on Melatonin for sleep disorders/ difficulties in children (NELFT). July 2015 version o Management of medications for Alzheimer’s disease. May 2015 version  Added reference to the new NICE Guideline 10 (Violence and aggression: short-term management in mental health, health and community settings, May 2015)  Added reference to the Community Initiation of Clozapine (Clozaril) Policy  Added updated NICE reference: Smoking: acute, maternity and mental health services  Appendix 15 – Application form for requesting use of an Unlicensed Medicinal Product updated. The updated form should be read in conjunction with the new process: “Use of an unlicensed medicinal product” (appended to the NELFT Medicines Policy) February 2016  New NELFT logo added Dr Elizabeth  Hyperlinks added where NELFT policies and medicines guidance cited Francis  Reviewed and updated the Introduction chapter  Hyperlink added to section e4.10.2 for the NELFT Smoking Cessation Guidance  Added additional information for Rivastigmine patch in section e4.11: EXELONPATCH - Patch Tracker: A guide to when and where to place the patch  Appendix 2b updated (List of NELFT approved unlicensed medicines)  New Appendix 4b added: Example clozapine dosing schedule for in- patients with Schizophrenia – The Maudsley Prescribing Guidelines in Psychiatry (12th Edition, 2015)  Appendix 6 – Antipsychotic Depot preparation table updated (Piportil depot no longer available)  Paliperidone LAI and Aripiprazole LAI Switching/Initiation forms updated (Appendices 13 and 14 respectively)  New Appendix 19 added: NELFT NICE Technology Appraisal Guidance (TAG) Adherence Check List – Mental Health Services  Added the update on Aripiprazole depot injection (section e4.2.2): The European Medicines Agency (EMA) approved the use of the deltoid muscle as a new injection site for Abilify Maintena. The product was previously approved for injection in gluteal muscle only. Manufacturer’s (OTSUKA) advice:  The Gluteal Only Pack should be only used in accordance with the Patient Information Leaflet enclosed in the pack  The Gluteal Only Pack does not contain needles suitable for deltoid injection and should not be used for deltoid injection

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 Health Care Professionals should not use needles from other sources for the purpose of either gluteal or deltoid injection  New Technology Appraisal Guidance (TAG) approved for use in NELFT by the MHS DTG (January 2016): TA367 (Vortioxetine for treating major depressive episodes) – added to the Formulary March 2016  Appendix 9 update: Dr Elizabeth o Psychotropic Drugs in Cardiovascular Disease (Relative risks, Francis Interactions, Cautions and contraindications)* removed, and, Governance Lead o Replaced with Psychotropic drugs and cytochrome P450 (CYP) Pharmacist, Head of interactions: Clinical Audit & NICE – 9a: Psychotropic drugs and cytochrome P450 (CYP) interactions March 2016: – 9b: Major cytochrome based drug and food interactions Presentation to the MHS Drugs & *The Summary of Product Characteristics for individual drugs should be Therapeutics Group consulted for the most up to date information (DTG) for approval of amendments to date

June 2016  Guanfacine (Intuniv®) been added to the Formulary following agreement Dr Elizabeth by the MHS DTG. Guanfacine may be prescribed under the following Francis conditions [under specialist supervision]: Governance Lead o 3rd line monotherapy option for prescribing in ADHD Pharmacist, Head of o To be prescribed on a named patient basis only Clinical Audit & NICE o Requests for prescribing Guanfacine to be emailed to the Chair of the

DTG for approval before initiation of therapy  Reference to the new NICE guidance on controlled drugs added: Controlled drugs: safe use and management. NICE guideline 46; Published: 12 April 2016

 NRT section updated – link to the new NELFT Smoking Cessation guidance added

July – August  Lurasidone (Latuda) Tablets [Latuda is indicated for the treatment of Dr Elizabeth 2016 schizophrenia in adults aged 18 years and over] Francis o Non-formulary Governance Lead o Named patient prescribing only Pharmacist, Head of  Reference to the following guidance updated following publication of the Clinical Audit & NICE 2016 edition: “Guidance on the Administration to Adults of Oil-based Depot and other Long-Acting Intramuscular Antipsychotic Injections”, 5th Edition (June 2016)  Warning about clozapine and associated gastrointestinal hypomotility reinforced following two recent publications (Every-Palmer et al, February 2016; Shirazi et al; June 2016)  Appendix 9a updated – specific antipsychotic-CYP interactions added  Form for the Request to use an Unlicensed Medicinal Product removed (to be added to the SOP) o Readers to refer to the NELFT Medicines Policy and Processes  Section on valproate prescribing updated following the MHRA Drug Safety

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Alert for Prescribing valproate and risk of abnormal pregnancy outcomes (February 2016). MHRA have provided updated guidance for healthcare professionals and service users:  Booklet for Healthcare Professionals  Consultation checklist  Guide to give to patients  Card to give to patients

 Links added for new Apps for smartphones o Lithium October 2016  Presentation of the Trevicta®: 3-monthly Paliperidone Palmitate prolonged Dr Elizabeth release suspension for injection document to the DTG – to note following Francis outcome: Governance Lead  Trevicta to remain non-formulary in the Trust Pharmacist, Head of  Initiation requires authorisation from the Chair of the DTG Clinical Audit & NICE December  Melatonin for insomnia in patients over the age of 55 Dr Elizabeth 2016 o Following discussion at the DTG meeting of December 2016, it was Francis agreed that melatonin may be used for insomnia in >55 years under Governance Lead the following conditions: Pharmacist, Head of  Alternative therapies have been ineffective Clinical Audit & NICE  Initiation is to be on a named-patient basis

 Approval for initiation is to be sought from the Chair of the DTG

February 2017  Section headings adapted to align with the new BNF format Dr Elizabeth  Update on indicated drug cost Francis  Paliperidone LAI initiation/switching form updated to include the Governance Lead requirement for indicating serum prolactin status [Appendix 13] Pharmacist, Head of Clinical Audit & NICE

August 2017  Asenapine sublingual tablets (Sycrest) added to antipsychotic section Dr Elizabeth  Licenced for use in bipolar disorder Francis  Updated information on valproate following the Patient Safety Alert Governance Lead received from MHRA / NHS Improvement in April 2017: Pharmacist, Head of  Resources to support the safety of girls and women who are being Clinical Audit & NICE treated with valproate, April 2017 https://improvement.nhs.uk/uploads/documents/Patient_Safety_Alert_- _Resources_to_support_safe_use_of_valproate.pdf

 https://www.gov.uk/government/publications/toolkit-on-the-risks-of- valproate-medicines-in-female-patients

 Two appendices (Appendices 22a and 22b) added for the following intervention documents published by POMH relating to QIP 15: Prescribing valproate for bipolar disorder  Potential intervention to support the implementation of the MHRA safety alert on the use of valproate in women of child-bearing age  Required safety precautions when prescribing valproate for women of child-bearing age. Document contains links for the following resources:

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• Booklet for healthcare professionals: http://www.medicines.org.uk/emc/RMM.420.pdf • Information for patients: http://www.medicines.org.uk/emc/RMM.421.pdf • A consent form incorporating a checklist: http://www.medicines.org.uk/emc/RMM.423.pdf • Cards to give to patients: the MHRA have made available ‘Valproate alert cards’ which pharmacy should routinely supply with outpatient prescriptions and TTOs for valproate for women age 50 years or younger: http://www.medicines.org.uk/emc/RMM.422.pdf

8th September  Following launch of the New BNF & BNFC App, link to download the new Dr Elizabeth 2017 App updated in this document Francis o New App is a combined BNF and BNFC App Governance Lead o The App includes a robust interactions checker that makes identifying Pharmacist, Head of potentially serious issues between combinations of drugs quick and Clinical Audit & NICE simple

 New Appendix [23] added o Appendix 23 Antipsychotic Dosage Ready Reckoner [Adults] September 2017: Presented to the  Following narrative added to the Antipsychotic Drugs section of this MHS Drugs & document: Therapeutics Group Rationale for prescribing Clopixol Acuphase [Zuclopenthixol Acetate] (DTG) for approval of must be documented, citing one of the following reasons: amendments to date – Approved 12/09/17 o It is clearly expected that the patient will be disturbed/violent over an extended period of time o A patient has a past history of good and timely response to Zuclopenthixol Acetate injection o A patient has a history of repeated parenteral administration o An advance decision has been made indicating that this is a treatment of choice

 Requirement for ECG and use of haloperidol reinforced with the following narrative: o Recent ECG [within last 3 months] must be available prior to haloperidol use o If patient refuses, document refusal AND include a statement on risk- benefit of haloperidol administration

 Statement added to the Antipsychotic Drugs section in this document, alerting clinicians that the maximum dose for the haloperidol injection in the SmPC differs from that in the BNF o BNF: Maximum dose of Haloperidol injection 12mg/24h o SmPC: Maximum dose of Haloperidol injection 18mg/24 15th September  Appendix 23 updated with the new version [6.1] of the Antipsychotic Dr Elizabeth 2017 Dosage Ready Reckoner Francis Governance Lead Pharmacist, Head of Clinical Audit & NICE

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12th November  Haloperidol* - dosage recommendations have changed and vary according Sushma Lau 2018 to the clinical indication (see Appendix 8) Deputy Chief (Refer to the ‘BNF/eBNF for Children’ for dosing guidance in children and Pharmacist (MHS) adolescents). – - Appendix 6 (calculating total daily prescribed antipsychotic doses) – – removed haloperidol from table to reflect the above.

 Valproate – updated following MHRA Drug Safety Alert – April 2018. Included the link to the NELFT guidelines.

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1.0 Introduction

1.1 The purpose of this “Formulary” is to detail psychotropic medicines that may be prescribed within the Trust, and includes medicines prescribed for related mental health problems

1.2 The drugs in the Formulary have been assessed by the Drug & Therapeutics Group (DTG) on the basis of their efficacy and safety to promote rational and economic prescribing. This includes prescribing for outpatients on Trust FP10 prescription forms.

1.3 Non-Formulary Drugs

It is recognised that the prescribing of non-formulary drugs may occasionally be unavoidable:  When a patient already taking a non-formulary drug is admitted to hospital and it would be inappropriate to change therapy  When a consultant wishes to use a non-formulary drug, where there is no suitable equivalent in the formulary

Pharmacy should be contacted, and a small supply will be obtained for that specific patient. There may be a short but unavoidable delay in obtaining the drug from the supplier.

1.4 . The formulary is intended for use in conjunction with the British National Formulary (BNF) and drugs are classified accordingly with the name, strengths and formulation of each drug being specified. Where local guidelines/guidance for drug usage are available, links are provided

1.5 The Formulary is arranged in the treatment section headings outlined in Table 1.

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Table 1 Formulary Section Headings

Treatment Section Headings Hypnotics and Anxiolytics Drugs used in psychoses and related disorders:  Antipsychotics – typical and atypical  Antipsychotic depot injections  Antimanic drugs Antidepressant drugs CNS stimulants and drugs used for attention deficit hyperactivity disorder Antiepileptic drugs:  Carbamazepine and valproate used in mood disorders  Clonazepam Drugs used in parkinsonism and related disorders:  Anti-muscarinic drugs used for antipsychotic-induced movement disorders Drugs used in substance dependence  Alcohol dependence  Nicotine dependence  Opioid dependence Drugs for dementia

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1.6 This formulary includes:  Psychotropic drugs approved for use in NELFT  Medicines formulations available  Guidance on physical health monitoring requirements for patients prescribed psychotropic medicines (refer to NICE guidance for full details)  Guidance on prescribing in Children and Adolescents (CAMHS: Appendix 1)  Guidance on prescribing drugs outside of the UK Marketing Authorisation ( Appendix 2)  List of NELFT approved unlicensed medicines (Appendix 2b)  Guidance on prescribing Clozaril (Clozapine) and registration with the Clozaril Patient Monitoring Service – CPMS (Appendices 3 and 4)  Psychotropic drugs in cardiovascular disease – cautions and contraindications (Appendix 9). Note that this list is not exhaustive  Information on Controlled Drugs Schedules (Appendix 17)  Medicine safety information from the MHRA and NPSA  Reference and links to the NICE Clinical Guidelines, Technology Appraisals and other relevant NICE documents  NICE Technology Appraisal Guidance Adherence check list (Appendix 19)

1.7 For details on prescribing information, refer to the latest editions/versions:  British National Formulary (BNF) and BNF for Children (BNFC). Online access via Medicines Complete (using Athens login details): http://w ww.medicinescomplete.com/mc/

 NICE BNF and BNFC App is available for Android and iPhone smartphones https://www.nice.org.uk/news/article/new-improved-bnf-and-bnfc-app-launched

 The Maudsley Prescribing Guidelines in Psychiatry. Online access via Medicines Complete (using Athens login details)

 Summary of Product Characteristics

 NICE guidance app available for Android and iPhone smartphones https://www.nice.org.uk/about/what-we-do/nice-apps-for-smartphones-and-tablets

Other useful links:  Downloadable medicines information and leaflets for staff, carers and patients: Choice and Medication website  MHRA Yellow Card Scheme including the Yellow Card Scheme apps available for Android and iPhones

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2.0 Principles

2.1 The overall responsibility for Formulary development will rest with the Drugs and Therapeutics Group (DTG), which reports to the Executive Management Team

2.2 Systems will be evidence-based and take account of the cost implications for both Primary and Secondary Care.

2.3 For non-psychotropic medication NELFT will use NICE and BNF guidances.

2.4 Treatment guidelines should reflect and incorporate the Formulary.

3.0 Formulary Management

Much of this work will be undertaken by Pharmacy on behalf of the DTG and NELFT. 3.1 Formulary Implementation

3.1.1 The Formulary applies to all prescribers and prescribing in the Trust whether on hospital, clinic or other premises.

3.1.2 The Trust Formulary is applicable to all patients.

3.1.3 Prescribing should be by generic drug name unless a particular preparation has to be prescribed by brand name due to differences in bioavailability. Drugs to be prescribed by brand name are identified in the BNF.

3.1.4 Patients admitted on non-Formulary medication may continue to be prescribed them if appropriate except where substitution policies have been agreed, e.g. iron and calcium supplements, laxatives.

3.1.5 Recommendations regarding medication made to other Trust staff and healthcare professionals external to the organisation, e.g. GPs, acute Trust prescribers, will be in accordance with this policy and with the Responsibility for Prescribing shared between Primary and Secondary Care Policies/procedures.

3.1.6 Pharmacy staff will query prescribing which is outside the Formulary and recommend alternatives from the Formulary. Prescribers are required to prescribe from the Formulary unless there is a good clinical reason for choosing non-Formulary medication. Rationale for prescribing non-Formulary items should be documented in the electronic patient records (RIO).

3.1.7 Implementation of the Trust formulary will be monitored by Pharmacy

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 Pharmacy will monitor:  Use of FP10 prescriptions  Medication supply on FP10 not to exceed 14-days  Prescribing of drugs from the North East London Medicines Management working group ‘Red List’ – drugs not to be prescribed by General Practitioners (GPs), for example, Paliperidone Palmitate long acting depot injection

 Some of the older drugs have been removed from the Trust Formulary due to lack of use. These drugs can still be prescribed.

3.2 Request for additions/changes to the Formulary

3.2.1 All requests for additions or changes to the Formulary must be made by a Consultant Psychiatrist to the Chair of the Drugs and Therapeutics Group (DTG) on the New Drug Request form (Appendix 12).

3.2.2 A consultant may prefer to evaluate a new product before requesting its inclusion in the formulary.

3.2.3 Pharmacy will undertake a formal evaluation of the available evidence associated with the requested medication. The evaluation will be based on information from clinical trials, peer reviewed journals and meta analyses where possible and include:

. Clinical efficacy and toxicity . Relevant NICE or other expert opinions . Cost implications for Secondary and Primary care . Other considerations, for example, licence status, medico-legal issues, status in other Mental Health trusts.

3.2.4 The DTG will use the evaluation as the basis of its decision-making and consider both the clinical effectiveness of the medication and the financial implications for the Trust and Primary Care if appropriate. Where there are medico-legal or significant clinical risk issues the DTG may seek legal advice and/or refer the matter to the Executive Medical Director.

3.2.5 The DTG will not authorise addition to the Formulary until it is satisfied that both clinical and financial issues have been addressed. This could include:

. A prescribing protocol/guideline . Primary/secondary care shared-care guidelines . Identification of funding

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3.2.6 Appeals

If a consultant wishes to appeal against a DTG decision with regard to a New Drug Request (s)he should follow the following process.

a) Write to the Chair of the DTG requesting that the DTG re-consider its decision and include reasons and additional evidence where available.

b) If the DTG confirms its original decision and the consultant still wants to use the medication (s)he will be invited to present the case.

c) Written grounds of any appeal and supporting information/evidence will be provided in advance of a Group meeting and should/will be limited to those relating to the original request.

d) The appeal panel will comprise the following:

 Executive Medical Director  DTG Chair  Chief Pharmacist

3.3 Funding issues

3.3.1 It is necessary to have a system for dealing with the significant financial implications associated with the introduction of a new medication/formulation or new indication.

3.3.2 Consultants are encouraged to participate in the forward planning process as described in section 3.4, especially if they are planning changes to their service provision in their area of work.

3.3.3 Lack of funding may delay the introduction of a new drug until prescribing guidelines are developed and funding identified.

3.4 Forward planning

3.4.1 This is a process which takes place in one financial year and attempts to estimate the impact of new medicines and therapeutic developments in the following, and subsequent, financial years.

3.4.2 The process will be led annually by Pharmacy and will involve clinicians through the Clinical Directors.

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3.4.3 Pharmacy will identify developments in medication and therapeutics, which will potentially impact on the Trust in the following financial year (and where possible the subsequent two years). This will be done using a variety of sources:

. Medicines Information Service Horizon Scanning documents . NICE Work Programme . NELFT business planning process . Identified service developments . Specialist (mental health) networks

3.4.4 This work will be shared with the directorates in order to determine likely take-up and impact in NELFT, i.e. potential patient numbers and cost implications and determine priorities.

3.4.5 During the process the Finance Directorate and DTG will be informed of progress.

3.4.6 It is, therefore, likely that the highest priority will be given to NICE and NSF associated medication and that other therapeutically important treatments and developments and generic cost pressures will not be funded through the forward planning process. It therefore follows that Directorates must identify medication related cost pressures when changing and developing services and in their business planning processes so that funding can potentially be secured in other ways.

3.4.7 For expensive therapies Pharmacy will, where possible, track expenditure through its computer record and present trends to the clinician on request and appropriate financial and governance staff.

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3.5 Drug price ranges

The list of drugs in the Formulary includes information on the price of the drugs.

Cost of drugs is based on prices from:

 Electronic Drug Tariff (February 2017) http://www.drugtariff.nhsbsa.nhs.uk/#/00232686-FA/FA00232236/Home

 Electronic BNF (January 2017) https://www.medicinescomplete.com/mc/bnf/current/

 Costing based on average cost of 28 days of treatment  Where drug is to be used on a ‘when required’ basis, costing is for average doses for 28 days treatment  Where cost has been provided, this should be used as a guide for cost implications  Where cost has been omitted, it is not applicable for comparative costing

3.6 Relevant policies and procedures

 NELFT Benzodiazepine and Z-Hypnotics Prescribing Policy (2015)

 NELFT High Dose Antipsychotic Prescribing Policy (2015)

 NELFT Medicines Policy (2016)

 NELFT Medicines Standard Operating Procedure (main body of the procedure) (Expiry date Mar 2019)

o Medicines Standard Operating Procedure (processes 1-45 listed as appendices)

 NELFT NICE Guidance Implementation Policy

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List of drugs

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Central Nervous System

Hypnotics and Anxiolytics

Hypnotics

Drug Class Drug Name Formulations Costing £ Benzodiazepines Temazepam  Tablets 10mg, 20mg 1 – 5 (Schedule 3 Controlled Drug)

CD  Oral Solution 100 – 150 10mg/5mL Non–benzodiazepine: Zopiclone Tablets 3.75mg, 7.5mg 1 – 5 Z-Drug (Schedule 4-1 Controlled Drug) Non–benzodiazepine: Zolpidem Tartrate Tablets 5mg, 10mg 1 – 5 Z-Drug (Schedule 4-1 Controlled Drug) Clomethiazole Clomethiazole Capsules 192mg 30 – 50 (older adults) Antihistamines Promethazine  Tablets 10mg, 25mg 5 – 10 Hydrochloride  Elixir 5mg/5mL 30 – 50  Injection 25mg/mL -

MHRA Advice  Benzodiazepines should be used to treat insomnia only when it is severe, disabling, or subjecting the individual to extreme distress.

NICE Recommendation on the use of Z-Drugs (TA77 2004):  When hypnotic drug therapy is considered appropriate for the management of severe insomnia interfering with normal daily life, it is recommended that hypnotics should be prescribed for short periods of time only, in strict accordance with their licensed indications.

 It is recommended that, because of the lack of compelling evidence to distinguish between zaleplon, zolpidem, zopiclone or the shorter acting benzodiazepine hypnotics, the drug with the lowest purchase cost (taking into account daily required dose and product price per dose) should be prescribed.

 It is recommended that switching from one of these hypnotics to another should only occur if a patient experiences adverse effects considered to be directly related to a specific agent. These are the only circumstances in which the drugs with the higher acquisition costs are recommended.

 Patients who have not responded to one of these hypnotic drugs should not be prescribed any of the others.

NICE technology appraisal guidance 77 (April 2004): Guidance on the use of zaleplon, zolpidem and zopiclone for the short-term management of insomnia

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Practice points No patient should be discharged on a hypnotic except those classified as established chronic users prior to admission, i.e. no new long-term users should be created as a result of hospital initiated treatment.

