Reference Number MMG, GMW, NICE TA 217 Classification SHARED CARE PROTOCOL. Issue Date May 2011

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1 SHARED CARE PROTOCOL for DONEPEZIL, GALANTAMINE, RIVASTIGMINE AND MEMANTINE in Dementia. SCOPE Greater Manchester West Mental Health NHS Foundation Trust NHS Salford NHS Bolton NHS Trafford Issue Date May 2011 Author(s) Originator(s) Gillian Moss, GMWMHT, NHS Trust Sue Watts, MMG, GMWMHT, NHS Trust Joan Miller, MMG, GMWMHT, NHS Trust Claire Vaughan NHS Salford To be read in conjunction with the following documents NICE Technology Appraisal no 217,March 2011 NICE Guideline Dementia, March 2011 British National Formulary (current edition) Summary of Product characteristics for individual drugs Authorised by MMG, GMW Mental Health NHS Foundation Trust Bolton, Trafford and Salford PCTs MMGs Review Date May 2013 Reference Number MMG, GMW, NICE TA 217 Classification SHARED CARE PROTOCOL Replaces Local Shared care Protocols for prescribing of anti dementia drugs Donepezil, Galantamine and Rivastigmine November Introduction The National Dementia Strategy has identified the need for effective collaboration among agencies and seamless services between primary care and specialist services. Local Memory Clinics are now well established and this Shared Care Protocol (SCP) will facilitate the prescribing of these amber drugs in primary care. Please note that specialist services are unlikely to remain involved indefinitely with people with dementia and their carers and will focus mainly on patients mental health issues. At present, Primary Care is the main source of continuity of care and support for people affected by dementias from time of diagnosis until end of life. However, dementia services will review all patients being managed under this SCP every six months and will be available to be consulted regarding this shared care throughout the time patients remain managed under it. 2. Scope This shared care protocol covers people referred with mild to moderate dementia who are clinically stable and those with moderate to severe dementia who require treatment with memantine as per NICE Guidance. Management of individuals with dementia with challenging behaviours, psychosis or significant mood disorder is beyond the scope of this document. 1

2 3. Drugs included Donepezil Galantamine Rivastigmine Memantine NICE concluded that therapy should be initiated with a drug with the lowest acquisition cost. However, an alternative acetyl cholinesterase inhibitor could be prescribed where it is considered appropriate having regard to adverse event profile, expectations around compliance, medical co morbidity, possibility of drug interactions, and dosing profiles. Memantine should only be used in patients with moderate Alzheimer s disease who are intolerant of or have a contraindication to AChE inhibitors or those patients with severe Alzheimer s disease. The drug patents for Rivastigmine, Galantamine and Donepezil all expire in early 2012 and generic forms with a cheaper acquisition cost are likely to become available. The solution, sustained release tablets and patch formulations will, however, remain branded products and the price of these will not reduce. For this reason these formulations should be reserved for when there are severe swallowing difficulties or compliance issues. 4. Licensed indications DRUG INDICATION DOSAGE RANGE FORMULATION Donepezil Mild to moderate Alzheimer s disease 5-10mg per day Tablets Orodispersible tablets. Galantamine Mild to moderate 8-24mg per day as single Sustained release tablets Alzheimer s disease daily dose 8-24mg per day in 2 divided 4mg per ml Oral solution doses 8-24mg per day in 2 divided Tablets doses Rivastigmine Mild to moderate 3-12mg daily in 2 divided Hard Capsules Alzheimer s disease, dementia in Parkinson s doses 3-12mg daily in 2 divided 2mg per ml oral solution disease doses 4.6mg in 24hours 9.5mg in 24 hours Transdermal patches 4.6mg or 9.5mg/24hr Memantine Treatment of patients with moderate to severe Alzheimer's disease. The recommended starting dose is 5 mg per day, which is stepwise increased over the first 4 weeks of treatment reaching the recommended maintenance dose as follows: Week 1: 5mg once daily Week 2: 10mg once daily Week 3: 15mg once daily Week 4: 20mg once daily Recommended maintenance dose is 20mg once daily Tablets 5mg 10mg 15mg 20mg Oral solution pump 5mg/0.5mls ( one pump) Lewy Body Disease This is a diagnosis of exclusion and there are no definitive investigations. Patients with Lewy Body Disease may present with complex and challenging symptoms, which are very difficult to manage. Patients with LBD are notoriously sensitive to medication, especially anti-psychotics and this causes unique management problems. There is no ICD 10 classification for LBD, however, Dementia in Parkinson s disease is classified and is part of the same spectrum of disorder. It is recognised within the NICE Guideline for Dementia that this condition may respond very well to the prescription of acetyl 2