Schedule 3 and 4 Controlled Drugs (CDs)

 Schedule 3 (CD3 No Register POM) o Include the barbiturates (except secobarbital, now Schedule 2), buprenorphine, diethylpropion, mazindol, meprobamate, midazolam, pentazocine, phentermine, temazepam, Tramadol o Are exempt from safe custody requirements and can be stored on the open dispensary shelf except for temazepam, buprenorphine and diethylpropion, which must be stored in a locked CD receptacle o Are subject to the same special handwriting requirements as Schedule 2 CDs, except for temazepam and phenobarbital. Phenobarbital and temazepam can be dispensed in response to a computer-generated prescription but the prescriber’s signature must be added by hand o There is no legal requirement for records of receipt or administration of Schedule 3 drugs to be kept in the Ward Controlled Drugs Record Book but may be enforced at the discretion of the Accountable Office

Schedule 3 Controlled Drugs treated as full CDs (i.e. as for Schedule 2 CDs) in NELFT, and include:  Phenobarbitone (Schedule 3 Controlled Drug)  Temazepam (Schedule 3 Controlled Drug)  Tramadol (Schedule 3 Controlled Drug)

Schedule 3 Controlled Drug Midazolam Oromucosal Solution (for status epilepticus) is to be treated as a full CD in regards to ordering, storage and daily stock checks but will be exempt from the requirement for two signatures during administration.

Note - Morphine sulphate 10mg/5mL oral solution (Oramorph®) (POM) is treated as a full CD in NELFT

 Schedule 4, Part I (CD Benz) and Part II (CD Anab) o Are exempt from safe custody requirements, with destruction requirements only applying to importers, exporters and manufacturers. o Specific CD prescription-writing requirements do not apply. o CD registers do not need to be kept, although records should be kept if such CDs are produced, or if a licensed person imports or exports such drugs.  Part 1: benzodiazepines (except temazepam and midazolam, which are in Schedule 3) and Zaleplon, Zolpidem, Zopiclone, which are subject to minimal control:  Includes most of the benzodiazepines, plus eight other substances including fencamfamin and mesocarb.  Possession of is an offence without an appropriate prescription  Possession by practitioners and pharmacists acting in their professional capacities is 11isperidon.  Part 2 includes androgenic and anabolic steroids, clenbuterol, human chorionic gonadotrophin (hCG), non-human chorionic gonadotrophin, somatotropin, somatrem, and somatropin:  Includes most of the anabolic and androgenic steroids such as testosterone, together with clenbuterol (adrenoreceptor stimulant) and growth hormones.  There is no restriction on the possession when it is part of a medicinal product

 Refer to the NICE guidance on controlled drugs: Controlled drugs: safe use and management. NICE guideline 46; Published: 12 April 2016 https://www.nice.org.uk/guidance/ng46

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Anxiolytics

Drug Class Drug Name Formulations Costing £ Benzodiazepines Diazepam  Tablets 2mg, 5mg, 5 – 10 (Schedule 4-1 Controlled Drug) 10mg  Oral solution 300 – 350 2mg/5mL Chlordiazepoxide Capsules 5mg, 10mg 30 – 50 (Schedule 4-1 Controlled Drug) Lorazepam  Tablets 1mg 30 – 50 (Schedule 4-1 Controlled Drug)  Injection 4mg/mL - Oxazepam Tablets 10mg, 15mg 10 – 30 (Schedule 4-1 Controlled Drug) Benzodiazepine Clonazepam Tablets 500microgram, 30 – 50 antiepileptic (Schedule 4-1 Controlled Drug) 2mg Buspirone Buspirone Tablets 5mg, 10mg 10 – 20 Antihistamine Hydroxyzine  Tablets 10mg, 25mg 1 – 5

MHRA Advice

 Benzodiazepines o The use of benzodiazepines to treat short-term ‘mild’ anxiety is inappropriate and unsuitable. o Benzodiazepines are licensed for the short-term (2 – 4 weeks) relief of anxiety only when it is severe, disabling, or subjecting the individual to extreme distress.

 Lorazepam: reduction of recommended maximum daily dose (Drug Safety Update October 2007; 1, Issue 3: 8) o Maximum dose of lorazepam for short term, symptomatic treatment is 4 mg per day for severe, disabling anxiety, and 2 mg per day for severe, disabling insomnia

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Practice points

 Long-term use of benzodiazepines should be avoided  No patient should be discharged on a benzodiazepine except those classified as established chronic users prior to admission, i.e. no new long-term users should be created as a result of hospital initiated treatment  Patients on long-term benzodiazepines should not have their treatment discontinued abruptly.  Withdrawal should be very gradual – follow BNF guidance on withdrawal of benzodiazepine

Benzodiazepines: Approximate equivalent doses to diazepam Benzodiazepine Approximate dose (mg) equivalent to 10 mg Diazepam Chlordiazepoxide 25 mg Clonazepam 1 – 2 mg Lorazepam 1 mg Nitrazepam 10mg Oxazepam 30 mg Temazepam 20 mg Source: The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition (2015)

 Note that this is only a guide  Patients must be monitored closely  Doses used must be within BNF maximum limits  Additional information can be found on: http://www.nta.nhs.uk/uploads/clinical_guidelines_2007.pdf

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Drugs used in psychoses and related disorders

Antipsychotic drugs

First-generation antipsychotic drugs Drug Class Drug Name Formulations Costing £ Butyrophenone Benperidol (Anquil®)  Tablet 250 microgram 150 – 200 Control of deviant antisocial sexual behaviour Phenothiazine, Chlorpromazine  Tablets 25mg, 50mg, 5 – 30 Group 1 Hydrochloride 100mg

 Oral solution 25mg/5mL, 10 – 30 100mg/5mL

 Injection 25mg/mL 50 - 100  Suppositories 25mg, Contact 100mg (Special-order) Pharmacy Phenothiazine, Promazine  Tablets 25mg, 50mg 150 – 200 Group 1  Oral solution 25mg/5mL 200 – 300  Oral solution 50mg/5mL Phenothiazine, Trifluoperazine  Tablets 1mg, 5mg Contact Group 3 Pharmacy  Oral solution (SF) 100 – 150 5mg/5mL Butyrophenone Haloperidol*  Tablets 500 microgram, 10 – 30 1.5mg, 5mg, 10mg, 20mg  Oral liquid SF 2mg/mL  Injection 5mg/1ml - Thioxanthene Flupentixol (Depixol®) Tablets 3mg 10 – 50 Thioxanthene Zuclopenthixol Tablets 2mg, 10mg, 25mg 10 – 30 Dihydrochloride (Clopixol®) Thioxanthene Zuclopenthixol Injection 50mg/mL (2mL 10 – 40 Acetate (Acuphase®)* ampoule) Substituted Sulpiride  Tablets 200mg, 400mg 10 – 40 benzamides  Oral solution SF 50 – 150 200mg/5mL * Rationale for prescribing Clopixol Acuphase must be documented, citing one of the follow ing reasons: . It is clearly expected that the patient w ill be disturbed/violent over an extended period of time . A patient has a past history of good and timely response to Zuclopenthixol Acetate injection . A patient has a history of repeated parenteral administration . An advance decision has been made indicating that this is a treatment of choice

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*Haloperidol – BNF maximum dose: Recommendation has changed.  The dosage recommendations for haloperidol in the British National Formulary have changed and vary according to the clinical indication. Users should now refer to the electronic version of the BNF for the maximum dose of haloperidol for the relevant treatment indication.

 Refer to Appendix 8 for calculating total daily dose of combined oral and intramuscular haloperidol for adults

 Elderly or debilitated patients or those with previous adverse reactions to neuroleptic agents may require less haloperidol and half the normal starting dose may be sufficient for therapeutic purpose. In such patients, the optimum response is usually achieved with more gradual titration and at lower dose levels.

 Refer to the eBNFC for dosing guidance in children

Refer to the Haloperidol SmPC for further information

Haloperidol and ECG  Baseline ECG is recommended prior to treatment in all patients, especially in the elderly and patients with a positive personal or family history of cardiac disease or abnormal findings on cardiac clinical examination  Recent ECG [within last 3 months] must be available prior to haloperidol use  If patient refuses, document refusal AND include a statement on risk-benefit of haloperidol administration  During therapy, the need for ECG monitoring (e.g. at dose escalation) should be assessed on an individual basis  Whilst on therapy, the dose should be reduced if QTc is prolonged, and haloperidol should be discontinued if the QTc exceeds 500 ms  Periodic electrolyte monitoring is recommended, especially for patients taking diuretics, or during intercurrent illness  Refer to the full SmPC for further informational, taking note that the maximum dose for the haloperidol injection in the SmPC differs from that in the BNF: https://www.medicines.org.uk/emc/medicine/23005

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Second-generation antipsychotic drugs Drug Class Drug Name Formulations Costing £ Atypical antipsychotics Amisulpride  Tablets 50mg, 10 – 40 100mg, 200mg, 400mg

 Solution 100mg/mL 50 – 150 (Solian®) Aripiprazole*  Tablets 5mg, 10mg, 5 – 30 15mg, 30mg

 Orodispersible tablets 50 - 100 10mg, 15mg

 Oral solution 1mg/mL 100 – 600

 Injection 7.5mg/mL - Asenapine (Sycrest®)  Sublingual tablets 100 - 150 Licensed for bipolar disorder Clozapine  Tablets 25mg, 100mg 10 – 50 (Clozaril®) (Consultant  Suspension Contact prescribing only) 100mg/5mL (‘Special Pharmacy order’) Olanzapine  Tablets 2.5mg, 5mg, 7.5mg, 10mg, 15mg, 1 – 5 20mg

 Orodispersible tablets 1 – 5 5mg, 10mg, 15mg, 20mg

 Injection 5mg/mL - Quetiapine**  Tablets 25mg, 5 – 10 100mg, 150mg, 200mg, 300mg Risperidone  Tablets 500 1 – 5 micrograms, 1mg, 2mg, 3mg, 4mg, 6mg

 Orodispersible tablets 50 – 200 0.5mg, 1mg, 2mg, 3mg, 4mg

 Liquid 1mg/mL 10 – 20 *NICE Technology Appraisal 213

**Switching patients from Quetiapine XL to IR – guidance and PIL. These documents can be accessed via the Pharmacy intranet site

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Summary of The Royal College of Psychiatrists (2014) recommendations on the use of high dose antipsychotics http://www.rcpsych.ac.uk/files/pdfversion/CR190.pdf

“The key recommendation is that any prescription of high-dose antipsychotic medication should be seen as an explicit, time-limited individual trial with a distinct treatment target. There should be a clear plan for regular clinical review including safety monitoring. The high-dose regimen should only be continued if the trial shows evidence of benefit that is not outweighed by tolerability or safety problems.”

Refer to the NELFT High Dose Antipsychotic Prescribing Policy (2015)

First-episode psychosis  There is no evidence that high-dose antipsychotic use is beneficial for patients with first-episode psychosis and such use should be avoided  Antipsychotic polypharmacy should be avoided. ‘Top up’ oral antipsychotic doses for patients on depot/long-acting injection medication should be used only as a short-term measure  Where antipsychotic response is poor, switching medication should be the preferred course of action, rather than increasing doses above BNF limits

Acute psychotic episode  For the majority of people with acute psychotic illness, the target dose for effective treatment is likely to be below the licensed maximum  Initiation of antipsychotic drug treatment in the first episode or in a subsequent untreated episode after a drug-free period should not involve starting more than one antipsychotic at the same time

Relapse prevention  There does not seem to be any justification in the published literature for the use of high dose antipsychotic medication for relapse prevention in schizophrenia.  There is no convincing evidence that incremental increase of antipsychotic dose at times of psychotic relapse, with subsequent continuation of the new, higher dose, provides better relapse prevention in the long term

Acute violence and emergency tranquillisation (refer to the NELFT Rapid Tranquillisation Policy and the NICE Guideline 10 (Violence and aggression: short-term management in mental health, health and community settings, May 2015)  Given the lack of evidence for use of high dose medication and the proven associated risks, the lowest dose compatible with effective treatment should be used and BNF maximum doses (over a 24-hour period) only exceeded in rare circumstances and with caution, increased monitoring, and the advice of a consultant psychiatrist  The indication for which any p.r.n. medication is prescribed should be explicit and clearly documented and all p.r.n. medications should be reviewed on a regular basis  Oral and intramuscular medication should be prescribed separately  As few medicines as possible should be used  The use of combinations from the same class of medicine should be avoided wherever possible  Patients should be regularly monitored for clinical benefit and side-effects from administered medication

Persistent aggression  There is no justification in the published literature for high-dose antipsychotics in the treatment of persistent aggression. Regular and frequent review of treatment plans in relevant clinical settings might allow for the safe and appropriate use of antipsychotic medication without any increase in violence  When prescribing medication to target the medium- or long-term risk of violence, the clinician should bear in mind the limited evidence and only prescribe medication after a thorough multidisciplinary assessment, risk–benefit evaluation and careful review of effects and side-effects

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Schizophrenia failing to respond to standard antipsychotic regimens  There is no convincing evidence that antipsychotic dosage higher than the maximum licensed dose is more effective than standard dosage for treatment-resistant schizophrenia.  Before resorting to high dosage, evidence based strategies for treatment-resistant illness should be exhausted, including optimised use of clozapine  If a clinician initiates a high-dose antipsychotic treatment regimen, this should be as a limited therapeutic trial, with dosage returned to conventional levels after a 3-month period unless the clinical benefits evidently outweigh the risks  The potential side-effects of high-dose antipsychotic regimens should be monitored appropriately, by systematic enquiry, physical examination, ECG and appropriate haematological investigations

Monitoring  Before prescribing high-dose antipsychotics carry out an ECG to establish a baseline, and exclude cardiac contraindications, including long QT syndromes. An ECG should be repeated after a few days and then every 1–3 months in the early stages of high-dose treatment. The ECG should be repeated as clinically indicated  Potential side effects of prescribing high dose/combination antipsychotics should be considered and include:  Extrapyramidal side effects  Neuroleptic malignant syndrome  Cardiac side effects (QTc prolongation, arrhythmia, sudden death)

See Appendix 6 for calculating cumulative antipsychotic dose when more than one antipsychotic has been prescribed

NICE clinical guideline 178: Psychosis and Schizophrenia in adults: treatment and management, issued February 2014, modified March 2014. Link to the guideline:

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Antipsychotics: initiative to reduce prescribing to older people with dementia https://www.gov.uk/drug-safety-update/antipsychotics-initiative-to-reduce-prescribing-to-older- people-with-dementia (MHRA Drug Safety Update May 2009, 2)

 There have been increasing concerns over recent years about the use of antipsychotics to treat the behavioural and psychological symptoms of dementia (BPSD). Antipsychotics are associated with an increased risk of cerebrovascular adverse events and greater mortality when used in this population. No antipsychotic (with the exception of risperidone in some circumstances) is licensed in the UK for the treatment of BPSD; however, antipsychotics are often prescribed off-label for this purpose.

 Only one antipsychotic, risperidone ▼, is licensed for treatment of dementia-related behavioural disturbances: and then only specifically for short-term (up to 6 weeks’) treatment of persistent aggression in Alzheimer’s dementia unresponsive to non-pharmacological approaches and where there is a risk of harm to the patient or others.

 Elderly people with dementia are at risk from specific serious and life-threatening side-effects when treated with antipsychotics.

 There is a clear increase in the risk of stroke with the use of the atypical antipsychotics risperidone ▼ or olanzapine in elderly people with dementia

 The balance of risks and benefits associated with risperidone treatment should be carefully assessed for every patient, taking into consideration the known increased mortality rate associated with antipsychotic treatment in the elderly. Prescribers should carefully conside r the risk of cerebrovascular events before treating with risperidone ▼ any patient who has a previous history of stroke or transient ischaemic attack. Consideration should also be given to other risk factors for cerebrovascular disease including hypertension, diabetes, smoking, and atrial fibrillation

 For prescribers considering using antipsychotics in patients without a current prescription (MHRA Drug Safety Update May 2012, 5): o Carefully consider, after a thorough clinical examination including an assessment for possible psychotic features (such as delusions and hallucinations) whether a prescription for an antipsychotic drug is appropriate

 For prescribers considering continuing antipsychotics in patients with a current prescription (MHRA Drug Safety Update May 2012 vol 5): o Identify and review patients who have dementia and are on antipsychotics, with the purpose of understanding why antipsychotics have been prescribed o In consultation with the patient, their family and carers, and clinical specialist colleagues such as those in psychiatry, establish: whether the continued use of antipsychotics is appropriate; whether it is safe to begin the process of discontinuing their use; and what access to alternative interventions is available.

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Antipsychotics: risk of venous thromboembolic events (MHRA Drug Safety Update June 2009, Volume 2, Issue 11) https://www.gov.uk/drug-safety-update/antipsychotics-risk-of-venous-thromboembolic-events

 A Europe-wide review of UK Yellow Card data and published studies on antipsychotics and the risk of venous thromboembolism (VTE; dangerous blood clots in the circulatory system) concluded that an increase in risk of VTE cannot be excluded (2009)

 Advice for healthcare professionals:  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 preventive measures undertaken  Refer to the NELFT Venous Thromboembolism Policy for further information

Useful documents and links:  A simple web calculator implementing a Qthrombosis algorithm* is publicly available: http://www.qthrombosis.org/

 MHRA Public Assessment Report: The risk of venous thromboembolism: http://www.mhra.gov.uk/home/groups/s-par/documents/websiteresources/con079334.pdf

 Pharmacy VTE guidance for MHS: http://nelftintranet/departments-and- services/medicines-management/other-medicine-related-documents.htm

*Hippisley-Cox J (2011). Development and validation of risk prediction algorithm (Qthrombosis) to estimate future risk of venous thromboembolism: prospective cohort study. BMJ; 343:d4656. Link to document: http://www.bmj.com/content/343/bmj.d4656

Practice points

Combination antipsychotics

 See Appendix 6 for calculating total daily prescribed antipsychotic dose and Appendix 7 for maximum recommended antipsychotic doses

 In the UK, The Royal College of Psychiatrists, NICE guidelines for the treatment of schizophrenia, The Maudsley Prescribing Guidelines in Psychiatry (12th Edition, 2015) and the BNF all advise against the routine prescribing of more than one antipsychotic

 Combinations are only justified in the following situations. o Where patients are being switched from one antipsychotic to another – a short (6 weeks) crossover period is acceptable o When giving a more sedating and/or injectable antipsychotic to someone who is very agitated and is already receiving another antipsychotic on a regular basis (part of Rapid Tranquilisation) o In cases where the patient is receiving clozapine but has not achieved adequate symptom control; or not tolerated clozapine due to neutropenia or agranulocytosis o Short-term/temporary measure with a depot medication during an acute exacerbation of

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the illness

 Inappropriate use of combination antipsychotics would include: o Failure to wait for an adequate period of time for the first antipsychotic to have an effect  6 months for clozapine  6 weeks for all other antipsychotics  8 weeks for depot medication o Patient may be treatment resistant and clozapine has not been tried

 Risk factors to consider o Cardiac abnormality o Glucose intolerance or diabetes o Hepatic or renal impairment o Epilepsy o Obesity o Smoking o Alcohol or illicit drug use

 Monitoring recommended for combination/high dose antipsychotics o Baseline ECG – frequently initially then every 1 – 3 months o Blood pressure – daily o Pulse – daily o Temperature – daily o Hydration status – daily o LFTs, Urea and electrolytes – weekly initially then 3-monthly when treatment stable http://www.rcpsych.ac.uk/files/pdfversion/CR190.pdf

Withdrawal of antipsychotic drugs

o Withdrawal of antipsychotic drugs after long-term therapy should be gradual and closely monitored to avoid the risk of acute discontinuation symptoms or rapid relapse

Auditing use of combination/high dose antipsychotic drugs in NELFT

 POMH-UK audits [Prescribing Observatory for Mental Health] o National audits carried out every 12 – 18 months o Co-ordinated by Dr Elizabeth Francis, Governance Lead Pharmacist, Head of Clinical Audit & NICE, POMH-UK Lead : [email protected] o POMH-UK Audit reports can be accessed via:  Following the Link: POMH-UK Final Reports  Contacting Dr Elizabeth Francis, Governance Lead Pharmacist, Head of Clinical Audit & NICE, POMH-UK Lead: Dr Elizabeth Francis

 Trustwide audits as part of the NELFT Annual Clinical Audit Programme o Benzodiazepine, Z-Hypnotics and High Dose Antipsychotic Prescribing Practice - annual audit. Contact Dr Elizabeth Francis for further details.

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Prescribing Clozapine (Clozaril®) Cautions and mandatory monitoring of FBC (Refer to the Clozaril SmPC for full details*)  Clozapine o Clozaril® is the proprietary brand used in NELFT o Clozaril Patient Monitoring Service (CPMS) manage the database for monitoring full blood counts (FBC) o The Consultant and the patient must be registered with the CPMS before Clozaril ® can be prescribed (registration forms are available on the CPMS website (https://www.clozaril.co.uk/ ) and Appendices 3 and 4; contact Pharmacy for further information) o Note that a satisfactory baseline FBC is required before Clozaril® can be safely initiated

 Suggested titration regimen o See Appendix 4 for an example dosing schedule o The Maudsley Prescribing Guidelines in Psychiatry (12th Edition, 2015) also has a titration regime o For initiating clozapine in the community (HTT, CMHT), refer to the Community initiation of clozapine (Clozaril) Policy and guidance

 Patient monitoring during dose-titration o Temperature (inform doctor if above 38°C) o Pulse (inform doctor if above 100 bpm) o Blood pressure (inform doctor if systolic drops by > 30 mm Hg) o Sedation

 Prophylactic anticonvulsant for high doses of clozapine o Consider prescribing valproate at 1000 mg – 2000 mg/day o To aid concordance, use modified release valproate (Epilim Chrono®) for once-daily administration

 Clozapine and myocarditis o Clozapine is associated with an increased risk of myocarditis which can be fatal. Risk is greatest in the first 2 months of treatment and signs include persistent tachycardia at rest and/or palpitations, arrhythmias, chest pain and other signs/symptoms of heart failure

Clozapine associated gastrointestinal hypomotility / obstruction  Clozapine’s anticholinergic properties can cause varying degrees of slowing of intestinal peristalsis ranging from constipation to intestinal obstruction, faecal impaction and paralytic ileus that may be fatal  Acute gastrointestinal obstruction is a medical emergency. Symptoms include abdominal distension, pain and vomiting. When suspected the medical team must be alerted and a surgical referral initiated if appropriate.  Fatalities resulting from clozapine-induced gastrointestinal hypomotility have been reported since at least 19951,2  Gastrointestinal hypomotility is exacerbated by co-administration of the anticholinergic drugs such as procyclidine, pirenzepine3, thereby increasing the anticholinergic burden  Risk factors include  Recent initiation of clozapine  High clozapine dose or serum level (> 0.5 mg/L) – specifically when the patient stops smoking  Concomitant anticholinergic use, e.g. tricyclic antidepressants, anti-Parkinsonian agents and other antipsychotics  Intercurrent illness  Sedentary lifestyle  Obesity  Reduced fiber intake  Dehydration  Recommendations include  Counsel patients about the risk of constipation  Question patients about their bowel movements

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 Patient education on healthy bowel habits and lifestyle may help, but for individuals without a structured routine and those not optimally controlled, monitoring for this adverse effect is essential  A patient prescribed clozapine, with or without a history of constipation, who presents with abdominal pain should be a cause for immediate concern and further investigation  Patients presenting with signs/symptoms of constipation should be managed with bulk forming laxatives, either alone or in combination with stimulant laxatives

 Mandatory monitoring of FBC o Pre-treatment FBC result is valid for 10 days o At least weekly for the first 18 weeks of treatment o At least fortnightly between weeks 18 and 52 o After 1 year of treatment with stable neutrophil counts, at 4 week intervals o Four weeks after stopping clozapine –weekly, fortnightly or 4-weekly depending on monitoring frequency

 Arrangements for carrying out full blood counts for patients prescribed clozapine in NELFT o NELFT in-patients - Attend the Clozapine clinic at Goodmayes Hospital, Wednesday of each week - Results will be sent to CPMS by the clozapine clinic o NELFT in-patients – blood taken on the ward – Blood sample to be taken (preferably beginning of the week) either: • By the ward doctor, or, • By prior arrangement with a phlebotomist in attendance at Goodmayes Hospital - Blood samples are sent to King George’s Hospital, Goodmayes - Once FBC results are available (BHR Pathology website ‘Cyberlab’), ward doctor(s) to ensure results are telephoned or faxed to CPMS  CPMS Fax number during normal working hours: 0845 769 8379/8541  CPMS Telephone number • 0845 769 8269 (normal working hours) • 01276 692504 (out of hours)

o Patients under the care of Community Mental Health teams  Patients attend one of four Clozapine Clinics for “One-Stop Clozapine Dispensing”

 Note that clozapine is not usually prescribed by GPs

 Plasma Clozapine/norclozapine levels (incurs an additional cost) o This is not routinely carried but may be useful w here toxicity, compliance or change in smoking habit is an issue o Measurements of plasma clozapine and norclozapine levels are carried out at Kings College Hospital, London o Information on sample requirements, collection and delivery to Kings College Hospital is available from the Kings College Hospital w ebsite – See Appendix 5 for link to the request forms o Contact Pharmacy for further information

* http://www.medicines.org.uk/emc/medicine/1277

References: 1. Every-Palmer et al (February 2016). Accessed 17/08/16 w ww.ebiomedicine.com 2. Shirazi et al (June 2016). Int J Mol Sci, 17:863 3. Communication from the Chief Pharmaceutical Officer for Wales, April 2012, All Wales Medicines Strategy Group; AWMSG)

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White blood cell and Neutrophil count interpretation

White blood cells Neutrophils Alert Action (x109/L) (x109/L) < 3.0 < 1.5 RED STOP Clozaril; < 2.5 (BEN*) < 1.0 (BEN) Contact CPMS and Pharmacy 3 – 3.5 1.5 – 2.0 AMBER Extra monitoring required; 2.5 – 3 (BEN) 1 – 1.5 (BEN) Contact CPMS and Pharmacy > 3.51 > 2.01 GREEN Administer as prescribed > 3.0 (BEN) > 1.5 (BEN) *Benign Ethnic Neutropenia – special consideration

Missed clozapine dose(s)

Missed dose Action All patients Less than 48 hours  Patient may continue at usual dose  No change in monitoring frequency More than 28 days  Patient re-registration w ith CPMS required  Re-titrate dose  All patients require 18 w eeks of w eekly monitoring Weekly monitoring More than 48 hours but less than 7 days  Inform CPMS – Re-titration advised “Treatment break”  No change in monitoring frequency 7 or more days  Inform CPMS – Patient re-registration w ith CPMS required  Re-titrate  Restart 18 w eeks of w eekly monitoring Fortnightly and 4-weekly monitoring More than 48 hours but less than 4 w hole days  Re-titration advised  No change in monitoring frequency  Inform CPMS 4 days or more but less than 28 w hole days  Inform CPMS – Re-titrate dose “Treatment break”  Weekly monitoring for 6 w eeks then back to previous monitoring frequency

 Full blood count monitoring follow ing cessation of treatment with clozapine Monitoring frequency FBC monitoring Weekly Weekly for FOUR w eeks after cessation Fortnightly Weekly every TWO w eeks after cessation 4-w eekly FOUR w eeks after cessation

 Smoking and clozapine (Appendix 10) o Cigarette smoke contains polycyclic aromatic hydrocarbons (PAH) w hich are potent inducers of CYP1A1, CYP1A2 (the main enzyme metabolising clozapine) and possibly CYP2E1 o Smoking can reduce the level of serum clozapine by as much as 70% o Note that the effect of enzyme induction is not immediate o When patients stop smoking, plasma clozapine levels w ill increase significantly, possibly resulting in toxicity o Smoking cannabis may also have a similar effect o Similar effect is also seen w ith olanzapine (serum levels reduced up to 50%) o Nicotine replacement therapy (NRT) has no effect on the activity of CYP enzymes

 Caffeine and clozapine (Appendix 11) o Caffeine can increase plasma clozapine levels by up to 60% o Caffeine is a competitive inhibitor of CYP1A2

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Physical health monitoring for all patients prescribed Antipsychotics Ref: NICE Clinical Guideline 178 (March 2014)

Summary Guidance – Antipsychotic Monitoring

Parameter Frequency Baseline During 1st year Annually Creatinine Clearance or estimated eGFR Yes Yes

Urea & Electrolytes Yes Yes

(U & Es)

Liv er Function Test, LFTs Yes Frequently with clozapine and chlorpromazine (associated Yes with hepatic failure)

Full blood Count Yes Clozapine requires intensive monitoring under a Yes mandatory blood monitoring screen (see section on “Clozapine Prescribing”)

Blood lipids, including cholesterol, Yes At 3 months Yes triglycerides More frequently (3-monthly) with clozapine, olanzapine, quetiapine

Weight (plotted on a chart) Yes Frequently for 3 months Yes BMI Waist circumference More frequently (3-monthly) with clozapine and olanzapine

Plasma glucose, glycosylated Yes At 6 months Yes haemoglobin (HbA1c)

More frequently with clozapine, olanzapine – obtain HbA1c Assessment of any mov ement disorders Yes

Assessment of nutritional status, diet and Yes lev el of physical activ ity

Prolactin Yes At 6 months Yes

ECG Yes** Patients identified as being at high risk Patients identified as **All inpatients and other patients identified as being at being at high high risk including: risk

- Presence of specific cardiovascular risk factor, for example, high blood pressure - Personal history of CV disease - After dose increase - On combination antipsychotics - Two or more antipsychotic combination is above 100% BNF maximum - Drug regimen changed - SMPC requirement – haloperidol, pimozideπ, sertindoleπ, zotepineπ [πNon-formulary in NELFT]

Blood Pressure / Pulse Yes Frequently during dose titration Yes

Smoking Status Yes Monitor if prescribed specific drugs where cigarette Yes smoking affects metabolism, for example, clozapine Number/day

Creatinine Phosphokinase If Neuroleptic Malignant Syndrome (NMS) suspected

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Patients with schizophrenia should have physical health monitoring (including cardiovascular disease risk assessment) at least once per year

 GPs and other primary healthcare professionals should monitor the physical health of people with psychosis or schizophrenia when responsibility for monitoring is transferred from secondary care, and then at least annually  The health check should be comprehensive, focusing on physical health problems that are common in people with psychosis and schizophrenia  Refer to the NICE clinical guidance, CG178*, for details on monitoring for cardiovascular disease, diabetes, obesity and respiratory disease  A copy of the results should be sent to the care coordinator and psychiatrist, and put in the secondary care notes

 Treatment with antipsychotic medication should be considered an explicit individual therapeutic trial. Include the following: o Discuss and record the side effects that the person is most willing to tolerate o 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 o 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 British national formulary (BNF) or SMPC o Justify and record reasons for dosages outside the range given in the BNF or SMPC o Record the rationale for continuing, changing or stopping medication, and the effects of such changes o Carry out a trial of the medication at optimum dosage for 4–6 weeks

Cautions – antipsychotic drugs Hepatic impairment All antipsychotic drugs can precipitate coma if used in hepatic impairment; phenothiazines are hepatotoxic. Refer to the BNF and SMPC for details on individual drugs.

Renal impairment Start with small doses of antipsychotic drugs in severe renal impairment because of increased cerebral sensitivity. Refer to the BNF and SMPC for details on individual drugs.

Prescribing for the elderly The balance of risks and benefit should be considered before prescribing antipsychotic drugs for elderly patients. In elderly patients with dementia, antipsychotic drugs are associated with a small increased risk of mortality and an increased risk of stroke or transient ischaemic attack. Furthermore, elderly patients are particularly susceptible to postural hypotension and to hyper- and hypothermia in hot or cold weather.

It is recommended that:  Antipsychotic drugs should not be used in elderly patients to treat mild to moderate psychotic symptoms.  Initial doses of antipsychotic drugs in elderly patients should be reduced (to half the adult dose or less), taking into account factors such as the patient’s weight, co-morbidity, and concomitant medication.  Treatment should be reviewed regularly. For further information/details refer to:  *NICE Clinical Guideline 178 (March 2014)  British National Formulary (BNF) or the eBNF

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Antipsychotic depot injections

Drug Class Drug Name Formulations Costing £ Depot antipsychotic: Flupentixol Decanoate  Depixol® Injection 10 – 200 First generation (Depixol®) 20mg/mL (Typical)  Depixol Concentrate® 100mg/mL  Depixol Low Volume® 200mg/mL Depot antipsychotic: Fluphenazine  Injection 25mg/mL, 5 – 20 First generation Decanoate 100mg/mL (Typical) (Modecate®) Depot antipsychotic: Haloperidol Decanoate  Injection 50mg/mL, 5 – 20 First generation (Haldol Decanoate®) 100mg/mL (Typical) Depot antipsychotic: Aripiprazole*  400mg Pre-filled 220 Second generation (Abilify Maintena®) disposable injection

(Atypical)  400mg vial Depot antipsychotic: 1-monthly Paliperidone Injection 50mg, 75mg, 200 – 400 Second generation palmitate** (Xeplion®) 100mg, 150mg Initiation: (Atypical) Days 1 and 8 700 Depot antipsychotic: Risperidone (LAI) Injection 25mg, 150 – 300 Second generation (Risperdal Consta®) 37.5mg, 50mg (Atypical) Depot antipsychotic: Zuclopenthixol  Clopixol® injection 10 – 40 First generation Decanoate 200mg/mL ® (Typical) (Clopixol )  Clopixol Concentrate® 500mg/mL *Requires completion of the Aripirazole LAI (Abilify Maintena®): Initiation or switching from other depot preparation form (see Appendix 14)  Aripiprazole depot injection: The European Medicines Agency (EMA) approved the use of the deltoid muscle as a new injection site for Abilify Maintena (2015). The product was previously approved for injection in gluteal muscle only. Manufacturer’s (OTSUKA) advice:  The Gluteal Only Pack should be only used in accordance with the Patient Information Leaflet enclosed in the pack  The Gluteal Only Pack does not contain needles suitable for deltoid injection and should not be used for deltoid injection  Health Care Professionals should not use needles from other sources for the purpose of either gluteal or deltoid injection

 Note that Piportil Depot preparation is no longer available. Refer to the “Switching patients from Piportil Depot® (Pipotiazine palmitate) to an alternative oral or depot antipsychotic” Guidance o Piportil switching guidance and the Patient Information Leaflet can be accessed via the NELFT Pharmacy intranet site

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Practice points

Note difference between:

 Clopixol Acuphase® – Zuclopenthixol acetate o IM injection o Short-term management of acute psychosis, mania, or exacerbation of chronic psychosis

 Clopixol® – Zuclopenthixol decanoate o Depot IM injection o Maintenance in schizophrenia and paranoid psychosis

Aripiprazole depot (Maintena®) https://www.medicines.org.uk/emc/medicine/28494/SMPC/ABILIFY+MAINTENA+400+mg+powder+and+solvent+for+prolongedrelease+suspension+for+injection/#POSOLOGY

† There is currently no manufacturer’s guidance on switching from typical or atypical depots to Abilify Maintena®. Switching first to oral aripiprazole for at least 14 days is recommended, and then if there is a suitable response, introduce the Abilify Maintena®. Note that 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. Refer to the SMPC for further details.

Paliperidone palmitate (Xeplion®) https://www.medicines.org.uk/emc/medicine/24403

†† Since the launch of XEPLION® on November 19, 2013, 21 fatal cases have been reported following XEPLION® administration up to April 16, 2014 (estimated number of users is approximately 10,900 patients). The causes of death in the reported fatal cases have not been established due to insufficient information and the causal relationship between death and XEPLION® use is unknown at the moment. Please pay attention to the following precautions (refer to the SMPC for further details and any additional precautions):  Xeplion should not be administered in patients who are rapidly agitated, or in unstable patients that are likely to require concomitant use of many types of antipsychotics  The main active metabolite of both Xeplion® and risperidone is paliperidone (9-hydroxy risperidone). Caution should be exercised in dosage and administration to avoid overdose when switching from Risperdal Consta® LAI to Xeplion®  For patients who have never been treated with paliperidone or risperidone, stability of symptoms with oral risperidone for a certain period should be established prior to initiating treatment with Xeplion®. Xeplion® treatment should be started without concomitant use of oral paliperidone or risperidone * http://www.pmda.go.jp/files/000152961.pdf

 Paliperidone palmitate (Xeplion®) depot o An initiation form must be completed by the Consultant in charge of the treatment (Appendix 13 “Paliperidone Palmitate LAI: Initiation and switching from other depot preparations”) o Note that paliperidone depot injection will not be supplied without the completed and approved form o Contact Pharmacy for further information

 Also see “Guidance on the Administration to Adults of Oil-based Depot and other Long-Acting Intramuscular Antipsychotic Injections”, 5th Edition (June 2016)

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Practice points

Licensed route/site of administration for antipsychotic depot injections:

Antipsychotic Depot Route/Site of administration (Intramuscular) Aripiprazole1(see note below) Deltoid or Gluteal (Abilify Maintena®) ** State site on prescription ** Flupentixol Decanoate Dorsogluteal or Lateral thigh (Depixol®) Fluphenazine Decanoate Gluteal (Modecate®) Haloperidol Decanoate Gluteal (Haldol Decanoate®)

1-monthly Paliperidone Initiation doses Day 1 and Day 8 = Deltoid palmitate (Xeplion®) Then Deltoid or Gluteal for monthly maintenance ** State site on prescription ** Risperidone (LAI) Deltoid or Gluteal (Risperdal Consta®) ** State site on prescription ** Zuclopenthixol Dorsogluteal or Lateral thigh Decanoate (Clopixol®)

Note 1: Aripiprazole (Abilify Maintena®) The European Medicines Agency (EMA) approved the use of the deltoid muscle as a new injection site for Abilify Maintena (2015). The product was previously approved for injection in gluteal muscle only. Manufacturer’s (OTSUKA) advice: o The Gluteal Only Pack should be only used in accordance with the Patient Information Leaflet enclosed in the pack o The Gluteal Only Pack does not contain needles suitable for deltoid injection and should not be used for deltoid injection o Health Care Professionals should not use needles from other sources for the purpose of either gluteal or deltoid injection

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Antimanic drugs

Drug Class Drug Name Formulations Costing £ (prescribe by brand Lithium Carbonate MR Priadel® tablets MR 1 – 5 name) Priadel® 200mg, 400mg (prescribe by brand Lithium Citrate Priadel® liquid 30 – 50 name) Priadel® 520mg/5mL Anti-epileptic Valproic Acid Tablets e/c 250mg, 30 – 50 (semisodium valproate) 500mg Depakote® Anti-epileptic Carbamazepine  Tablets 100mg, 5 – 30 200mg, 400mg  MR Tablets 200mg, 400mg

MHRA Drug Safety Update (April 2009; 2, Issue 9)  Antiepileptics: adverse effects on bone Phenytoin, carbamazepine, primidone, and sodium valproate are associated with decreased bone mineral density, which may lead to osteopenia, osteoporosis, and increased fractures in at-risk patients o Phenytoin, carbamazepine, phenobarbital, and primidone are associated with an increased risk of osteomalacia o Vitamin D supplementation should be considered for at-risk patients who receive long-term treatment with primidone, phenytoin, carbamazepine, phenobarbital, or sodium valproate

MHRA/NHSI Patient Safety Alert (PSA) (April 2017)  Refer to the PSA for further information on Resources to support the safety of girls and women who are being treated with valproate, which includes action for mental health and LD Trusts to implement by 6th of October 2017  https://improv ement.nhs.uk/uploads/documents/Patient_Safety_Alert_- _Resources_to_support_safe_use_of_v alproate.pdf

 https://www.gov.uk/government/publications/toolkit-on-the-risks-of-valproate-medicines-in-female-patients

Refer to Appendices 22a and 22b for POMH intervention document relating to QIP 15: Prescribing valproate for bipolar disorder, containing the follow ing links to resources:  Booklet for healthcare professionals: http://w w w.medicines.org.uk/emc/RMM.420.pdf  Information for patients: http://w w w.medicines.org.uk/emc/RMM.421.pdf  A consent form incorporating a checklist: http://w ww.medicines.org.uk/emc/RMM.423.pdf  Cards to give to patients: the MHRA have made available ‘Valproate alert cards’ w hich pharmacy should routinely supply w ith outpatient prescriptions and TTOs for valproate for w omen age 50 years or younger: http://w w w.medicines.org.uk/emc/RMM.422.pdf

Practice points

 Carbamazepine o Measurement of serum drug levels  Every 6 months  Note that carbamazepine has a narrow therapeutic index  Switching from Epilim (sodium valproate) to Depakote (semisodium valproate): Equivalent amount of valproic acid:

Depakote 500mg Epilim EC 500mg Epilim Chrono 500mg 500mg 433mg 433mg

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Prescribing Lithium Baseline, on-going monitoring and cautions( Refer to the Priadel SMPC for full details*)  Lithium o Priadel® is the proprietary brand used in NELFT o Bioavailability varies between brands of lithium – brand must be stated when prescribing o Where patients are admitted on a different brand of lithium carbonate, the same brand should be continued (refer to the Lithium Share Care Guideline for further information) o Changing brands requires increased serum lithium monitoring

 Lithium initiation (Ref: NICE CG185 September 2014) o Advise the person that poor adherence or rapid discontinuation may increase the risk of relapse o Measure the person’s weight or BMI and arrange tests for urea and electrolytes including calcium, estimated glomerular filtration rate (eGFR), thyroid function and a full blood count o Arrange an ECG for people with cardiovascular disease or risk factors for it ensure the person is given appropriate national information (or a locally available equivalent) on taking lithium safely o Establish a shared-care arrangement with the person’s GP for prescribing lithium and monitoring adverse effects. Refer to the NELFT Lithium Shared Care Guidelines

 Serum lithium monitoring following lithium initiation (Ref: NICE CG185 September 2014) o Measure plasma lithium levels 1 week after starting lithium and 1 week after every dose change, and weekly until the levels are stable o Aim to maintain plasma lithium level between 0.6 and 0.8 mmol per litre in people being prescribed lithium for the first time o Monitor serum lithium levels every 3 months

 Monitoring of patients maintained on lithium therapy (Ref: NICE CG185 September 2014) o After the first year, measure plasma lithium levels every 6 months, or every 3 months for people in any of the following groups: – Older people – People taking drugs that interact with lithium – People who are at risk of impaired renal or thyroid function, raised calcium levels or other complications – People who have poor symptom control – People with poor adherence – People whose last plasma lithium level was 0.8 mmol per litre or higher  Measure the person’s weight or BMI and arrange tests for urea and electrolytes including calcium, estimated glomerular filtration rate (eGFR) and thyroid function every 6 months, and more often if there is evidence of impaired renal or thyroid function, raised calcium levels or an increase in mood symptoms that might be related to impaired thyroid function  Monitor lithium dose and plasma lithium levels more frequently if urea levels and creatinine levels become elevated, or eGFR falls over 2 or more tests, and assess the rate of deterioration of renal function. For further information see NICE’s guidance on chronic kidney disease and acute kidney injury.  Monitor renal function more often if the patient has other risk factors such as starting ACE inhibitors NSAIDs or diuretics  When discussing whether to continue lithium, take into account clinical efficacy, other risk factors for renal impairment and cardiovascular disease, and degree of renal impairment; if needed seek advice from a renal specialist and a clinician with expertise in managing bipolar disorder  Monitor the person at every appointment for symptoms of neurotoxicity, including paraesthesia, ataxia, tremor and cognitive impairment, which can occur at therapeutic levels of lithium