3 cholinesterase inhibitors and as such their use is included within this protocol. Rivastigmine is licensed for Dementia in Parkinson s disease. The GMMMG RAG group has recently reclassified the use of acetyl cholinesterase inhibitors in the treatment of Lewy Body Disease as amber, and so it is covered by this SCP. 5. Therapeutic use These drugs will be prescribed in line with NICE guidance TA 217; March Contraindications and Cautions For full list of cautions/ contra indications and more information see BNF/SPC. Cholinesterase Inhibitors Contraindications Patients with known sensitivity to the active ingredient or excipients Pregnancy and lactation Severe liver disease (see individual SPCs for advice) Severe renal disease (see individual SPCs for advice) Although not an absolute contraindication, the service would advise avoiding cholinesterase inhibitors in individuals with second or third degree heart block, sick sinus syndrome or bradycardia persistently less than 50 until assessed and treated. Avoid or stop in patients with gastro-intestinal obstruction or recovering from gastrointestinal surgery. Cautions First degree AV Block and any bradycardia Other acute or uncontrolled cardiac conditions Predisposal to seizures (Note that the illness itself can cause predisposal to seizures - in investigating such patients the possibility of heart block or long sinusal pauses should be considered.) History of syncope Active peptic ulceration or predisposition to same as cholinesterase inhibitors can cause an increase in gastric acid secretions Patients predisposed to urinary obstruction (theoretical risk of bladder outflow obstruction) Asthma or Chronic Obstructive Pulmonary Disease - observe for any worsening of airways disease Body weight below 50kg (GI side effects more likely) Epilepsy Parkinsonian Syndrome (May cause a worsening of extra pyramidal symptoms). Administration concomitantly with other inhibitors of acetyl cholinesterase - agonists or antagonists of the cholinergic system should be avoided. (See drug interactions). Memantine Contraindications Hypersensitivity to the active substance or to any of the excipients. Cautions Caution in epilepsy, former history of convulsions or patients with predisposing factors for epilepsy Concomitant use of NMDA antagonists such as amantadine, ketamine and dextromethorphan should be avoided. Adverse drug reactions esp. CNS-related may be more frequent or more pronounced. Some factors that may raise urine ph may necessitate careful monitoring of the patient. These include drastic changes in diet e.g. from carnivore to vegetarian or massive ingestion of 3

4 alkalising gastric buffers. Urine ph may also be increased by states of renal tubular acidosis (RTA) or severe infections of the urinary tract with Proteus bacteria. Patients who have had a recent MI, uncompensated CCF(NYHA III-IV), or uncontrolled hypertension should be closely monitored due to limited evidence. Oral solution contains sorbitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. 7. Prescribing in pregnancy and lactation N/A 8. Dose regimen and titration Drug Initial Dose Increased / Maximum Doses Donepezil 5mg once daily at increased if necessary to 10mg after one month bedtime 1 Galantamine 4mg twice daily for 4weeks Increased to 8mg twice daily for 4weeks then consider increasing to 12mg twice daily Galantamine XL 8mg once daily for 4 weeks Increased to 16mg once daily for 4 weeks then consider increasing to 24mg daily Rivastigmine 1.5mg twice daily for at least 2weeks 3mg twice daily for at least two weeks, 4.5mg twice daily for at least two weeks,6mg twice daily for at least two weeks. Usual maintenance dose 3-6mg Rivastigmine patches Initially 4.6mg/24hour applied daily for at least 4weeks twice daily. Then 9.5mg/24hour daily (site of replacement patches needs to be rotated. Avoid using same area for 14days Memantine 5mg od for 7 days Then 10mg once daily for 7 days 15mg once daily for 7 days 20mg once daily thereafter Memantine solution 5mg/0.5mls : one downward pump for 7 days Then 10mg/1mls; two downward pumps for 7 days 15mg/1.5mls three downward pumps for 7 days 20mg/2mls; four downward pumps thereafter For detail explanation of using the pump see PIL or SPC. 1 Although the SPC suggests taking the once daily dose at bedtime, generally it is preferable to take the tablet after food, which reduces the risk of side effects in addition it may be practical to prescribe the tablet to be taken in the morning or when home carers visit. An individual who is frequently sensitive to a range of medications may need a smaller starting dose and a slower titration. Individuals who have difficulty with swallowing tablets may prefer a liquid or orodispersible preparation. A patient who suffers unpleasant gastrointestinal side effects may tolerate a transdermal patch. A patient or carer who has difficulty with complicated dose titrations may prefer the relatively straightforward titration regime of Donepezil. A patient who is receiving supervision in the community may need the drug prescribed at a specific time or via a monitored dosage system, which may dictate the choice of drug. 9. Drug Interactions Individuals being treated with drugs affecting cognitive function will require review as below before initiation of these drugs. Alcohol misuse: 4