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 Non-compliance with lithium tablets o For patients non-compliant with tablets, Priadel® liquid 520mg/5mL is available which contains 5.4mmol lithium/5mL  5mL Priadel® liquid (520mg/5mL; Li+ 5.4 mmol) is equivalent to 200mg lithium carbonate MR tablet (Li+ 5.4 mmol) [Priadel®]  Note that Priadel® liquid requires TWICE DAILY administration

 Lithium toxicity o Lithium has a narrow therapeutic index and therefore requires regular serum-lithium concentration monitoring – as per Lithium Monitoring Policy o Lithium toxicity can occur due to  Sodium depletion, i.e. concurrent use of diuretics especially thiazides  Dehydration o For details on interactions refer to the Priadel SMPC*, BNF or contact pharmacy

 Counselling o Patients should be advised to report signs and symptoms of lithium toxicity, to maintain adequate fluid intake and avoid dietary changes which reduce or increase sodium intake o Lithium may impair performance of skilled tasks, e.g. driving, operating machinery o Signs and symptoms of lithium toxicity include:  Tremor  Hypothyroidism  Renal dysfunction (including polyuria and polydipsia)  Benign intracranial hypertension (persistent headache and visual disturbance)

NPSA/NRLS Safety Alert: Safer lithium therapy (December 2009)  Action to have been taken by all organizations in the NHS and independent sector by 31st December 2010  Patients prescribed lithium are monitored in accordance with NICE guidance  There are reliable systems to ensure blood test results are communicated between laboratories and prescribers  At the start of lithium therapy and throughout their treatment, patients receive appropriate ongoing verbal and written information and a record book to track lithium blood levels and relevant clinical tests  Prescribers and pharmacists check that blood tests are monitored regularly and that it is safe to issue a repeat prescription and/or dispense the prescribed lithium  Systems are in place to identify and deal with medicines that might adversely interact with lithium therapy

 The NPSA has developed a patient pack containing: patient information booklet, lithium alert card and record book for tracking blood tests (‘Lithium Therapy. Important information for patients’) o All patients prescribed lithium should be given the lithium information package  Available on the wards (packs may be purchased from 3M)  Contact pharmacy for further information

Audit of monitoring patients prescribed lithium:  POMH-UK audits [Prescribing Observatory for Mental Health] o National audits carried out every 12 – 18 months o Co-ordinated by Dr Elizabeth Francis, NELFT POMH-UK Lead, Head of Clinical Audit & NICE  POMH-UK Audit reports available on request. Contact Dr Elizabeth Francis, Governance Lead Pharmacist, Head of Clinical Audit & NICE: [email protected]

For further information/details refer to:  Bopolar disorder: Assessment and management. NICE Clinical Guideline 185 (September 2014)  British National Formulary – refer to the Medicines Complete site for the most recent version (requires an Athens login)  *Priadel® SMPC http://w ww.medicines.org.uk/emc/medicine/25501

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Prescribing Valproate Baseline, on-going monitoring and cautions (Refer to the Sodium valproate SMPC for full details*)  Valproate initiation (Ref: NICE CG185 September 2014) o When starting valproate, measure the person’s weight or BMI and carry out a full blood count and liver function tests o Do not offer valproate to women of childbearing potential for long-term treatment or to treat an acute episode o Advise people taking valproate, and their carers, how to recognise the signs and symptoms of blood and liver disorders and to seek immediate medical help if any of these develop Stop valproate immediately if abnormal liver function or blood dyscrasia is detected o When prescribing valproate, be aware of its interactions with other anticonvulsants (particularly carbamazepine and lamotrigine) and with olanzapine and smoking

 Monitoring patients prescribed valproate (Ref: NICE CG185 September 2014) o Do not routinely measure plasma valproate levels unless there is evidence of ineffectiveness, poor adherence or toxicity o Measure the person’s weight or BMI o Carry out liver function tests and a full blood count before therapy then after 6 months of treatment with valproate and repeat annually o Monitor sedation, tremor and gait disturbance carefully in older people

Cautions Liver toxicity: Hepatic impairment: avoid if possible—hepatotoxicity and hepatic failure may occasionally occur (usually in first 6 months); avoid in active liver disease

Monitor liver function before therapy and during first 6 months especially in patients most at risk. Liver dysfunction (including fatal hepatic failure) has occurred in association with valproate (especially in children under 3 years and in those with metabolic or degenerative disorders, organic brain disease or severe seizure disorders associated with mental retardation) usually in first 6 months and usually involving multiple antiepileptic therapy. Raised liver enzymes during valproate treatment are usually transient but patients should be reassessed clinically and liver function (including prothrombin time) monitored until return to normal—discontinue if abnormally prolonged prothrombin time (particularly in association with other relevant abnormalities).

Blood or hepatic disorders Patients or their carers should be told how to recognise signs and symptoms of blood or liver disorders and advised to seek immediate medical attention if symptoms develop

Pancreatitis Patients or their carers should be told how to recognise signs and symptoms of pancreatitis and advised to seek immediate medical attention if symptoms such as abdominal pain, nausea, or vomiting develop; discontinue if pancreatitis is diagnosed

Valproate : Drug safety update April 2018 Valproate must not be prescribed unless the conditions of the Pregnancy Prevention Programme are met. See NELFT guidelines Final valproate guidance July 18 (5).docx.pdf Other materials are also available to support discussions of these risks w ith w omen of childbearing potential and girls w ho are on Valproate.

 Booklet for Healthcare Professionals  Guide to give to patients  Card to give to patients

For further information/details refer to:  Bipolar disorder: Assessment and management. NICE Clinical Guideline 185 (September 2014).  British National Formulary (electronic version)  *Sodium valproate SmPC http://w ww.medicines.org.uk/emc/medicine/22515/SmPC

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Prescribing Lamotrigine Baseline, on-going monitoring and cautions (Refer to the Lamotrigine SMPC for full details*)  Lamotrigine initiation (Ref: NICE CG185 September 2014) o When starting lamotrigine: – Carry out a full blood count, urea and electrolytes and liver function tests – Be aware of its interaction with valproate – Follow the instructions for initial dosage and dosage titration outlined in the SMPC* and BNF, taking into account the need for slow titration in people who have not taken lamotrigine before o Advise people taking lamotrigine to: – Contact their doctor immediately if they develop a rash while the dose of lamotrigine is being increased – Tell you if they are pregnant or planning a pregnancy

 Monitoring Lamotrigine (Ref: NICE CG185 September 2014) Do not routinely measure plasma lamotrigine levels unless there is evidence of ineffectiveness, poor adherence or toxicity

 Monitoring patients prescribed lamotrigine o Carry out an annual physical health check o Monitor patient closely for any skin reactions: – Stevens-Johnson syndrome, toxic epidermal necrosis – Most rashes occur in the first 8 weeks of treatment – Factors for increased risk of serious skin reactions:  Concomitant use of valproate  Initial lamotrigine dosing higher than recommended – refer to the BNF  More rapid dose escalation than recommended – refer to the BNF o Blood disorders o Patients and carers should be alert for signs and symptoms suggestive of bone-marrow failure – anaemia, bruising or infections

Cautions Closely monitor and consider withdrawal if rash, fever, or other signs of hypersensitivity syndrome develop; avoid abrupt withdrawal (taper off over 2 weeks or longer) unless serious skin reaction occurs

Blood disorders Patients and their carers should be alert for symptoms and signs suggestive of bone-marrow failure, such as anaemia, bruising, or infection. Aplastic anaemia, bone-marrow depression, and pancytopenia have been associated rarely with lamotrigine

Hepatic impairment Halve dose in moderate impairment; quarter dose in severe impairment

Renal impairment Caution in renal failure; metabolite may accumulate; consider reducing maintenance dose in significant impairment

For further information/details refer to:  Bopolar disorder: Assessment and management. NICE Clinical Guideline 185 (September 2014)  British National Formulary – most recent version  *Lamotrigine SMPC https://w w w .medicines.org.uk/emc/medicine/4228

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Antidepressant drugs

Tricyclic and related antidepressant drugs

Drug Class Drug Name Formulations Costing £ Tricyclic Amitriptyline  Tablets 10mg, 1 – 5 antidepressants Hydrochloride 25mg, 50mg

 Oral solution 50 – 75 25mg/5mL, 50mg/5mL Clomipramine  Capsules 10mg, 10 – 30 Hydrochloride 25mg, 50mg  Modified release tablets 75mg Imipramine  Tablets 10mg, 25mg 10 – 30 Hydrochloride  Oral solution 200 – 250 25mg/5mL Lofepramine  Tablets 70mg 25 – 50

 Oral suspension 50 – 75 70mg/5mL Tricyclic-related Trazodone  Tablets 150mg 50 – 75 antidepressant Hydrochloride  Capsules 50mg, nd (2 generation) 100mg

 Liquid SF 50mg/5mL 250 – 500

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Hyponatraemia and antidepressant therapy  Usually occurs in the elderly but consider in all patients who develop drowsiness, confusion or convulsions while taking an antidepressant  Possibly due to inappropriate secretion of antidiuretic hormone  Reported more frequently with the SSRIs than with other antidepressants

 Tricyclic antidepressants o All tricyclics except Lofepramine are potentially fatal in overdose due to cardiotoxicity o Anticholinergic side-effects are common with tricyclic antidepressants, e.g. dry mouth, blurred vision, constipation and urinary retention o May cause excessive sweating o Avoid in glaucoma

 Amitryptyline o Dangerous in overdose

 Lofepramine o Lower incidence of anticholinergic side-effects o Less cardiotoxic than dosulepin, amitriptyline or imipramine o Less dangerous in overdose than other tricyclic antidepressants o Infrequently associated with hepatic toxicity – raised liver enzymes and jaundice have been reported; avoid in hepatic o Avoid in severe renal disease

 Trazodone o Has a lower incidence of anticholinergic side-effects o May also be associated with a lower risk of cardiotoxicity in overdose

Practice points

 Monitor for potential postural hypotension and arrhythmias with all tricyclic antidepressants

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Monoamine oxidase inhibitors

Drug Class Drug Name Formulations Costing £ Non-reversible Phenelzine (Nardil®) Tablets 15mg 25 – 50 monoamine oxidase (Initiation and inhibitor prescribing by a Consultant only) Reversible inhibitor of Moclobemide Tablets 150mg, 10 – 30 monoamine oxidase-A 300mg (RIMA)

 Monoamine oxidase inhibitors o MAOIs are used much less frequently because of the dangers of dietary and drug interactions (see BNF) o A washout period is required when switching to or from MAOIs (see BNF) o Interaction with tyramine-rich* foods can result in a hypertensive crisis o WARNING SIGNS OF A REACTION – can occur within 1 – 2 hours:  Headache  Light headedness or dizziness  Flushing of the face and pounding of the heart  Numbness or tingling of the hands or feet  Pain or stiffness in the neck  Feeling sick and/or being sick

 Moclobemide o Avoid in agitated or excited patients; may provoke manic episodes in bipolar disorders; thyrotoxicosis o Moclobemide is claimed to cause less potentiation of the pressor effect of tyramine than phenelzine, but patients should avoid consuming large amounts of tyramine-rich foods

*Tyramine-rich foods include mature cheese, pickled herring, broad bean pods, fermented/smoked food, processed meat/fish, Bovril®, Oxo®, Marmite®/yeast extracts, soy/soy beans, offal, beer, red wine ***This list is not exhaustive***

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Practice points

MAOIs  Due to the potential for life-threatening interactions with other drugs and tyramine containing foods, patients should be encouraged to carry a warning card at all times  Warning card states:

Carry this card with you all the time, in a wallet, purse, or handbag, where it is likely to be found in case of emergency. Show it to any doctor or dentist who may treat you other than the doctor who prescribed this medicine, and to your dentist if you require dental treatment.

Read the following carefully: While taking this medicine, and for 10 days after stopping taking it, you must follow these instructions:

1. Do not eat CHEESE, PICKLED HERRING or BROAD BEAN PODS. 2. Do not eat or drink BOVRIL, OXO, MARMITE or ANY SIMILAR MEAT OR YEAST EXTRACT. 3. Do not take ANY OTHER MEDICINES (including tablets, capsules, nose drops, inhalations or suppositories) whether bought by you or prescribed by your doctor, without first consulting your doctor or your pharmacist. Note: Treatments for coughs and colds, pain relievers and tonics are medicines. 4. Drink ALCOHOL only in moderation, and avoid CHIANTI WINE completely. 5. Notify your surgeon, anaesthetist or dentist well before requiring any treatment which may require an anaesthetic.

Report any severe symptoms to your doctor and follow any other advice given by him.

This information is adapted from: MAOI: Prepared by the pharmaceutical Society and the British Medical Association on behalf of the Health Departments of the United Kingdom.

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Selective serotonin reuptake inhibitors

Drug Class Drug Name Formulations Costing £ SSRIs Citalopram  Tablets 10mg, 1 – 5 20mg, 40mg

 Oral drops 10 – 30 40mg/mL

(4 drops [8mg] are equivalent in therapeutic effect to 10mg tablet) Escitalopram for GAD  Tablets 5mg, 10mg, 10 – 15 only 20mg

 Oral drops SF 30 – 50 20mg/mL Fluoxetine  Capsules 20mg 1 – 5

 Capsules 60mg 50 – 75

 Oral Solution [SF] 25 – 75 20mg/5mL Paroxetine  Tablets 10mg, 10 – 50 20mg, 30mg

 Oral suspension SF 20 – 50 10mg/5mL (Seroxat®) Sertraline (unlicensed Tablets 50mg, 100mg 10 – 25 for GAD*) Serotonin receptor Vortioxetine (Brintellix®) Tablets 5mg, 10mg, 20 – 30 modulator; serotonin 20mg transporter inhibitor *Generalised Anxiety Disorder

MHRA Drug Safety Update (MHRA: Drug Safety Update Dec 2011; 5, issue 5: O2) https://www.gov.uk/drug-safety-update/citalopram-and-escitalopram-qt-interval-prolongation

Citalopram and escitalopram: QT interval prolongation – new maximum and daily dose restrictions (including in elderly patients)

 Citalopram and escitalopram are associated with dose-dependent QT interval prolongation and should not be used in those with:  Congenital long QT syndrome; known pre-existing QT interval prolongation; or in combination with other medicines that prolong the QT interval o ECG measurements should be considered for patients with cardiac disease o Electrolyte disturbances should be corrected before starting treatment  For citalopram, new restrictions on the maximum daily doses now apply: o 40 mg for adults

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o 20 mg for patients older than 65 years o 20 mg for those with hepatic impairment.  For escitalopram, the maximum daily dose for patients older than 65 years is now reduced to 10 mg/day; other doses remain unchanged

Summary of maximum daily dose schedule: Adults with hepatic Adults Adults >65 years impairment Citalopram 40 mg 20 mg 20 mg Escitalopram 20 mg 10 mg 10 mg

 Patients who currently take doses higher than the new recommended daily maximum should have their treatment reviewed

Drug Interactions (Refer to the full SmPC for the individual drugs for specific interactions)  Use with drugs known to prolong QT Interval Citalopram and escitalopram may have an additive effect to other drugs that prolong the QT interval. Co-administration of citalopram and escitalopram with medicines that prolong the QT interval is therefore contraindicated. These include:  Class IA and III antiarrhythmics (eg, amiodarone, dronedarone, quinidine)  Antipsychotics (eg, phenothiazine derivatives, pimozide, haloperidol)  Tricyclic antidepressants  some antimicrobial agents (eg, sparfloxacin, moxifloxacin, erythromycin IV, pentamidine, antimalaria treatment—particularly halofantrine)  Some antihistamines (astemizole, mizolastine)  Some antiretrovirals (eg, ritonavir, saquinavir, lopinavir)

 Use with drugs that increase escitalopram and citalopram levels Patients taking concomitant medications known to increase plasma levels of escitalopram and citalopram may require a dose reduction in light of these most recent QT data. Drugs known to increase plasma concentrations of escitalopram and citalopram include:  Some antiretroviral medications  Omeprazole  Cimetidine

Monitoring recommendations  In patients with cardiac disease, an ECG review should be considered before treatment with citalopram and escitalopram  Electrolyte disturbances, for example, hypokalaemia and hypomagnesaemia, should be corrected before treatment with citalopram and escitalopram  Monitoring of serum magnesium is advised, particularly in elderly patients, who may be taking diuretics or proton pump inhibitors  If cardiovascular symptoms, such as palpitations, vertigo, syncope or seizures develop during treatment, cardiac evaluation including ECG should be undertaken to exclude a possible malignant cardiac arrhythmia  If QTc interval is >500 milliseconds, treatment should be withdrawn gradually  If QTc interval duration is between 480 milliseconds and 500 milliseconds, the balance of benefits and risks of continued treatment should be carefully considered, alongside options for dose reduction or gradual withdrawal

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Practice points

 Selective serotonin reuptake inhibitors o Have few anticholinergic side-effects o Have lower cardiotoxicity risk than tricyclic antidepressants o May cause hyponatraemia o May enhance the anticoagulant action of warfarin o Discontinuation symptoms may occur if SSRIs are stopped suddenly, especially paroxetine o A washout period may be required when switching one SSRI to another SSRI to prevent Serotonin Syndrome o Are associated with increased risk of bleeding so gastroprotective medicine may be required in the elderly or those concurrently prescribed non-steroidal anti-inflammatory drugs or aspirin  Alternative antidepressants recommended by NICE (CG90/91, 2009) for patients on NSAIDs – Trazodone – Mirtazapine – Moclobemide – Mianserin – Reboxetine (non-formulary in Trust)

 If no suitable alternative identified, offer gastroprotective medicine, for example, proton pump inhibitor, with the SSRI

 Fluoxetine and paroxetine o More likely to cause drug interactions than other SSRIs

 Paroxetine o Associated with higher incidence of discontinuation symptoms

References: Depression in adults: recognition and management. NICE Clinical Guideline 90 (2009). https://www.nice.org.uk/guidance/cg90/resources/depression-in-adults-recognition-and-management- 975742636741

Depression The treatment and management of depression in adults. NICE Clinical Guidleine 90 (2009). http://www.nccmh.org.uk/downloads/Depression_update/CG90NICEguideline.pdf.pdf

Depression in adults with chronic physical health problem: recognition and management. NICE Clinical Guideline 91 (2009). https://www.nice.org.uk/guidance/cg91/resources/depression-in- adults-with-chronic-physical-health-problem-recognition-and-management-975744316357

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Other antidepressant drugs

Drug Class Drug Name Formulations Costing £ Serotonin and noradrenaline Duloxetine Capsules 30mg, 60mg 5 – 10 reuptake inhibitor (SNRI)

Thioxanthene Flupentixol Tablets 500 micrograms, 1 – 5 (Fluanxol®) 1mg α2 adrenoceptor antagonist Mirtazapine  Tablets 15mg, 30mg, 1 – 5 (Noradrenaline specific 45mg serotonin antidepressant: NASSA)  Orodispersible tablets 15mg, 30mg, 45mg

 Oral solution 15mg/mL 50 – 75 Serotonin and noradrenaline Venlafaxine  Tablets 37.5mg, 75mg 5 – 10 reuptake inhibitor (SNRI)  MR tablets 37.5mg, 50 – 75 75mg, 150mg, 225mg

Practice points

 Duloxetine o Monitor blood pressure in patients with hypertension and other cardiac disease, especially during first month of treatment (Refer to the SMPC for further details: https://www.medicines.org.uk/emc/medicine/15694/SMPC/Cymbalta+30mg+hard+gastro- resistant+capsules,+Cymbalta+60mg+hard+gastro-resistant+capsules/ )

 Mirtazapine o Fewer anticholinergic side effects o Causes sedation during initial treatment

 Venlafaxine o Lacks the sedative and anticholinergic side effects of tricyclic antidepressants o Associated with a greater risk of death from overdose o Higher risk of discontinuation symptoms compared to other antidepressants if stopped suddenly o Caution in patients with established cardiac disease that may increase risk of ventricular arrhythmias (e.g. recent myocardial infarction) o Monitor blood pressure in patients with hypertension and other cardiac disease o Higher doses: Noradrenaline reuptake inhibition > serotonin reuptake inhibition

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CNS stimulants and other drugs used for attention deficit hyperactivity disorder [ADHD] (CAMHS use only)

Drug Class Drug Name Formulations Costing £ CNS stimulant Dexamfetamine Tablets 5mg 75 – 100 Sulphate CD (Schedule 2 Controlled Drug) CNS stimulant Lisdexamfetamine Capsule 30mg, 50mg, 50 – 150 (Pro-drug of (Elvanse®) CD 70mg Dexamfetamine) (Schedule 2 Controlled Drug) CNS stimulant Methylphenidate  Tablets 5mg, 10mg, 10 – 50 Hydrochloride CD 20mg (Medikinet®) (Schedule 2 Controlled Drug)  Equasym XL® 20 – 100 Capsules10mg, 20mg, 30mg

 Concerta XL® Tablets 18mg, 27mg, 36mg 30 – 100

 Medikinet XL® Capsules 5mg, 10mg, 20 - 100 20mg, 30mg, 40mg

Selective Atomoxetine  Strattera® 50 – 150 noradrenaline Strattera® Capsules 10mg, 18mg, reuptake 25mg, 40mg, 60mg, inhibitor 80mg, 100mg

 Strattera® 50 - 300 Sugar free solution 4mg/mL Selective Guanfacine*  Intuniv® XL Tablets 56 - 150 alpha2A- *Seek approval from the 1mg, 2mg, 3mg, 4mg adrenergic Chair of the DTG for receptor agonist prescribing on a named patient basis. Requires Pre- treatment screening & ongoing monitoring during treatment – refer to the SmPC for full information

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Practice points

 CNS stimulants and drugs used for ADHD o Initiated by a Consultant o GP prescribing under shared care guidelines

 Atomoxetine o Hepatic disorders  Patients and carers to be advised of the risk of hepatic disorders  Any abdominal pain, unexplained nausea, malaise, darkening of the urine or jaundice to be reported to the clinician promptly o Suicidal ideation  Patients and carers to be advised of the risks of suicidal thoughts and behaviour  Clinical w orsening, suicidal thoughts or behaviour, irritability, agitation or depression to be reported to the clinician promptly

Atomoxetine (Strattera▼): increases in blood pressure and heart rate —new contraindications, warnings, and advice for monitoring (MHRA: Drug Safety Update Jan 2012, 5, issue 6) https://w w w.gov.uk/drug-safety-update/atomoxetine-strattera-increases-in-blood-pressure-and-heart-rate

 Atomoxetine causes clinically important increases in blood pressure or heart rate, or both, in a small proportion of patients. Atomoxetine should not be used in patients w ith severe cardiovascular or cerebrovascular disorders. Thorough pretreatment screening and regular monitoring of cardiovascular status is recommended. Specialist cardiac evaluation and advice should be sought if pretreatment findings suggest cardiac disease or history, or if symptoms suggesting cardiac disease are found during treatment

References:  Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in children and adolescents: Methylphenidate (Ritalin TM, Equasym TM, Equasym XL TM, Medikinet TM, Medikinet XL TM, Concerta XL TM), Dexamphetamine (Dexedrine TM) and Atomoxetine (Strattera TM). Shared Care Guideline by Dr Manas Sarkar, July 2015 edition. Guideline can be accessed via the NELFT Pharmacy intranet site – Shared Care Guidelines

 NICE clinical guideline (CG72): Attention deficit hyperactivity disorder. Diagnosis and management of ADHD in children, young people and adults, issued September 2008, modified March 2013. Link to the document: https://w ww.nice.org.uk/guidance/cg72/resources/attention-deficit-hyperactivity-disorder-diagnosis-and- management-975625063621

 NICE Technology Appraisal (TA98): Attention deficit hyperactivity disorder (ADHD) – methylphenidate, atomoxetine and dexamfetamine (2006) Link to the document: https://w ww.nice.org.uk/guidance/ta98/resources/methylphenidate-atomoxetine-and-dexamfetamine-for-attention- deficit-hyperactivity-disorder-adhd-in-children-and-adolescents-2294886169285

 Attention deficit hyperactivity disorder in children and young people: guanfacine prolonged-release. Evidence summary: new medicine; 22 March 2016. https://w ww.nice.org.uk/guidance/esnm70/resources/attention-deficit- hyperactivity-disorder-in-children-and-young-people-guanfacine-prolongedrelease-1502681158970053

 Controlled drugs: safe use and management. NICE guideline 46; Published: 12 April 2016 https://w ww.nice.org.uk/guidance/ng46

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Differences in extended release methylphenidate for ADHD Extended Release Brand Concerta XL Medikinet XL Equasym XL Percentage immediate/extended 22/78 50/50 30/70 release Duration of action Up to 12 hours At least 7 hours Up to 8 hours

Administration  Tablets must  Capsules may be  Capsules may be be swallowed swallowed whole, or  swallowed whole, or whole with opened and the contents opened and the contents liquid, and sprinkled onto a small sprinkled onto a small must not be amount of apple sauce amount of apple sauce chewed, and given immediately and given immediately crushed or divided  Capsules should not be  Capsules should not be chewed or crushed chewed or crushed Food requirements Tablets can be Tablets should be taken with Tablets should be taken taken with or or after breakfast before breakfast without food

Methylphenidate: immediate- and modified-release dose equivalents (mg) Extended Release Brand Immediate Release Concerta XL Medikinet XL Equasym XL Methylphenidate 10 mg - 10 mg 10 mg 15 mg 18 mg - - 20 mg - 20 mg 20 mg 30 mg 36 mg 30 mg 30 mg - - - 40 mg 45 mg 54 mg - - 60 mg 72 mg 60 mg - Licensed up to 54 mg NICE CG72; Summary of Product Characteristics (SmPC); SIGN 112 (October 2009)

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Antiepileptics in psychiatric disorders

Drug Class Drug Name Formulations Costing £ Antiepileptics Clonazepam – Tablets 500 micrograms, 20 – 150 unlicensed use 2mg [management of acute, agitated behaviour] Lamotrigine  Tablets 25mg, 50mg, 5 – 10 100mg, 200mg  Dispersible tablets 25mg, 100mg Pregabalin  Capsules 150mg, 200mg, 50 - 75 [Generalised anxiety 225mg, 300mg disorder]

Sodium Valproate –  Crushable tablets 100mg 5 – 75 unlicensed  Tablet e/c 200mg, 500mg 5 – 10 [gastro-resistant]

 Modified release tablets ® (Epilim Chrono ) 200mg, 10 – 30 300mg, 500mg

 MR Granules (Epilim Chronosphere®) 50mg, 50 – 75 10mg, 250mg, 500mg, 1000mg

®  MR Capsules (Episenta ) 10 – 30 150mg, 300mg

 Oral solution [SF] 10 – 30 200mg/5mL 30 – 50  Epilim® oral solution 200mg/5ml [for epilepsy only] See BNF for further preparations

MHRA warning

 Lamotrigine – skin reactions o Serious skin reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis have developed (especially in children) o Most rashes occur in the first 8 weeks o Rash is sometimes associated with hypersensitivity syndrome o Due to increased risk of serious skin reactions avoid  Concomitant use of valproate  Initial lamotrigine dosing higher than recommended (see BNF)

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 More rapid dose escalation than recommended (see BNF) o Warn patients to see their doctor immediately if rash or signs/symptoms of hypersensitivity syndrome develop (fever, rash, lymphadenopathy most commonly)

MHRA Drug Safety Update (November 2013; volume 7, Issue 4) https://www.gov.uk/drug-safety-update/antiepileptic-drugs-new-advice-on-switching-between- different-manufacturers-products-for-a-particular-drug

** Note that this advice relates only to AEDs used for the treatment of epilepsy; it does not apply in other indications, e.g. mood stabilisation, neuropathic pain **

Antiepileptic drugs (AEDs): new advice on switching between different manufacturers’ products for a particular drug  Different antiepileptic drugs vary considerably in their characteristics, which influences the risk of whether switching between different manufacturers’ products of a particular drug may cause adverse effects or loss of seizure control.  AEDs have been divided into three risk-based categories to help healthcare professionals decide whether it is necessary to maintain continuity of supply of a specific manufacturers’ product

Category 1 – phenytoin, carbamazepine, phenobarbital, primidone For these drugs, prescribers are advised to ensure that their patient is maintained on a specific manufacturer’s product

Category 2 – valproate, lamotrigine, perampanel, retigabine, rufinamide, clobazam, clonazepam, oxcarbazepine, eslicarbazepine, zonisamide, topiramate For these drugs, the need for continued supply of a particular manufacturers’ product should be based on clinical judgement and consultation with patient and/or carer, taking into account factors such as seizure frequency and treatment history

Category 3 – levetiracetam, laxosamide, tiagabine, gabapentin, pregabalin, ethosuximide, vigabatrin For these drugs, it is usually unnecessary to ensure that patients are maintained on a specific manufacturer’s product unless there are specific reasons such as patient anxiety and risk of confusion or dosing errors

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Drugs used in parkinsonism and related disorders

Antimuscarinic drugs used in parkinsonism

Drug Class Drug Name Formulations Costing £ Antimuscarinics Orphenadrine  Tablets 50mg Contact pharmacy  Oral solution [SF] 200 - 300 50mg/5mL Procyclidine  Tablets 5mg 10 – 80

 Oral solution [SF] 10 – 70 5mg/5mL

 Injection 5mg/mL 15 – 50 Trihexyphenidyl  Tablets 2mg, 5mg 10 – 30 (Benzhexol)  Syrup 5mg/5mL 10 - 50

Practice points

Antimuscarinics  Should not be withdrawn abruptly in patients on long term treatment  Have potential for abuse due to mood-elevating properties

Drugs used in essential tremor, chorea, tics, and related disorders

Drug Class Drug Name Formulations Costing £ Central monoamine Tetrabenazine  Tablets 25mg 25 – 200 depleting agent  Liquid: 12.5mg/5mL, Contact 25mg/5mL pharmacy

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Drugs used in substance dependence

Alcohol dependence

Drug Class Drug Name Formulations Costing £ GABA receptor-agonist Acamprosate calcium Tablets 333mg 10 – 40 and NMDA receptor- (Campral®) antagonist Aldehyde Disulfiram* (Antabuse®) Tablets 200mg 50 – 120 dehydrogenase inhibitor Opioid receptor Naltrexone (Nalorex®) Tablets 50mg 25 – 50 antagonist Opioid receptor Nalmefene** (Selincro®) Tablets 18mg 75 – 100 antagonist Actions include AMPA/ Topiramate* ** Tablets 100mg, 10 – 30 GABAA Inhibitory 200mg mechanisms *Disulfiram o Should be considered in combination with a psychological intervention for service users who wish to achieve abstinence but for whom acamprosate or naltrexone are not suitable o Treatment should be started at least 24 hours after the last drink and should be overseen by a family member or carer o Medical monitoring should be continued at 6 monthly intervals after the first 6 months. o Patients must not consume alcohol while taking disulfiram o Due to rapid and unpredictable onset of the rare complication of hepatotoxicity; advise service users that if they feel unwell or develop a fever or jaundice that they should stop taking disulfiram and seek urgent medical attention

**Nalmefene – Initiation by substance misuse consultant only o Licensed for the reduction of alcohol consumption in patients with alcohol dependence who have a high drinking risk level without physical withdrawal symptoms, and who do not require immediate detoxification o It should only be prescribed in conjunction with continuous psychosocial support focused on treatment adherence and reducing alcohol consumption o Nalmefene is not recommended for patients aiming to achieve immediate abstinence o Before initiating treatment, prescribers should evaluate the patient’s clinical status, alcohol dependence, and level of alcohol consumption o Nalmefene should only be prescribed for patients who continue to have a high drinking risk level two weeks after the initial assessment. o During treatment, patients should be monitored regularly and the need for continued treatment assessed. Caution is advised if treatment is continued for more than 1 year

***Topirate as adjunctive treatment of alcohol dependence o Off-label use (unlicensed indication) o Third line drug in management of alcohol dependence o Initiation by substance misuse consultant only o Prescribing responsibility to be retained within NELFT

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NICE recommendations (CG100, 2010)

 Wernicke’s encephalopathy: Prevention and treatment  Offer thiamine to people at high risk of developing, or with suspected, Wernicke’s encephalopathy. Thiamine should be given in doses toward the upper end of the ‘British national formulary’ range. It should be given orally or parenterally

 Offer prophylactic oral thiamine to harmful or dependent drinkers: o if they are malnourished or at risk of malnourishment or o if they have decompensated liver disease or o if they are in acute withdrawal or o before and during a planned medically assisted alcohol withdrawal

 Offer prophylactic parenteral thiamine (Pabrinex®, intramuscular) followed by oral thiamine to harmful or dependent drinkers: o if they are malnourished or at risk of malnourishment or o if they have decompensated liver disease

 And in addition o They attend an emergency department, or o Are admitted to hospital with an acute illness or injury

 Offer parenteral thiamine to people with suspected Wernicke’s encephalopathy. Maintain a high level of suspicion for the possibility of Wernicke’s encephalopathy, particularly if the person is intoxicated. Parenteral treatment should be given for a minimum of 5 days, unless Wernicke’s encephalopathy is excluded. Oral thiamine treatment should follow parenteral therapy

References:  Alcohol-use disorders: diagnosis, assessment and management of harmful drinking and alcohol dependence (2011). NICE clinical guideline (CG115) – Link to the document: https://www.nice.org.uk/guidance/cg115/resources/alcoholuse-disorders-diagnosis- assessment-and-management-of-harmful-drinking-and-alcohol-dependence-35109391116229

 Alcohol-use disorders: diagnosis and management of physical complications (2010). Nice clinical guideline (CG100). https://www.nice.org.uk/guidance/cg100/resources/alcoholuse- disorders-diagnosis-and-management-of-physical-complications-35109322251973

 eBNF (February 2016)

 The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition (2015)

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Practice points

Before starting treatment with acamprosate, oral naltrexone, or disulfiram, conduct a comprehensive medical assessment (baseline urea and electrolytes and liver function tests including gamma glutamyl transferase [GGT]). In particular, consider any contraindications or cautions (refer to the SMPC for further details), and discuss these with the service user.

 Acamprosate o Initiated as soon as possible after abstinence has been achieved o Continued for 1 year o Monitor for efficacy o Treatment maintained if patient has a temporary relapse o Stop treatment if patient returns to regular or excessive drinking that persists 4 – 6 weeks after starting treatment

 Disulfiram o Disulfiram is only effective if taken daily o Disulfiram gives rise to an extremely unpleasant systemic reactions after ingestion of even a small amount of alcohol because it leads to accumulation of acetaldehyde in the body  Even toiletries and mouthwashes that contain alcohol should be avoided  Alcohol should be avoided for at least 1 week after stopping treatment  Symptoms can occur within 10 minutes (and last several hours) of ingesting alcohol and include . Flushing of the face . Throbbing headache . Palpitation . Tachycardia . Nausea . Vomiting o Consuming large amounts of alcohol can result in arrhythmias, hypotension, collapse

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Nicotine dependence

Drug Class Drug Name Formulations Costing £ Nicotinic NiQuitin® Clear Patches,  Nicotine ‘7mg’ 80 – 140 acetylcholine self-adhesive releasing (10-weeks) receptor agonist 7mg/24hours (nicotine)  Nicotine ‘14mg’ releasing 14mg/24hours  Nicotine ‘21mg’ releasing 21mg/24hours Nicotinic acetylcholine Nicotinell® Mint Lozenge, Lozenges 1mg, 2mg, 50 – 200 receptor agonist sugar free 4mg (6-12 weeks) (nicotine)

Nicotinic acetylcholine Nicorette® Inhalator 10mg/cartridge 25 – 170 receptor agonist 15mg/cartridge (6-weeks) (nicotine)

Nicotinic acetylcholine Nicorette® Nasal Spray 500microgram/metered 25 – 125 receptor agonist spray (6-weeks) (nicotine)

Nicotine receptor Varenicline (Champix®) Tablets 500microgram, 150 - 200 partial agonist 1mg (12-weeks)

Nicotine Replacement Therapy (NRT): Patches, Lozenges, Inhalator, Nasal Spray – Dosing schedules

 Dosing schedules are based on the total number of cigarettes smoked daily

Further information on Smoking Cessation is available on the Pharmacy intranet site: Smoking Cessation and Medication

NiQuitin® Clear Patches, self-adhesive

Apply on waking to dry, non-hairy skin site, removing after 24 hours and site replacement patch on different area (avoid using same area for 7 days)

 Individuals smoking less than 10 cigarettes daily,  Initially 14-mg patch daily for 6 weeks, then,  7-mg patch daily for 2 weeks  Review treatment if abstinence not achieved within 9 months

 Individuals smoking 10 or more cigarettes daily,  Initially 21-mg patch daily for 6 weeks, then,  14-mg patch daily for 2 weeks, then,  7-mg patch daily for 2 weeks

 Patients using the 21-mg patch who experience excessive side effects which do not resolve within

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a few days, should switch to the 14-mg patch for the remainder of the initial 6 weeks before switching to the 7-mg patch for the final 2 weeks

Nicotinell® lozenge

 Individuals smoking less than 20 cigarettes daily,  Initially suck one low strength lozenge (1mg or 2mg) every 1 – 2 hours when urge to smoke occurs

 Individuals smoking 20 or more cigarettes daily and those who fail to stop smoking with the low-strength lozenges should use the higher-strength lozenges,  Initially suck one higher strength lozenge (4mg) every 1 – 2 hours when urge to smoke occurs

 Patients should not exceed 15 lozenges daily  Lozenge should not be chewed or swallowed  Patients should not eat or drink while a lozenge is in the mouth  Treatment should continue for 6 – 12 weeks before attempting a reduction in dose

Nicorette® Inhalator (requires service user engagement with the NELFT Smoking Cessation team)

The cartridges can be used when the urge to smoke occurs or to prevent cravings Patients should not exceed 12 cartridges of the 10 mg strength daily, or, 6 cartridges of the 15 mg strength daily.

 Administration  Insert the cartridge into the device and draw in air through the mouthpiece; each session can last for approximately 5 minutes  The amount of nicotine from 1 puff of the cartridge is less than that from a cigarette, therefore, it is necessary to inhale more often than when smoking a cigarette  A single 10 mg cartridge lasts for approximately 20 minutes of intense use; a single 15 mg cartridge lasts for approximately 40 minutes of intense use.

Nicorette® Nasal Spray (requires service user engagement with the NELFT Smoking Cessation team)

Patients can use 1 spray in each nostril when the urge to smoke occurs, up to twice every hour for 16 hours daily (maximum 64 sprays daily). If attempting smoking cessation, treatment should continue for 8 weeks before reducing the dose.

 Administration  Initially 1 spray should be used in both nostrils but when withdrawing from therapy, the dose can be gradually reduced to 1 spray in 1 nostril  Maximum 64 sprays per day

References:  Electronic BNF (June 2016). Accessed 23rd June 2016  The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition (2015)  NICE PH10 (Issued 2008, modified November 2013)

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NICE guidance on smoking cessation Smoking: acute, maternity and mental health services (Public health guideline, 27 November 2013)

Recommendations from NICE: 1. All hospitals have an on-site stop smoking service [The term ‘smokefree’ is used to mean air that is free of tobacco smoke] 2. Identifying people who smoke at the first opportunity, advising them to stop, providing pharmacotherapy to support abstinence, offering and arranging intensive behavioural support, and following up with them at the next opportunity. 3. Providing intensive behavioural support and pharmacotherapy as an integral component of secondary care, to help people abstain from smoking, at least while using secondary care services. 4. Ensuring continuity of care by integrating stop smoking support in secondary care with support provided by community-based and primary care services. 5. Ensuring staff are trained to support people to stop smoking while using secondary care services. 6. Supporting all staff to stop smoking or to abstain while at work. 7. Ensuring there are no designated smoking areas, no exceptions for particular groups, and no staff-supervised or staff-facilitated smoking breaks for people using secondary care services.

Advise on and provide stop smoking pharmacotherapies  Advise people who smoke that licensed nicotine-containing products and other stop smoking pharmacotherapies help people to stop smoking and reduce cravings.  Emphasise that nicotine is not the major cause of damage to people’s health from smoking tobacco, and that any risks from using licensed nicotine-containing products or other stop smoking pharmacotherapies are much lower than those of smoking.  Recommend and offer:  licensed nicotine-containing products (usually a combination of transdermal patches  with a fast-acting product such as an inhalator, gum, lozenges or spray) to all people who smoke or  varenicline or bupropion as sole therapy as appropriate.  Do not offer varenicline* or bupropion to pregnant or breastfeeding women or people under the age of 18.  Varenicline and bupropion can be used with caution in people with mental health problems

 Encourage people who do not want (or do not feel able) to stop smoking completely (including pregnant or breastfeeding women) to use licensed nicotine-containing products to help reduce cravings to smoke during their stay or visit.  If stop smoking pharmacotherapy is accepted, ensure that it is provided immediately.  When people are discharged from hospital ensure they have sufficient stop smoking pharmacotherapy to last at least 1 week or until their next contact with a stop smoking service.  Encourage people who are already using an unlicensed nicotine-containing product (such as unlicensed electronic cigarettes) to switch to a licensed product. Advise the person of local policies on indoor and outdoor use of unlicensed nicotine-containing products.