5 Patients currently drinking unsafe amounts of alcohol will not be treated with cholinesterase inhibitors or memantine, but may be considered for treatment if they have Alzheimer s disease or Lewy Body Disease and their alcohol intake is reduced to be within safe limits. Benzodiazepines: Consideration must be given to whether the benzodiazepines may be affecting cognitive function especially in large doses, if so they must be reduced gradually and stopped. Non Steroidal Anti Inflammatory Drugs (NSAID): Increased risk of acid production with Cholinesterase inhibitors review need for NSAID. Patients may need increased monitoring for gastric complications if using NSAID. Drugs that may cause bradycardia e.g. digoxin, beta blockers: There is an increased risk of potentiation of bradycardia with cholinesterase inhibitors. This is particularly important in sick sinus syndrome or AV block. Increased monitoring is required. Tricyclic antidepressants have anticholinergic effects: Tricyclic antidepressants as an antidepressant: Consider changing to an SSRI/ SNRI or Mirtazapine if still requiring treatment. Individual drugs vary in their capacity to interact so check before prescribing an antidepressant. For example there is an interaction between paroxetine and galantamine, which may increase the levels of the cholinesterase inhibitor. Tricyclic Antidepressants as an adjunct to pain control: If prescribed for pain in small dosage, and still required after review, continue with caution. Other Anticholinergic drugs: review the need for these drugs as they may oppose the effect of cholinesterase inhibitors. Drugs with Cholinomimetic properties: o Peripherally Acting Cholinesterase inhibitors: Such as neostigmine or pyridostigmine. o Cholinergic drugs e.g. pilocarpine. Drug Interactions with memantine Warfarin: Memantine has been seen to increase INR in some patients and so close monitoring of INR may be required until patient is stabilised. L-dopa.dopaminergic agonists and anticholinergics may be enhanced. Effects of barbiturates and antipsychotics may be reduced. Concomitant administration with antispasmodics, dantrolene or baclofen can modify their effects and dosage adjustment may be necessary. Amantadine should be avoided due to risk of pharmacotoxic psychosis. Ketamine and dextromethorphan may have same effects and one case with phenytoin. Increased plasma levels possible with cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine. Possible reduced serum level of hydrochlorothiazide 10. Adverse effects See SPC for full list of side effects The main side effects seen in clinical practice for cholinesterase inhibitors are diarrhoea, muscle cramps, fatigue, nausea, vomiting, anorexia and insomnia. These are usually seen at initiation and at dose increases. The main side effects for memantine are dizziness, headache, constipation, somnolence and hypertension though adverse events were usually mild to moderate. 11. Baseline investigations Before referral to the memory service or specialist the GP should have carried out 5

6 Full Blood count Biochemical profile (include U and E s and LFT s) Thyroid function Serum B12 and folate Syphilis serology if applicable Lipid profile Cognitive screening (e.g. AMTS etc) 12. Ongoing monitoring by the GP The GP will monitor for ongoing side effects and discuss with memory clinic or specialist if any arise for advice on dose reduction, discontinuation etc. If patients cardiac health changes appropriateness of prescription will need to be discussed with the memory clinic team/specialist. 13. Secondary care contact information See local appendices. 14. Criteria for shared care Patient has been assessed in line with NICE guidance by memory services/specialist services. 15. Responsibilities for secondary care NICE guidelines state that these medications should be initiated by specialist services after a formal diagnosis has been made. Monitoring of the effects of these medications is undertaken by specialist services within a shared care protocol. See Appendices for local procedures in Bolton, Salford and Trafford. The following is a list of interventions that should be provided but this is subject to local variation and available resources. Undertake a comprehensive assessment of people newly presenting with possible mild to moderate dementia including domiciliary assessment when appropriate Arrange, undertake or refer for specialist investigations as appropriate, for example: o Neuroimaging MRI, SPECT, CT o Psychometric assessment Sensitive delivery of diagnosis Formulate an appropriate care plan involving other agencies as necessary Provide information and support including adjustment to diagnosis, advice around secondary prevention and management of condition to patients and carers. Provide advice about psychosocial management of cognitive impairments Occupational Therapy interventions, as required Initiate, or provide information for GP to initiate or continue medication where appropriate. Monitor effects of medication and associated side effects Signpost patients to other services where appropriate Inform GP of patient s progress. Inform GP of any change in medication or if medication is to be stopped. Liaison with o Primary Care o Social services o Liaison with local voluntary agencies o CMHT o Cerebral Function Unit or local specialist neurology service. o Other agencies as relevant e.g. Court of Protection, DVLA, Police 6