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References  *Varenicline for smoking cessation. NICE technology appraisal guidance [TA123] Published date: July 2007  Stop smoking services NICE guidelines [PH10] Published date: February 2008

NICE guidance on pharmacotherapies for smoking cessation Smoking cessation services in primary care, pharmacies, local authorities and workplaces, particularly for manual working groups, pregnant women and hard to reach communities (PH10, February 2008)

 NRT, varenicline and bupropion are recommended for those who want to stop smoking  NRT, varenicline and bupropion should only be prescribed as part of an ‘abstinent- contingent treatment’ model (see full PH10 guidance)  NHS-funded smoking cessation treatments should not usually be offered within 6 months of an unsuccessful attempt at smoking cessation with NRT, varenicline or bupropion, unless there were external circumstances which led to relapse  Do not offer NRT, varenicline and bupropion in any combination  Consider offering a combination of nicotine patches and another form of NRT such as gum, inhalator, lozenge or nasal spray  When deciding which therapies to use and in which order, discuss the options with the client and take into account: o whether a first offer of referral to the NHS Stop Smoking Service has been made o contraindications and the potential for adverse effects o the client’s personal preferences o the availability of appropriate support o the likelihood that the client will follow the course of treatment o their previous experience of smoking cessation aids

 Stop smoking services. NICE Public Health guidance 10 (PH10) (Issued 2008, Modified 2013). https://www.nice.org.uk/guidance/ph10/resources/stop-smoking-services- 1996169822917

 Varenicline for smoking cessation (2007). NICE Technology Appraisal 123 (TA123) https://www.nice.org.uk/guidance/ta123/resources/varenicline-for-smoking-cessation- 82598131665349

 The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition (2015)

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Opioid dependence

Drug Class Drug Name Formulations Costing £ Long-acting opioid Methadone liquid Oral solution SF 30 – 50 agonist (tablets are not licensed 1mg/mL for this indication) Partial opioid agonist Buprenorphine Sublingual tablets 400 75 – 100 and opioid micrograms, 2mg, antagonist activity tablets 8mg

® Alpha2-adrenergic Lofexidine (BritLofex ) Tablets 200 100 – 350 agonist micrograms

Opioid receptor Naltrexone (Nalorex®) Tablets 50mg 10 – 30 antagonist

NICE technology appraisal guidance: Methadone and buprenorphine for the management of opioid dependence (TA114, January 2007)

 Methadone and buprenorphine o Methadone and buprenorphine (oral formulations), using flexible dosing regimens, are recommended as options for maintenance therapy in the management of opioid dependence o Methadone and buprenorphine should be administered daily, under supervision, for at least the first 3 months o Supervision should be relaxed only when the patient’s compliance is assured o Both drugs should be given as part of a program of supportive care o Higher strengths of methadone should not be used due to risk of errors in administration

NICE Technology Appraisal 115: Naltrexone for the management of opioid dependence (TA115, January 2007)

 Naltrexone o Recommended for the prevention of relapse in formerly opioid-dependent patients who are motivated to remain in a supportive care abstinence programme o Naltrexone should be administered under supervision o Effectiveness in preventing opioid misuse should be reviewed regularly

 Missed doses o Patient who miss 3 days or more of their regular prescribed dose of opioid maintenance therapy are at risk of overdose because of loss of tolerance  Consider reducing the dose in these patients o Patients who miss 5 or more days of treatment, an assessment of illicit drug use is also recommended before restarting substitution therapy  Particularly important for patients taking buprenorphine – due to risk of precipitated withdrawal Practice points Opioid dependence managed by the Community Drug and Alcohol Team (CDAT)

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Drugs used in dementia (old age psychiatry only)

Drug Class Drug Name Formulations Costing Reversible Donepezil  Tablets 5mg, 10mg 1 – 5 acetylcholinesterase inhibitor  Orodispersible 5 – 15 tablets 5mg, 10mg Reversible Galantamine  Tablets 8mg, 12mg 60 – 75 acetylcholinesterase 50 – 100 (AchE) inhibitor and  MR capsules 8mg,16mg, 24mg nicotinic receptor agonist

350 – 750  Oral solution 4mg/mL Glutamate receptor Memantine  Tablets 10mg, 1 – 5 antagonist 20mg

 Oral solution 30 – 70 10mg/mL (5mg/actuation)

Reversible non- Rivastigmine  Capsules 1.5mg, 30 – 75 competitive 3mg, 4.5mg, 6mg acetylcholinesterase inhibitor  Patches 4.6mg/24 25 – 75 hours, 9.5mg/24 hours

 Oral solution SF 75 – 150 2mg/mL

MHRA Drug Safety Updates

 Memantine pump device (Ebixa): risk of medication errors (Drug Safety Update Nov 2010; 4, issue 11: O1) https://www.gov.uk/drug-safety- update/memantine-pump-device-ebixa-risk-of-medication-errors

o There are differences in dose delivery between the pump device and dropper device for memantine . One actuation of the pump device delivers 0.5 mL of solution, corresponding to 5 mg memantine. The maximum daily dose is 20 mg or four pump actuations, whereas 40 drops could be given with the dropper . Please be vigilant regarding dose delivery for memantine products, particularly during the transition period from the dropper device to the new pump device . Advise patients and their caregivers:  How to use the new pump device to deliver the prescribed dose

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 To carefully read the Patient Information Leaflet for memantine oral solution delivered by a pump device

 Rivastigmine (Exelon) transdermal patch: risk of medication errors (Drug Safety Update June 2010; 3, Issue 11) https://www.gov.uk/drug-safety- update/rivastigmine-exelon-transdermal-patch-risk-of-medication-errors

o Symptoms of rivastigmine overdose include nausea, vomiting, diarrhoea, hypertension, and hallucinations; bradycardia and/or syncope, associated with malaise or falls, may also occur o In case of suspected overdose, all rivastigmine patches should be removed immediately and no further patch should be applied for the next 24 hours o It is important to instruct patients and caregivers on the proper use of the transdermal patch, particularly that:  Only one patch should be applied per day to healthy skin on the upper or lower back, upper arm, or chest  The patch should be replaced by a new one after 24 hours, and the previous day’s patch must be removed before application of a new patch to a different skin location  It is not recommended to apply the transdermal patch to the thigh or to the abdomen due to decreased bioavailability of rivastigmine observed when the transdermal patch is applied to these areas of the body*  Application to the same skin location within 14 days should be avoided to minimise skin irritation  The patch should not be cut into pieces

*Refer to the Rivastigmine patch SMPC for further information

Other useful information:  EXELONPATCH - Patch Tracker: A guide to when and where to place the patch

NICE guidance: Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease (review), (TA217, March 2011)

 The three acetylcholinesterase (AchE) inhibitors donepezil, galantamine and rivastigmine are recommended as options for managing mild to moderate Alzheimer’s disease  Memantine is recommended as an option for managing Alzheimer’s disease for people with: o Moderate Alzheimer’s disease who are intolerant of or have a contraindication to AchE inhibitors, or o Severe Alzheimer’s disease

 Assessment of severity of Alzheimer’s disease o Healthcare professionals should not rely solely on cognition scores in circumstances in which it would be inappropriate to do so:  if the cognition score is not, or is not by itself, a clinically appropriate tool for assessing the severity of that patient’s dementia because of the patient’s learning difficulties or other disabilities (for example, sensory impairments), linguistic or other communication difficulties or level of education or  if it is not possible to apply the tool in a language in which the patient is sufficiently fluent for it to be appropriate for assessing the severity of dementia or  if there are other similar reasons why using a cognition score, or the score alone, would be inappropriate for assessing the severity of dementia

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 Treatment should be under the following conditions: o Only specialists in the care of patients with dementia (that is, psychiatrists including those specializing in learning disability, neurologists, and physicians specializing in the care of older people) should initiate treatment. Carers’ views on the patient’s condition at baseline should be sought. o Treatment can be continued by the general practitioner under a shared-care protocol o Treatment should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional or behavioural symptoms o Patients who continue on treatment should be reviewed regularly using cognitive, global, functional and behavioural assessment o Treatment should be reviewed by an appropriate specialist team, unless there are locally agreed protocols for shared care. Carers’ views on the patient’s condition at follow-up should be sought

 Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer’s disease (2011). NICE Technology Appraisal 217 (TA217). https://www.nice.org.uk/guidance/ta217/resources/donepezil-galantamine-rivastigmine- and-memantine-for-the-treatment-of-alzheimers-disease-82600254699973

 Dementia: supporting people with dementia and their carers in health and social care. NICE clinical guideline 42, November 2006 (revised March 2011) https://www.nice.org.uk/guidance/cg42/resources/dementia-supporting-people-with- dementia-and-their-carers-in-health-and-social-care-975443665093

Practice points

Refer to:  Shared care guideline: Management of medications for Alzheimer’s disease. Guideline w ritten by Dr Stephen O’Connor, May 2015 version. Guideline can be accessed via the NELFT Pharmacy intranet site – Shared Care Guidelines

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Appendix 1 Prescribing in Children and Adolescent Mental Health Services (CAMHS)

See Appendix 2 for guidance on unlicensed prescribing in NELFT

 Prescribing for children and adolescents often means medicines are used outside the terms of their Marketing Authorisation (off-label)

 Currently pharmaceutical companies do not usually test their medicines on children and as a consequence, cannot apply to license their medicines for use in the treatment of children

 The Medicines Act 1968 (Section 9) and the European legislation make provisions for doctors to prescribe medicines in an off-label or unlicensed capacity

Unlicensed medicines or licensed medicines for unlicensed applications: summary of the recommendations from the joint Royal College of Paediatrics and Child Health/Neonatal and Paediatric Pharmacists Group standing Group on medicines (Royal College of Paediatrics and Child Health, 2000) http://www.rcpsych.ac.uk/files/pdfversion/cr142.pdf

 Those who prescribe for a child should choose the medicine which offers the best prospect of benefit for that child, with due regard to cost

 The informed use of some unlicensed medicines or licensed medicines for unlicensed applications is necessary in paediatric practice

 Health professionals should have ready access to sound information on any medicine they prescribe, dispense or administer

 In general, it is not necessary to take additional steps, beyond those taken when prescribing licensed medicines, to obtain the consent of parents, carers, and child patients to prescribe or administer unlicensed medicines or licensed medicines for unlicensed applications

 NHS trusts and health authorities should support therapeutic practices that are advocated by a respectable, responsible body of professional opinion

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Reference sources and guidance for prescribing psychotropics and other drugs in children and adolescents

 British National Formulary for Children

 Children and adolescents. Chapter 5. The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition, 2015

 Royal College of Paediatrics and Child Health http://www.rcpch.ac.uk/

 Use of licensed medicines for unlicensed applications in psychiatric practice (2007) http://www.rcpsych.ac.uk/files/pdfversion/cr142.pdf

 NICE Clinical Guideline 28 (2005). Depression in children and young people: Identification and management in primary, community and secondary care

 NICE Clinical Guideline 72 (2008). Attention deficit hyperactivity disorder: Diagnosis and management of ADHD in children, young people and adults

 NICE Clinical Guideline 158 (2013). Antisocial behaviour and conduct disorders in children and young people: recognition, intervention and management

 NICE Technology Appraisal 213 (2011). Aripiprazole for the treatment of schizophrenia in people aged 15 to 17 years: Safe and Appropriate Care for Young People on Adult Mental Health Wards, Pilot programme report, July 2009. http://www.nice.org.uk/resource/pttomzytgj4ld2oms5gjjm6uma

 Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder. NICE Technology Appraisal 292 (2013). https://www.nice.org.uk/guidance/ta292/resources/aripiprazole-for-treating-moderate-to-severe- manic-episodes-in-adolescents-with-bipolar-i-disorder-82600730031301

 Antisocial behaviour and conduct disorders in children and young people: recognition and management. NICE Clinical Guideline 158 (2013). http://www.nice.org.uk/guidance/cg158/resources/antisocial-behaviour-and-conduct-disorders-in- children-and-young-people-recognition-and-management-35109638019781

 Medicines for Children – Unlicensed Medicines: Information for parents and carers (leaflet) http://www.medicinesforchildren.org.uk/search-for-a-leaflet/unlicensed-medicines/

 Medicines for Children – leaflets on individual medicines to download http://www.medicinesforchildren.org.uk/search-for-a-leaflet/

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Appendix 2a Drugs used outside of the UK Marketing Authorisation

Unlicensed Medicines – Background

Medicines and Healthcare Products Regulatory Agency (MHRA) http://www.mhra.gov.uk/Howweregulate/Medicines/Reviewofunlicensedmedicines/

 Under European medicines legislation (Directive 2001/83/EC), a medicinal product placed on the market is required to have a marketing authorisation granted following demonstration of safety, quality and efficacy  Under Article 5 (1) of Directive 2001/83, Member States are permitted to put in place national arrangements to allow an authorised healthcare professional to commission the manufacture of an unlicensed medicinal product to meet the special needs of an individual patient under their direct personal responsibility.  The UK has made use of this derogation to establish national provisions. There are currently arrangements in place for unlicensed medicines manufactured in the UK and a notification scheme for medicines imported into the UK. Those national provisions are set out in the Medicines for Human Use (Marketing Authorisations) Regulations 1994, as amended and the Medicines for Human Use (manufacturing, wholesale dealing and miscellaneous amendments) Regulations 2005  Licensing arrangements are implemented by the MHRA The Human Medicines Regulations 2012 http://www.legislation.gov.uk/uksi/2012/1916/contents/made

The Human Medicines Regulations 2012 (SI 2012/1916) contains certain important exemptions from licensing and makes provision for further exemptions to be included in statutory orders. This section outlines three of the more important exemptions: the manufacture and supply of unlicensed relevant medicinal products for individual patients (‘specials’) (Regulation 167); the importation and supply of unlicensed relevant medicinal products for individual patients; and herbal remedies exemptions. Definitions

 Medicines which do not have a UK Market Authorisation (an unlicensed medicine) These may include medicines manufactured by a licensed manufacturer which are awaiting a UK Market Authorisation, are manufactured for export, have been withdrawn from the UK market, or where the manufacturer does not intend to apply for a UK licence. These products are usually obtained on a “named patient” or “named clinician” basis.

 Unlicensed medicines prepared by a manufacturer with a Special Manufacturing Licence These are widely referred to as “specials”. Pharmacy supplies a small number of patient-specific products that are made in a manufacturing unit that holds a Manufacturing License (Specials) issued by the MHRA.

 The use of licensed medicines outside their Market Authorisation (Off-label use) The indication may be unlicensed, the dose or the age of the patient may be outside the licence, the route or the method of administration may be outside the licence. In some circumstances, the product may require unlicensed reformulation before administration.

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Prescribing

o Psychiatric Consultants frequently prescribe licensed drugs for indications not covered by the marketing authorisation (product license) of the drug – unlicensed use/off-label

o Drugs used for unlicensed indications are no longer covered by the product license. In this situation, the prescribing clinician and the Trust are liable for any adverse consequences arising as a result of the treatment

o The ultimate responsibility for prescribing any drug lies with the doctor who signs the prescription and is professionally accountable for his/her judgement

o Doctors have a duty in common law to take reasonable care and to act in a way consistent with practice of a responsible body of their peers of similar professional standing

MHRA: Off-label or unlicensed use of medicines: prescribers’ responsibilities (MHRA Drug Safety Update April 2009; 2, issue 9)

 Before prescribing a medicine off-label, be satisfied that such use would better serve the patient’s needs than an appropriately licensed alternative  Before prescribing an unlicensed medicine or using a medicine off-label:  Be satisfied that there is sufficient evidence base and/or experience of using the medicine to show its safety and efficacy  Take responsibility for prescribing the medicine and for overseeing the patient’s care, including monitoring and follow-up  Record the medicine prescribed and, where common practice is not being followed, the reasons for prescribing this medicine; you may wish to record that you have discussed the issue with the patient

General Medical Council: Prescribing unlicensed medicines in “Good practice in prescribing and managing medicines and devices (2013)” http://www.gmc-uk.org/guidance/ethical_guidance/14316.asp

 Some medicines are routinely used outside the scope of their licence, for example in treating children  Where current practice supports the use of a medicine in this way it may not be necessary to draw attention to the licence when seeking consent. However, it is good practice to give as much information as patients, or those authorising treatment on their behalf, require or which they may see as significant. If patients or their carers express concern, you should also explain, in broad terms, the reasons why medicines are not licensed for their proposed use.  You must always answer questions from patients (or their parents or carers) about medicines fully and honestly.

Prescribing medicines for use outside the terms of their licence (off-label)  You may prescribe medicines for purposes for which they are not licensed  Although there are a number of circumstances in which this may arise, it is likely to occur most frequently in prescribing for children  Currently pharmaceutical companies do not usually test their medicines on children and as a consequence, cannot apply to license their medicines for use in the treatment of children. The use of medicines that have been licensed for adults, but not for children, is often necessary in paediatric practice

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When prescribing a medicine for use outside the terms of its licence you must  Be satisfied that it would better serve the patient’s needs than an appropriately licensed alternative  Be satisfied that there is a sufficient evidence base and/or experience of using the medicine to demonstrate its safety and efficacy. The manufacturer’s information may be of limited help in which case the necessary information must be sought from other sources  Take responsibility for prescribing the unlicensed medicine and for overseeing the patient’s care, including monitoring and any follow up treatment, or ensure that arrangements are made for another suitable doctor to do so  Make a clear, accurate and legible record of all medicines prescribed and, where you are not following common practice, the reasons for prescribing an unlicensed medicine  Refer to the ‘Hierarchy of Risk’ guidance issued by the MHRA – see below: The Hierarchy of Risk – based on product origin

Preferred  UK-licensed medicine Lowest choice  Off-label use of a UK-licensed medicine net risk  An Imported product licensed in the country of origin  A UK manufactured special made in MHRA licensed facilities  An extemporaneously dispensed medicine Last  An imported product not licensed in the country of origin Highest choice net risk  A non-UK-made unlicensed medicine or food supplement

Requests for use of unlicensed medicines in NELFT

 Refer to the NELFT Medicines Policy for further information or contact Pharmacy  Before a new unlicensed medicine is introduced into use ensure o There is no suitable licensed alternative o There is no equivalent or better unlicensed alternative already available o The prescriber is aware that a medicine he/she has requested is only available as an unlicensed product  Patient or carer should be informed of the use of unlicensed medicine  Patient consent should be sought  Any new request must be approved by the chair of the Trust’s Drug and Therapeutics Group (application form included in the process for “Use of unlicensed Medicinal Products”)

Audits  Audits may be carried out on prescribing to gain information on the extent of, and reasons for, prescribing for unlicensed applications in individual patients

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Appendix 2b List of NELFT approved unlicensed medicines (Unlicensed indication)

Drug Unlicensed indication Dosing guidance Comment Acetylcholinesterase Combination therapy not Total daily doses w ithin  Acetylcholinesterase inhibitors inhibitor plus memantine recommended by NICE. BNF limits only licensed for mild-moderate dementia and memantine for

moderate-severe dementia

Antipsychotics – first and Use in those less than 18 Total daily dose w ithin second generation years of age limits indicated in the BNF for Children Antipsychotics – second Psychotic illness other than Total daily dose w ithin BNF generation schizophrenia limits Antipsychotics – high Psychotic illness Refer to the: dose/combination  NELFT High Dose Antipsychotic Prescribing Policy http://nelftintranet/policies-and- guidelines/medicines- management-policies.htm  Guidance from the Royal College of Psychiatry Aripiprazole Hyperprolactinaemia Total daily dose w ithin BNF  Accepted practice* limits

Baclofen Alcohol dependence Total daily dose w ithin BNF  Specialist prescribing only limits  Six months (max. 100mg daily)

Benzodiazepines – Aggression, acute phase of Total daily dose w ithin BNF  NELFT Rapid Tranquilisation including clonazepam mania, rapid tranquilisation limits Policy

Carbamazepine Bipolar disorder Total daily dose w ithin BNF  Currently only licensed for limits prophylaxis of bipolar disorder unresponsive to lithium Clonidine ADHD in children Total daily dose w ithin BNF Limited evidence limits Cyproheptadine Akathisia Total daily dose w ithin BNF limits Dosulepin Depressive illness Total daily dose w ithin BNF  Initiated by a specialist limits  Note guidance from: - NICE (CG90, October 2009): “Do not sw itch to, or start, dosulepin” - MHRA (December 2007): “Dosulepin: measures to reduce risk of fatal overdose”

Haloperidol In absence of ECG Total daily dose w ithin BNF limits Hyoscine hydrobromide Antipsychotic-induced Total daily dose w ithin BNF hypersalivation limits Lithium Clozapine Total daily dose w ithin BNF induced neutropenia limits

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® Melatonin (Circadin ) Sleep disorder in ADHD Total daily dose w ithin BNF  Shared care guidelines on limits Melatonin for sleep (CMHS use only) disorders/difficulties in children (NELFT)

 See NICE Evidence Summaries (ESUOM2):

“Sleep disorders in children and young people w ith attention deficit hyperactivity disorder: Melatonin”

Melperone Treatment-refractory  Start at 25mg at night  Medicine not licensed in the UK schizophrenia w ho have not Increase according to responded to or cannot tolerability  Initiation by Consultant tolerate clozapine  Non-refractory illness Psychiatrist – total daily doses of 100-300mg are  Named patient prescribing only effective  Higher doses may be needed in refractory illness Omega-3 fatty acid Schizophrenia compounds Pirenzepine – Clozapine-induced 25-50 mg up to TWICE  Medicine not licensed in the UK antimuscarinic hypersalivation daily  Third line option for clozapine- induced hypersalivation Promethazine Intramuscular Max. 100mg daily* Rapid Tranquilisation only

Propranolol Antipsychotic-associated Total daily dose w ithin BNF Akathisia limits

Risperidone Autism Total daily dose w ithin BNF limits Sertraline GAD Total daily dose w ithin BNF  NICE recommendation (2012) limits Sodium valproate – Mood stabiliser Total daily dose w ithin BNF Tablets, Chrono, Liquid limits Topiramate Management of alcohol Total daily dose up to Refer to the DTG meeting of 1st of dependence 300mg April 2014 for further information

* The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition, 2015

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Appendix 2c Medicines available as a Special-order (‘Specials’) Unlicensed medicines prepared by a manufacturer with a Special Manufacturing Licence

Name Strength Pack size Price £ £ * Exc VAT, P & P Clonazepam Oral Suspension 2mg/5mL 100mL 299.35

Clonazepam Sugar-free Oral Suspension 2mg/5mL 100mL 108.30

Clozapine Oral Suspension 100mg/5mL 100mL 44.53

Dantrium IV Powder for Injection 20mg 12 vials 612.00

Flupenthixol Liquid 1mg/1mL 100mL 246.12

Fluspirilene Injection (Imap®) 2mg/mL 6mL vial 54.49

Melatonin Sugar-free Oral Liquid (Traces 1mg/1mL 200mL 77.84 of Alcohol)**

Melperone Tablets 100mg 50 56.76

Melperone Tablets 50mg 50 40.45

Naloxone Injection 400 10 Ampoules 53.70 microgram/mL

Pirenzepine Tablets (Gastrozepin®) 50mg 100 52.90

Quetiapine suspension 50mg/5mL 140mL 180.33

Tetrabenazine liquid 12.5mg/5mL 200mL 204.71

25mg/5mL 200mL 231.27

Zopiclone Oral Suspension 3.75mg/5mL 100mL 105.33

*Guide price for 2016

** Refer to the “Shared care guidelines on Melatonin for sleep disorders/difficulties in children (NELFT)”. This can be accessed via the NELFT Pharmacy intranet site – Shared Care Guidelines

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Appendix 3 Clozaril Patient Monitoring Service (CPMS) Registration Forms – Links

The following forms may be downloaded from the CPMS website: [ https://www.clozaril.co.uk/ ]

 Patient Registration/Re-registration Form

 Supervising/Specialist Registration Form

 Clozaril Website Access Form

Contact pharmacy for copies of the following forms if you do not have Clozaril Website access:

 New Patient Enrolment Form

 Change of Patient Details Form

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Appendix 4a Example clozapine dosing schedule for in-patients with Schizophrenia – CPMS

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Appendix 4b Example clozapine dosing schedule for in-patients with Schizophrenia: Maudsley guidelines*

*The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition, 2015

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 13 125 125* 14 125 150 15 150 150 18 150 200** 21 200 200 28 200 250***

*Target dose for female non-smokers (250mg/day) **Target dose for male non-smokers (350mg/day) ***Target dose for female smokers (450mg/day)

For initiating clozapine in the community (HTT, CMHT), refer to the Community initiation of clozapine (Clozaril) Policy and guidance

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Appendix 5 Plasma Clozapine and Olanzapine Assay Request Forms – Links

** Note that these tests are carried out by Kings College Hospital, London**

 Clozapine Assay Request Form link: http://www.viapath.co.uk/sites/default/files/upload/2RF- CB-TOX-CLOZ%20-%20Clozapine%20Request%20Form%20v3%20(2).pdf

 Olanzapine Assay Request Form link: http://kingspath.co.uk/tests/toxicology/191/

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Appendix 6 Calculating total daily prescribed antipsychotic dose (Adults)

% BNF Maximum Route 10 % 20 % 25 % 33 % 40 % 50 % 67 % 75 % 100 % Oral Doses mg / Day Amisulpiride Oral 400mg 600mg 800mg 1200mg Aripiprazole Oral 10mg 15mg 20mg 30mg Benperidol Oral 0.5mg 0.75mg 1mg 1.5mg Chlorpromazine Oral 100mg 250mg 330mg 500mg 750mg 1000mg Clozapine Oral 225mg 300mg 450mg 600mg 900mg Flupenthixol Oral 6mg 9mg 12mg 18mg Levomepromazine Oral 250mg 500mg 750mg 1000mg Olanzapine Oral 5mg 10mg 15mg 20mg Paliperidone Oral 3mg 6mg 9mg 12mg Promazine Oral 200mg 400mg 800mg Quetiapine – for mania Oral 200mg 400mg 600mg 800mg Quetiapine – for Oral 150mg 187.5 375mg 750mg schizophrenia Risperidone Oral 4mg 8mg 12mg 16mg Sulpiride Oral 600mg 800mg 1200mg 2400mg Trifluoperazine Oral 5mg 10mg 20mg 25mg 50mg Zuclopenthixol Oral 30mg 60mg 75mg 100mg 150mg

% BNF Maximum Route 10 % 20 % 25 % 33 % 40 % 50 % 67 % 75 % 100 % IM doses mg / Day Aripiprazole IM 10mg 15mg 20mg 30mg Olanzapine IM 5mg 10mg 15mg 20mg Zuclopenthixol Acetate IM Maximum single dose = 150 mg 75mg (Acuphase) Maximum cumulative dose in a two-week period = 400mg; maximum 4 injections

*NB: The dosage recommendations for haloperidol in the British National Formulary have changed and vary according to the clinical indication. Users should now refer to the electronic version of the BNF for the maximum dose of haloperidol for the relevant treatment indication.

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Appendix 6 continued Calculating total daily prescribed antipsychotic dose (Adults)

% BNF Maximum Route 10 % 20 % 25 % 33 % 40 % 50 % 67 % 75 % 100 % Depot doses mg / Week Aripiprazole Depot 50mg 100mg (Abilify Maintena®) Flupenthixol decanoate Depot 100mg 200mg 300mg 400mg (Depixol® depot) Fluphenazine decanoate Depot 25mg 37.5mg 50mg (Modecate® depot) Haloperiodol decanoate Depot 25mg 37.5mg 75mg (Haldol® depot) Olanzapine embonate Depot 75mg 150mg (ZypAdhera®) 1-Monthly Paliperidone Depot 18.75mg 25mg 37.5mg palmitate (Xeplion®) 3-Monthly Paliperidone Depot 10.94mg 21.88mg 29mg 43.75mg palmitate (Trevicta®)

Risperidone LAI Depot 12.5mg 18.75mg 25mg (Risperdal Consta®) Zuclopenthixol decanoate Depot 150mg 200mg 300mg 400mg 600mg (Clopixol® depot) Produced by Dr Elizabeth Francis Adapted from the POMH-UK Antipsychotic Dosage Ready Reckoner, Version 6 (March 2015); eBNF (February 2016) Unless otherwise stated, doses in the BNF are licensed doses – any higher dose is therefore off-label

The prescribing of licensed medicines outside the recommendations of the Marketing Authorisation increases the doctor’s professional responsibility (see GMC guidance (2013) on off-label prescribing at: http://www.gmc-uk.org/guidance/ethical_guidance/14327.asp)

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Appendix 7 Maximum recommended/licensed antipsychotic doses (Adults)

Refer to the electronic BNF for further information – Accessed via the Medicines Complete site (requires an Athens login)

Oral Antipsychotics Antipsychotic Maximum licensed dose (mg/day)* for adults unless specified otherwise (100% BNF maximum dose) Amisulpiride 1200 Aripiprazole 30 Clozapine 900 Flupenthixol 18 Haloperidol 20 Olanzapine 20 Quetiapine 750 – Schizophrenia 800 – Manic episode in Bipolar Affective Disorder 600 – Depression in Bipolar Affective Disorder Risperidone 16 – Psychosis in adults [Persistent aggression in Alzheimer’s dementia: 2mg] Trifluoperazine Not stated in BNF – 30mg recommended** Zuclopenthixol 150 **Recommendation from The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition, 2015 Depot Antipsychotics Depot Maximum licensed dose Recommended (mg)* interval (100% BNF maximum dose) Aripiprazole 400 / monthly Monthly (Abilify Maintena®) Flupenthixol decanoate 400 / week 2 – 4 weeks (Depixol®) Fluphenazine decanoate 50 / week 2 – 5 weeks (Modecate®) Haloperidol decanoate 300 / 4-weekly 4 weeks (Haldol Decanoate®) 1- Monthly Paliperidone 150 / monthly Monthly Palmitate (Xeplion®) Risperidone Long Acting 50 / fortnightly 2 weeks Injection (Risperdal Consta®) Zuclopenthixol decanoate 600 / weekly 1 – 4 weeks (Clopixol®)

* The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition, 2015; eBNF

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Appendix 8 Haloperidol: Oral and Intramuscular Equivalent Doses for Adults

HALOPERIDOL: ADULT ORAL AND INTRAMUSCULAR EQUIVALENT DOSES FOR RAPID CONTROL OF SEVERE ACUTE PSYCHOMOTOR AGGITATIONS ASSOCIATED WITH PSYCHOTIC DISORDER OR MANIC EPISODES OF BIPOLAR 1 DISORDER.

ORAL OR IM PRESCRIBED

Route Maximum Adult Total Daily Dose of Haloperidol

ORAL route only 20 mg

Intramuscular route only 20mg

For guidance on maximum doses in children and adolescents, and older adults, please refer to the latest editions of:  Electronic BNF for Children (eBNFC)  Electronic BNF (eBNF)

Both documents can be accessed via the Medicines Complete website (requires an Athens login)

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Appendix 9a Psychotropic drugs and cytochrome P450 (CYP) interactions*: Substrates, inhibitors and inducers of major cytochrome isozymes for psychotropic drugs1,2,3,4,5

Enzyme Substrate Inhibitors Inducers Antipsychotics: Fluphenazine, perphenazine, thioridazine, Amitriptyline None known haloperidol, chlorpromazine, clozapine, risperidone, olanzapine, Bupropion aripiprazole, iloperidone, zuclopenthixol Duloxetine CYP2D6 Fluoxetine Antidepressants: Citalopram, escitalopram, fluoxetine, Paroxetine paroxetine, fluvoxamine, amitriptyline, nortriptyline, clomipramine, Sertraline desipramine, Imipramine, mirtazapine, venlafaxine

Antipsychotics: Haloperidol, pimozide, clozapine, risperidone, Erythromycin Carbamazepine quetiapine, ziprasidone, aripiprazole, iloperidone, lurasidone Ketoconazole Nefazodone Antidepressants: Citalopram, escitalopram, amitriptyline, CYP3A4 clomipramine, imipramine, mirtazapine, nefazodone, sertraline, venlafaxine

Anxiolytics: Alprazolam, clonazepam, diazepam, buspiron

Sedatives/hypnotics: Zolpidem, zaleplon, flurazepam, triazolam Antipsychotics: Haloperidol, chlorpromazine, perphenazine, Fluvoxamine Carbamazepine thioridazine, clozapine, olanzapine, asenapine, pimozide, loxapine, Moclobemide Perphenazine CYP1A2 thiothixene, trifluoperazine

Antidepressants: Fluvoxamine, amitriptyline, clomipramine, imipramine, duloxetine, Mirtazapine Valproic acid Fluoxetine Carbamazepine CYP2C9 Fluvoxamine Antipsychotics: Clozapine Fluvoxamine Carbamazepine CYP2C19 Antidepressants: Citalopram, escitalopram, clomipramine,imipramine, amitriptyline

Specific antipsychotic-CYP interactions* Antipsychotic CYP Inhibitors Inducers Psychotropics Other drugs Psychotropics Other drugs Aripiprazole CYP2D6 Amitriptyline Amiodarone None know n None know n Bupropion Cimetidine Duloxetine Quinidine Fluoxetine Terbinafine Paroxetine Sertraline

Clozapine CYP1A2 Fluvoxamine Cimetidine Carbamazepine Omeprazole (major pathw ay) Moclobemide Ciprofloxacin Phenobarbital Perphenazine Phenytoin Rifampcin (PAH** - smoking) CYP3A4 Clarithromycin Carbamazepine Barbiturates (minor pathw ay) Erythromycin Efavirenz Fluconazole Nevirapine Itraconazole Phenytoin Ketoconazole Pioglitazone Nefazodone Rifampicin Verapamil (St John’s w ort) Diltiazem Antiretrovirals *List is not exhaustive **PAH: Polyaromatic hydrocarbons

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Appendix 9b Major cytochrome based drug and food interactions1,2,3

Major cytochrome-based interactions* Anxiolytics Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction Alprazolam CYP3A4 + − − Propoxyphene and ketoconazole Increased level of alprazolam Diazepam CYP3A4 + − − Ketoconazole Increased level of diazepam CYP2C19 + − − Barbiturates and carbamazepine Decreased level of diazepam Fluoxamine Increased level of diazepam Clonazepam CYP3A4 + − − Ketoconazole and nefazodone Increased level of clonazepam Chlordiazepoxide CYP3A4 + − − Grapefruit juice Increased level of chlordiazepoxide Buspirone CYP3A4 + − − Grapefruit juice and nefazodone Increased level of buspirone Hypnotic sedatives Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction Flurazepam CYP3A4 + − − Cimetidine and erythromycin Increased level of flurazepam Triazolam CYP3A4 + − − Nefazodone and diltiazem Increased level of flurazepam Zolpidem CYP3A4 + − − Grapefruit juice and fluconazole Increased level of zolpidem Zaleplon CYP3A4 + − − Cimetidine Increased level of zaleplon Zopiclone CYP3A4 + − − Grapefruit juice and erythromycin Increased Mood stabilisers Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction Carbamazepine CYP3A4 + + − Aripiprazole, risperidone, quetiapine, Decreased levels of these antipsychotics and ziprasidone CYP1A2 + + − Clozapine and olanzapine Decreased levels of these drugs CYP2C9 − + − Sertraline Decreased level of sertraline CYP2C19 − + + Phenytoin Increased level of phenytoin CYP2B6 − + − Bupropion Decreased level of bupropion Valproate CYP2C19 + − − Carbamazepine Increased level of valproate metabolite CYP2C9 + − + Phenytoin Increased level of phenytoin Topiramate CYP3A4 − + − Carbamazepine Decreased level of carbamazepine CYP2C19 − − + Phenytoin Increased level of phenytoin Oxcarbazepine CYP2C19 − − + Phenytoin Increased level of phenytoin

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Major cytochrome-based interactions* Herbal and food products Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction St. John’s wort CYP3A4 − + − Buspirone and statins Decreased levels of these drugs CYP1A2 − + − Clozapine and olanzapine Decreased levels of these drugs CYP2C9 − + − Valproic acid Decreased level of valproic acid Ginkgo biloba CYP2C9 − − + S-warfarin Increased level of s-warfarin Grapefruit juice CYP3A4 − − + Aripiprazole and alprazolam Increased levels of these drugs Star fruit juice CYP3A4 − − + Atorvastatin and alprazolam Increased levels of these drugs Cranberry juice CYP2C9 − − + S-warfarin Increased level of s-warfarin CYP3A4 − − + Midazolam Increased level of midazolam Caffeine CYP1A2 + − + Clozapine, olanzapine, and Increased levels of these drugs fluvoxamine Over-the-counter drugs Drug CYP Substrate Inducer Inhibitor Important interacting drugs Interaction isozymes Acetaminophen CYP2E1 + − − Isoniazid and ethanol Decreased level of acetaminophen Ibuprofen CYP2C9 + − − Fluvoxamine and fluconazole Increased level of ibuprofen Naproxen CYP2C9 + − − Fluoxetine and fluvoxamine Increased level of naproxen Dextromethorphan CYP2D6 + − − Bupropion and fluoxetine Increased level of dextromethorphan CYP3A4 + − − Carbamazepine and barbiturates Decreased level of dextromethorphan Smoking and alcohol Drug CYP isozymes Substrate Inducer Inhibitor Important interacting drugs Interaction Smoking CYP1A2 − + − Clozapine, olanzapine, and Decreased levels of these psychotropic fluvoxamine drugs Alcohol CYP2E1 + + − Disulfiram Increased level of alcohol *List is not exhaustive

1. Madhusoodanan S, Velama U, Parmar J, Goia D, Brenner R. A current review of cytochrome P450 interactions of psychotropic drug s. Annals of clinical psychiatry 2014;26(2):120-138 2. http://bioinformatics.charite.de/supercyp/ 3. http://w w w.pharmgkb.org/gene/PA128 4. http://medicine.iupui.edu/clinpharm/ddis/table.aspx 5. The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition, 2015

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Appendix 10 Smoking and psychotropic drugs Smoking and psychotropic drugs Drug Effect of smoking Action to be taken on Action to be taken on stopping smoking restarting smoking Benzodiazepines Plasma levels reduced by 0-50% Monitor closely. Consider Monitor closely. Consider restarting (depends on drug and smoking reducing dose by up to 25% over ‘normal’ smoking dose status) one week Carbamazepine Unclear, but smoking may reduce Monitor for changes in severity of Monitor plasma levels carbamazepine plasma levels to a adverse effects small extent Chlorpromazine Plasma levels reduced. Varied Monitor closely, consider dose Monitor closely, consider restarting estimates of exact effect reduction previous smoking dose Clozapine Reduces plasma levels by up to 50- Take plasma level before Take plasma level before restarting. 70%. Plasma level reduction may be stopping. On stopping, reduce Increase dose to previous smoking dose greater in those receiving valproate. dose gradually (over a week) over one week. Repeat plasma level. until around 75% of original dose Predicting change in plasma reached (i.e. reduce by 25%). clozapine level: Repeat plasma level one week Non-smoking level = 45.3 + (1.474 x after stopping. Consider further smoking level)* dose reductions.

Duloxetine Plasma levels may be reduced by up Monitor closely. Dose may need Consider re-introducing previous smoking to 50% to be reduced dose Fluphenazine Reduces plasma levels up to 50% On stopping, reduce dose by On restarting, increase dose to previous 25%. Monitor carefully over smoking dose. following 4-8 weeks. Consider further dose reductions Fluv oxamine Plasma levels decreased by around a Monitor closely. Dose may need Dose may need to be increased to third to be reduced previous level Haloperidol Reduces plasma levels by around Reduce dose by around 10% On restarting, increase dose to previous 20% Monitor carefully. Consider smoking dose further dose reductions Mirtazapine Unclear, but effect probably minimal Monitor Monitor

Olanzapine Reduces Plasma levels by up to 50% Take plasma level before Take plasma level before restarting. stopping. On stopping, reduce Increase dose to previous smoking dose dose by 25%. After one week, over one week. Repeat plasma level. repeat plasma level. Consider further dose reductions

Tricyclic Plasma levels reduced by 25-50% Monitor closely. Consider Monitor closely. Consider restarting antidepressants reducing dose by 10-25% over previous smoking dose one week. Consider further dose reductions. Zolpidem Clearance is increased in smokers. Sedation may increase. Monitor Half-life may be 30% shorter. Zopiclone Smoking has no clinically significant No known clinically significant Monitor effect on the plasma concentration. effects Possibly less hypnotic effect due to CNS stimulation from nicotine Zuclopentixol Unclear, but effect probably minimal Monitor Monitor

 The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition (2015)  *Psychotropic Drug directory 2014 (Stephen Bazire)  NICE PH 10 (2008): Stop Smoking Services  UKMI Smoking and Drug interactions (June 2007)

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Appendix 11 Caffeine and psychotropic drugs

Caffeine and psychotropic drugs

Caffeine and psychotropic drug interactions Interacting drug Effect Comment Benzodiazepines Caffeine may bind to receptor, Reduced benzodiazepine efficacy acting as an antagonist Clozapine Caffeine may increase plasma Caffeine thought to be a competitive levels by up to 60% CYP1A2 inhibitor Disulfiram – Reduce caffeine clearance  Effects of caffeine prolonged or CYP1A2 inhibitor increased  Adverse effects may be increased  May precipitate caffeine toxicity Fluvoxamine – May decrease caffeine clearance  Effects of caffeine prolonged or CYP1A2 inhibitor by 80% increased  Adverse effects may be increased  May precipitate caffeine toxicity Lithium High caffeine doses may reduce Caffeine withdrawal may cause lithium levels increase in serum lithium level MAOIs Caffeine may enhance stimulant CNS effect SSRIs Large caffeine doses may increase risk of serotonin syndrome The Maudsley Prescribing Guidelines in Psychiatry, 12 th Edition (2015); Psychotropic Drug directory 2014 (Stephen Bazire)

Caffeine content of drinks (mg/cup or can) Black tea 45 Brewed coffee 100 Green tea 20 – 30 Instant coffee 60 Red Bull 80 (other energy drinks may contain substantially more) Soft drinks 25 – 50 The Maudsley Prescribing Guidelines in Psychiatry, 12th Edition (2015)

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Appendix 12 New Drug Request form DRUG & THERAPEUTICS GROUP New Drug Request

New drugs may be requested only by a consultant

Please note that any requests for new drugs will not be discussed without the attendance of the requesting Consultant

Name of drug: …...... ……..

Indication: …...... ……..

1) Is this: a) A new drug? YES NO

b) A new clinical indication for an existing drug? YES NO

c) An unlicensed use of an existing drug? YES NO

2) Will this drug replace another on the formulary? YES NO

State drug: …...... …….

3) If YES, why do you consider this requested drug to be superior?

SAFETY FEWER SIDE EFFECTS

MORE COST EFFECTIVE WILL IMPROVE PRACTICE

Briefly state your reasons:

…......

4) Estimated annual usage of this new drug …...... (patients)

5) Are the cost implications significant? YES ☐ NO ☐

For the Trust (i.e. equal to/more than £5000) YES ☐ NO ☐

For primary care YES ☐ NO ☐

6) If yes, does your Clinical Director support this request? YES ☐ NO ☐

7) If significant, has funding been identified by the Directorate? YES ☐ NO ☐

If no, need to identify funding for drug when presenting case

at the Drug and Therapeutics Group.

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8) Implications for primary care:

Should this drug be limited to secondary care? YES ☐ NO ☐

Could this drug be initiated in primary care? YES ☐ NO ☐

Is it appropriate for a GP to take on clinical responsibility YES ☐ NO ☐

for the patient and for prescribing on-going treatment?

Are shared-care protocols necessary? YES ☐ NO ☐

Is there specific information a GP should be aware of YES ☐ NO ☐

before prescribing this drug?

If yes, please state below: (eg special precautions / monitoring requirements / adverse effects) …...... … …...... … …......

9) Any other supporting information?

…...... …...... …...... …...... …......

Signature of Consultant: …...... Date: …......

Name of Consultant: …......

Where the cost implications of this new drug request are likely to be £5000 per annum or more, please obtain a supporting signature from your Clinical Director.

Signature of Clinical Director: …...... Date: …......

Name of Clinical Director: …......

You will be invited to the next possible meeting of the Drug and Therapeutics Group to present your case.

Please return the completed form to: Dr Richard Duffett [email protected]

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Appendix 13 1-monthly Paliperidone Palmitate Long Acting Injection (Xeplion®) Initiation or switching from other depot preparations † Completed form (password protected) to be submitted to the Chair† of the DTG: Dr Richard Duffett: [email protected] Or, Pharmacy: [email protected]; [email protected] ; [email protected] Patient Initials Gender Date of Birth NHS or RIO Number

Diagnosis …………………………………………………………………………………………………..

If schizophrenia, is it treatment-resistant: ☐ Yes ☐ No

Inpatient ward ………………………………… Community team …………………………………

Please select all that apply: Patient has had oral risperidone in the past ☐ Yes ☐ No ☐ Not known Patient is currently on maintenance treatment with oral risperidone ☐ Yes ☐ No Patient has had a therapeutic response to oral risperidone ☐ Yes ☐ No Patient has had Risperdal Consta (depot) in the past ☐ Yes ☐ No ☐ Not known Patient is currently on Risperdal Consta (depot) ☐ Yes ☐ No Patient has had a therapeutic response to Risperdal Consta ☐ Yes ☐ No Prolactin level ☐ Normal ☐ Raised Patient has had renal function checked: ☐ Yes ☐ No*

*If Renal function not checked/ not known, state reason (e.g. patient refusing blood test): ……………………………………………………

State patient’s creatinine clearance or eGFR: Creatinine Clearance ______mL/min

eGFR ______mL/min/1.73m2

Link to calculate eGFR: http://egf rcalc.renal.org/ XEPLION is not recommended in patients with moderate or severe renal impairment (creatinine clearance < 50 mL/min)

Reason(s) for initiation or switching: ☐ Poor adherence to oral antipsychotic ☐ Poor adherence to current depot antipsychotic ☐ Poor response to other antipsychotics ☐ Less frequent injections ☐ Other – state reason: …………………………………………………………………………………………………….

Which antipsychotic are you planning to discontinue ………………………………………………………………….

Sw itching to Paliperidone Palmitate LAI from other depot preparations – Can be approv ed by Pharmacy Paliperidone LAI one-week initiation regimen is not necessary when switching from other depot preparations

Name of Doctor ………………………………………….. Telephone No./Ext …………………………..

Signature …………………………………………………. Date ……………………….

Initiation of Paliperidone Palmitate LAI (loading dose then maintenance) - To be approv ed by the Chair of the DTG

Name of Consultant ………………………………………… Telephone No./Ext …………………………..

Signature …………………………………………………. Date ……………………….

TO BE COMPLETED BY THE CHAIR OF THE DTG OR PHARMACY

☐ Approve switching to Paliperidone LAI ☐ Approve initiation of Paliperidone LAI ☐ Not approved Comment(s) ……………………………………………………………………………………………………..

Approv ed by: Name ………………………………………….....

Signature ……………………………………….. Date ……………………….

Completed & approv ed form faxed to Lloyds Pharmacy: ☐ Yes ☐ No Fax number: 01708 335268 Date faxed …………………

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Appendix 14 Aripiprazole Long Acting Injection (Abilify Maintena®) Initiation or switching from oral or other depot antipsychotic preparations † Completed form (password protected) to be submitted to the Chair† of the DTG: Dr Richard Duffett: [email protected] Or, Pharmacy: [email protected]; [email protected] ; [email protected]

Patient Initials Gender Date of Birth NHS or RIO Number

Diagnosis …………………………………………………………………………………………………..

If schizophrenia, is it treatment-resistant: ☐ Yes ☐ No

Inpatient ward ………………………………… Community team …………………………………

Please select all that apply: Patient has had oral aripiprazole in the past ☐ Yes ☐ No ☐ Not known Patient is currently on maintenance treatment with oral aripiprazole ☐ Yes ☐ No Patient has had a therapeutic response to oral aripiprazole ☐ Yes ☐ No Potential for interactions (CYP2D6, CYP3A4) with concurrent drugs ☐ Yes ☐ No has been checked* *Refer to the Aripiprazole LAI SMPC or pharmacy for guidance

 ALL service users MUST have been on oral aripiprazole for at least 2 to 4 weeks before the injection is started to establish tolerability and response  Oral aripiprazole at 10mg-20mg per day must continue for two weeks after the first injection to maintain therapeutic aripiprazole concentrations during initiation of therapy

Reason(s) for initiation or switching: ☐ Poor adherence to oral antipsychotic ☐ Poor adherence to current depot antipsychotic ☐ Poor response to other antipsychotics ☐ Less frequent injections ☐ Adverse effect(s) with other antipsychotics (e.g. cardiac side effects, hyperprolactinaemia, weight gain)

☐ Other – state reason: …………………………………………………………………………………

Which antipsychotic are you planning to discontinue ………………………………………………………………….

 There is currently no manufacturer’s guidance on switching from typical or atypical depots to Abilify Maintena ®  Switching first to oral aripiprazole for at least 14 days is recommended, and then if there is a suitable response, introduce the Abilify Maintena®.  In general, no dosage adjustment for Abilify Maintena® is required based on hepatic function or renal function Refer to the SmPC for further information or contact pharmacy

Initiation or Sw itching to Aripiprazole LAI from oral or other depot antipsychotic preparations

Name of Requesting Doctor ………………………………………….. Telephone No./Ext …………………………..

Signature ………………………………………………………………… Date ……………………….

TO BE COMPLETED BY THE CHAIR OF THE DTG OR PHARMACY

☐ Approve initiation or switching to Aripiprazole LAI

☐ Not approved

Comment(s) ……………………………………………………………………………………………………..

Approv ed by: Name ………………………………………….....

Signature ……………………………………….. Date ……………………….

Completed & approv ed form faxed to Lloyds Pharmacy: ☐ Yes ☐ No Fax number: 01708 335268 Date faxed ……………… …

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Appendix 15

THIS PAGE HAS BEEN LEFT BLANK DELIBERATELY

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Appendix 16 Olanzapine Embonate (ZypAdhera®)* Administration: cautions, guidelines and physical observation chart

*Non-formulary in NELFT. Requires authorisation from the Chair of the DTG

OLANZAPINE LONG-ACTING INJECTION: ADMINISTRATION GUIDELINES FOR NURSES

 After each injection, patients should be observed in a healthcare facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose.

 Immediately prior to leaving the healthcare facility, it should be confirmed that the patient is alert, oriented, and absent of any signs and symptoms of overdose.

 If an overdose is suspected, close medical supervision and monitoring should continue until examination indicates that signs and symptoms have resolved.

 The 3-hour observation period should be extended as clinically appropriate for patients who exhibit any signs or symptoms consistent with olanzapine overdose.

 Very common symptoms in overdose (>10% incidence) include tachycardia, agitation/aggressiveness, dysarthria, various extrapyramidal symptoms, and reduced level of consciousness ranging from sedation to coma.

 During clinical trials, post-injection syndrome (consistent with symptoms of Olanzapine overdose) has been seen to occur in less than 1 in 1000 injections within the 3 hour period, and in less than 1 in 10,000 injections after 3 hours.

SYMPTOMS OF POST-INJECTION SYNDROME

 Sedation (ranging from mild to coma)  Delirium (inc. Confusion / Disorientation / Agitation / Anxiety)  Cognitive impairment  Dizziness  Aggression  Weakness  Acute extrapyramidal symptoms (Dyskinesias are movement disorders and can include any of a number of repetitive, involuntary, and purposeless body or facial movements. They can include: Tongue movements, such as “tongue thrusts” or “fly-catching” movements, Lip smacking, Finger movements, Eye blinking ‘Movements of the arms or legs. While dystonias are muscle tension disorders)  Dysarthria (disorder of speech)  Ataxia (affect balance, coordination, and speech)  Hypertension  Convulsions  Respiratory depression,  Aspiration  Hypotension,  Cardiac arrhythmias  Cardiopulmonary arrest

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CHECKS PRIOR TO ADMINISTRATION OF THE INJECTION Select Patient is aware, and agrees, to the 3 hour post-injection monitoring requirements and Yes / No precautions before administration of EACH dose of the injection

Confirm that the patient has consented to the Olanzapine Long-Acting Injection and that the patient has been made clearly aware of the side effects, the reasons why they Yes / No are being prescribed this medication and the alternatives to it

Confirm that the patient is not sedated and is orientated to time place and person (except where pervasive mental state due to psychotic illness is affecting orientation) Yes / No

Complete standard observations of TPR (Temp. Pulse Resp.) & BP before administration of Olanzapine Long-Acting Injection, enter onto RIO and record on the Yes / No recording form. Include observation of mental state and level of alertness and orientation. Complete a baseline observation Yes / No (continue weekly monitoring of blood glucose, weight, girth measurement)

Above points must be entered onto RIO as well as using the physical health monitoring/recording form included with this document Yes / No

ADMINISTRATION OF OLANZAPINE LONG-ACTING INJECTION

Olanzapine Long-Acting Injection should only be administered via deep intramuscular gluteal injection by a healthcare professional trained in the appropriate injection technique.

CHECKS FOLLOWING ADMINISTRATION OF THE INJECTION Patient must be observed by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with Olanzapine overdose

If an overdose is suspected, close medical supervision and monitoring should be initiated and continued until examination indicates that signs and symptoms have resolved. This may require immediate referral and transfer to the Accident & Emergency Department for management of the patient’s symptoms. Information (e.g. SMPC) relating to Post Injection Syndrome and Olanzapine Long-Acting Injection should accompany the patient.

Complete standard observations of TPR (Temp. Pulse Resp.) & BP at 1, 2, and 3 hours and enter onto RIO and complete the recording form provided

For the remainder of the day following Olanzapine Long-Acting Injection dose administration, patients should be advised to be vigilant for signs and symptoms of Olanzapine overdose secondary to post injection adverse reactions, be able to obtain medical assistance if needed and not drive or operate machinery.

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OLANZAPINE LONG-ACTING INJECTION PHYSICAL HEALTH OBSERVATION CHART

This form must be completed, uploaded on WinDip, and filed in the case notes following any instance of Olanzapine long-acting injection administration.

Patient Name: ______NHS Number: ______

Date of Birth: ______Consultant: ______

Name of Healthcare Facility:______

Administered by: ______Designation: ______

Date of administration:______Time of administration:______

Pre- and 3-hour Post-Injection Observations

**Observations should be made every hour**

Time Pulse/min Temp B/P Respiratory Conscious Orientation Signature rate/min level *

Before injection

1 hour

2 hour

3 hour

* 1) Wide awake & active, 2) wide awake but calm, 3) Asleep but arousable, 4) Asleep but unrousable

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WEEKLY OBSERVATIONS

Date

Pulse/min

Temp.

Respiratory rate/min

Blood glucose

Weight

Girth measurement

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Appendix 17 Controlled Drugs Schedules

 Schedule 1 (CD Lic)

 These drugs have virtually no therapeutic use, e.g. hallucinatory drugs (LSD, “Ecstasy”) and cannabis

 A special Home Office licence is required for their possession, usually for academic or research purposes

 Practitioners and pharmacists may not lawfully possess Schedule 1 drugs except under licence

 Schedule 2 (CD2 POM)

 This includes the opiates (e.g. morphine, diamorphine, methadone), synthetic opiates/related compounds (e.g. pethidine, fenta nyl), lisdexamfetamine and the major stimulants (e.g. amphetamines)

 Are subject to safe custody requirements and must be stored in a locked receptacle, usually in an appropriate CD cabinet or a pproved safe, which can only be opened by the person in lawful possession of the CD or a person authorized by that person

 A licence is required to import or export drugs in Schedule 2

 The drug may be administered to a patient by a doctor or dentist, or by any person acting in accordance with the directions o f a doctor or dentist

 A register must be kept for Schedule 2 CDs and this register must comply with the relevant regulations

 The destruction of CDs in Schedule 2 must be appropriately 89uthorized and the person witnessing the destruction must be authorized to do so

 Schedule 3 (CD3 No Register POM)

 Includes a small number of minor stimulant drugs and other drugs which are less likely to be misused than the drugs in Schedu le 2

 Examples are the barbiturates (except secobarbital, now Schedule 2), buprenorphine, diethylpropion, mazindol, meprobamate, midazolam, pentazocine, phentermine, and temazepam

 Includes Tramadal (2014)

 Are exempt from safe custody requirements and can be stored on the open dispensary shelf except for temazepam, buprenorphine and diethylpropion, which must be stored in a locked CD receptacle

 Are subject to the same special handwriting requirements as Schedule 2 CDs, except for temazepam and phenobarbital. Phenobarbital and temazepam can be dispensed in response to a computer-generated prescription but the prescriber’s signature must be added by hand

 There is no legal requirement for records of receipt or administration of Schedule 3 drugs to be kept in the Ward Controlled Drugs Record Book but may be enforced at the discretion of the Accountable Officer

 The requirements relating to destruction do not apply unless the CDs are manufactured by the individual

 Invoices must be retained for a minimum of two years

 Schedule 4, Part I (CD Benz POM) and Part II (CD Anab POM)

 Are exempt from safe custody requirements, with destruction requirements only applying to importers, exporters and manufacturers

 Specific CD prescription-writing requirements do not apply

 CD registers do not need to be kept, although records should be kept if such CDs are produced, or if a licensed person imports or exports such drugs

 Part 1: benzodiazepines (except temazepam and midazolam, which are in Schedule 3), Zopiclone, Zaleplon and Zolpidem, which are subject to minimal control:

 Includes most of the benzodiazepines, plus eight other substances including fencamfamin and mesocarb

 Possession of is an offence without an appropriate prescription. Possession by practitioners and pharmacists acting in their professional capacities is authorized

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 Are subject to full import and export control

 Part 2 includes androgenic and anabolic steroids, clenbuterol, human chorionic gonadotrophin (hCG), non-human chorionic gonadotrophin, somatotropin, somatrem, and somatropin:

 Includes most of the anabolic and androgenic steroids such as testosterone, together with clenbuterol (adrenoreceptor stimulant) and growth hormones

 There is no restriction on the possession when it is part of a medicinal product

 A Home Office licence is required for the importation and exportation of substances unless the substance is in the form of a medicinal product and is for self-administration by a person

 Schedule 5 (CD Inv )

 Includes preparations of certain controlled drugs (e.g. codeine, pholcodine, morphine) which are exempt from full control when present in medicinal products of low strengths, as their risk of misuse is reduced

 No restriction on the import, export, possession, administration or destruction of these preparations and safe custody regula tions do not apply

 A practitioner, pharmacist or a person holding an appropriate licence may manufacture or compound any CD in Schedule 5

 Therefore exempt from virtually all CD requirements other than that invoices must be kept for a minimum of two years

http://www.legislation.gov.uk/uksi/2006/3148/pdfs/uksi_20063148_en.pdf

http://www.dhsspsni.gov.uk/pas-schedules-1to5.pdf

http://psnc.org.uk/sunderland-lpc/wp-content/uploads/sites/89/2014/05/RPS-support-alert-CD- changes-May2014.pdf

http://www.legislation.gov.uk/uksi/2014/1275/contents/made?utm_medium=email&utm_source=Roya l+Pharmaceutical+Society&utm_campaign=4155214_200514+- +Support+Alert&dm_i=EQ,2H26M,1OD9TL,9042W,1

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Appendix 18 Non-formulary drugs

 Approval from the Chair of the DTG must be sought for each patient before initiation of the drugs listed below  Request must be emailed to the Chairperson  Approval w ill be on a named-patient basis

Drug Class Drug Name Formulations Costing Melatonin receptor agonist and Agomelatine Tablets 25mg 50 – 75 selective serotonin-receptor (Valdoxan®) antagonist

Second generation (atypical) Asenapine *(Sycrest®) for Sublingual Tablets 5mg, 10mg 100 – 150 antipsychotic Schizophrenia

* Licensed for Bipolar 1 disorder in Europe

Selective Serotonin Reuptake Escitalopram  Tablets 5mg, 10mg, 20mg 1 – 5 Inhibitor Licensed for GAD only  Oral drops SF 20mg/mL (Cipralex®) 30 – 50 Melatonin receptor Melatonin MR Tablets 2mg 10 – 30 (MT1, MT2) agonist (Circadin®) – insomnia (short-term use) in adults over 55 years

Nicotine replacement therapy Nicotine tablets (Nicorette Sublingual tablets 100 – 150 Microtab®)

Second generation (atypical) Olanzapine Embonate Long acting injection 300 – 500 antipsychotic (ZypAdhera®) depot

Second generation (atypical) Paliperidone MR Tablets 100 – 200 antipsychotic (Invega®)

Second generation (atypical) Quetiapine XL Tablets 200 – 250 antipsychotic (Seroquel® XL and branded generic versions of quetiapine XL) Selective noradrenaline Reboxetine Tablets 4mg 20 – 75 reuptake inhibitor (NARI) (Edronax®)

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Practice points

 Olanzapine Embonate (ZypAdhera®) Long Acting Injection [depot] o Monitoring for post-injection syndrome  After each injection of ZypAdhera®, patients should be observed in a healthcare facility by appropriately qualified personnel for at least 3 hours for signs and symptoms consistent with olanzapine overdose  Ensure NELFT guidelines for administration and monitoring are followed at all times (see Appendix 16)  Ensure a physical observation chart is completed for each dose of ZypAdhera® administered (see Appendix 16)

Refer to the Summary of Product Characteristics (SMPC) for further information http://www.medicines.org.uk/emc/medicine/21361/SMPC/ZYPADHERA+210+mg,+300+mg,+and+405+ mg,+powder+and+solvent+for+prolonged+release+suspension+for+injection/#CLINICAL_PRECAUTIO NS

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Appendix 19 NELFT NICE Technology Appraisal Guidance (TAG) Adherence Check List – Mental Health Services

NICE TAG TAG Title Date of Issue Approved for Reference local use TA367 Vortioxetine for treating major depressive episodes 25 November 2015 Yes TA325 Nalmefene for reducing alcohol consumption in people with 26 November 2014 alcohol dependence Yes

TA292 Aripiprazole for treating moderate to severe manic episodes 24 July 2013 in adolescents with bipolar I disorder Yes

TA286 Loxapine inhalation for treating acute agitation and 22 May 2013 disturbed behaviours associated with schizophrenia Terminated appraisal and bipolar disorder TA217 Donepezil, galantamine, rivastigmine and memantine for the 23 March 2011 treatment of Alzheimer's disease Yes

TA213 Aripiprazole for the treatment of schizophrenia in people January 2011 aged 15 to 17 years Yes

TA123 Varenicline for smoking cessation July 2007 Yes

TA114 Methadone and buprenorphine for the management of 24 January 2007 opioid dependence Yes

TA115 Naltrexone for the management of opioid dependence 24 January 2007 Yes

TA98 Methylphenidate, atomoxetine and dexamfetamine for 22 March 2006 attention deficit hyperactivity disorder (ADHD) in children Yes and adolescents

TA97 Computerised cognitive behaviour therapy for depression 22 February 2006 and anxiety Yes

TA77 Guidance on the use of zaleplon, zolpidem and zopiclone for 28 April 2004 the short-term management of insomnia Yes

TA59 Guidance on the use of electroconvulsive therapy 2 May 2003 Yes

For further information on the NICE guidance implementation process in NELFT contact Dr Elizabeth Francis, Governance Lead Pharmacist, Head of Clinical Audit & NICE, POMH-UK Lead: [email protected]

Link to the NELFT NICE All Things NICE intranet site: http://nelftintranet/departments-and- services/clinical-audit-and-all-things-NICE/all-things-nice.htm

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Appendix 20 NELFT Approved Psychotropic Drugs

Drug Drug Acamprosate (Campral) Nalmefene Amisulpride Naltrexone (Nalorex) Amitriptyline Nicorette Inhalator Aripiprazole Nicorette Nasal Spray Atomoxetine Nicotinell Lozenges Benperidol NiQuitin Clear Patches Buprenorphine sublingual tablets Olanzapine Buspirone Orphenadrine Carbamazepine Oxazepam Chlordiazepoxide 1-monthly Paliperidone Palmitate depot (Xeplion) Chlorpromazine Paroxetine Citalopram Phenelzine (Nardil) Clomethiazole Pregabalin Clomipramine Procyclidine Clonazepam Promazine Clonazepam Promethazine Clozapine (Clozaril) Quetiapine Dexamfetamine Risperidone Diazepam Risperidone Long Acting Injection (Risperdal Consta) Disulfiram (Antabuse) Rivastigmine Donepezil Sertraline Duloxetine Sodium valproate Escitalopram (for GAD only) Sulpiride Fluoxetine Temazepam Flupentixol Tetrabenazine Flupentixol (Fluanxol) Topiramate Flupentixol Decanoate depot (Depixol) Trazodone Fluphenazine Decanoate depot (Modecate) Trifluoperazine Galantamine Trihexyphenidyl (Benzhexol) Guanfacine Valproic Acid/Semisodium valproate (Depakote) Haloperidol Venlafaxine Haloperidol Decanoate depot (Haldol Decanoate) Vortioxetine Hydroxyzine Zolpidem Imipramine Zopiclone Lamotrigine Zuclopenthixol Acetate (Clopixol Acuphase) Lisdexamfetamine Zuclopenthixol Decanoate depot (Clopixol) Lithium Carbonate MR (Priadel) Zuclopenthixol dihydrochloride Lithium Citrate (Priadel) Lofepramine NELFT approved Non-Formulary drugs: Prescribed in special circumstances Lofexidine (BritLofex) Baclofen Lorazepam Dosulepin Memantine Melatonin Methadone liquid Melperone Methylphenidate Omega-3-fatty acid compounds Mirtazapine Pirenzepine Moclobemide Propranolol Topiramate

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Appendix 21 List of Abbreviations

AED(s) Antiepileptic Drug(s) Anab Anabolic [steroids] BEN Benign Ethnic Neutropenia Benz Benzodiazepines BNF British National Formulary CAMHS Children and Adolescents Mental Health Services

CD CD Controlled Drug CG Clinical Guideline CNS Central Nervous System CPMS Clozaril Patient Monitoring Service DTG Drugs and Therapeutics Group FBC Full Blood Count MAOI(s) Monoamine Oxidase Inhibitor(s) MHRA Medicines and Healthcare Products Regulatory Agency NELFT North East London NHS Foundation Trust NG Nice Guideline NICE National Institute of Health and Clinical Excellence NPSA National Patient Safety Agency PIL Patient Information Leaflet POM Prescription Only Medicine POMH Prescribing Observatory for Mental Health SF Sugar-free SmPC Summary of Product Characteristics TAG/TA [NICE] Technology Appraisal Guidance

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Appendix 22a Potential intervention to support the implementation of the MHRA safety alert on the use of valproate in women of child-bearing age

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Appendix 22b Required safety precautions when prescribing valproate for women of child-bearing age

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Appendix 23 Antipsychotic Dosage Ready Reckoner [Adults]

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