7 If and when dementia becomes severe or treatment has been ineffective, review and discontinue medication as appropriate, provide support and further signposting to services as needed. 16. Responsibilities for GP Provide regular prescriptions for cholinesterase inhibitors or memantine as per locally agreed protocols. See Appendices for local procedures in Bolton, Salford and Trafford. Be aware of side effects and common drug interactions as documented in this SCP. Provide regular health checks including where relevant the review of clients with vascular dementia or mixed dementia and provision of advice about lifestyle. Inform specialist services of any relevant physical health problems at the earliest opportunity. If patient suffers any adverse reaction, GP should liaise with secondary care/specialist services. If patient develops bradycardia with symptoms on cholinesterase inhibitors, such as lightheadedness or syncope, stop the drug and notify Memory Clinic. If patient develops bradycardia without symptoms and if the rate is persistently less than 50, stop the drug and notify Clinic, if rate is 50-60, continue drug and notify Memory Clinic. If patient develops second or third degree AV block, stop drug, consider referral to cardiology and notify memory clinic. The specific needs of older and cognitively impaired people should be taken into account. Please consider: Simple drug regimes, preferably no more than once or twice daily dosages Use of compliance aids Involving carers in discussions about medication and heath promoting advice Providing essential information in writing Effects of polypharmacy medication regimes need regular review and simplification Prompt treatment of intercurrent physical conditions that may worsen symptoms of dementia People with dementia may need a more flexible appointments system It may be in the best interests of people with dementia to keep carers informed and capacity assessments may need to be undertaken when considering issues of confidentiality Assessment of needs and health of informal carers should be offered. Advice for patients having General Anaesthetics: Donepezil, Galantamine and Rivastigmine Donepezil, Galantamine and Rivastigmine can enhance the effects of suxamethonium and the duration of the block may be prolonged. Donepezil and Rivastigmine can antagonise the effects of non-depolarising muscle relaxants such as atracurium, cisatracurium, mivacurium, pancuronium, rocuronium, vecuronium. Memantine No specific studies looking at use of memantine in patients undergoing surgery.in addition the company are not aware of any studies looking at memantine use with anaesthetics. Theoretically there may be a risk of pharmacotoxic psychosis if memantine is used concomitantly with ketamine. This is based on a report for amantadine as there are no reports with ketamine specifically (April2011). Neuroleptics and anticholinergics used in surgical procedures may interact with memantine. The effect of neuroleptics may be reduced and the effect of anticholinergics may be enhanced although these interactions may be overcome by change of dose. See section 9 and SPC for full list of drug interactions. 7

8 Drug Situation Advice Donepezil Planned operations Stop 2 3 weeks before operation for complete wash out. Rivastigmine Emergency operations Post-operative Planned Operations Emergency operations Post-operative Inform the anaesthetist of potential of prolonged muscle relaxation. Re-introduce during post-surgical rehabilitation. Miss the last dose prior to surgery, i.e., if the operation is in the morning miss the previous night-time dose. Inform the anaesthetist of potential of prolonged muscle relaxation. Re-introduce during post-surgical rehabilitation. Galantamine Planned Operations stop two days before surgery for washout Emergency operations Inform the anaesthetist of potential of prolonged muscle relaxation. Post-operative re-introduce during post-surgical rehabilitation Memantine Planned operations If a decision is made to discontinue memantine before surgery the total washout period would be 2 to 3weeks. When to restart memantine will depend on the dose and half life of the drug used in surgery. 17. Responsibilities of the patient/carer The GP or memory clinic/specialist staff should be informed of any adverse effects to treatment, compliance issues with treatment, deterioration in physical health and progression of dementia. 8

9 18. Supporting documentation APPENDIX 1 : Statement of Agreement between GP and Consultant. REFFERAL FORM FROM CONSULTANT PSYCHIATRIST TO GP SHARED CARE PROTOCOL for CHOLINESTERASE INHIBITORS From: (Name of Consultant Psychiatrist) To: (Name of GP) Name of GP practice: Name of Patient: Date of Birth: NHS Number: Medication Prescribed: Reason for Choice (tick as appropriate): Indication (delete as appropriate): Name of Memory Clinic Contact: Telephone Number Cost effectiveness Poor tolerance of other options Simplicity of regime Licensed indication Swallowing problems Side effect profile Compliance Other Alzheimer s Disease / Dementia in Parkinson s Disease For the Consultant Psychiatrist I would be grateful if we could adopt the shared care protocol for the above patient. I accept my responsibilities as outlined in the enclosed SCP. Signed Consultant Date: Psychiatrist/Senior Clinician For the GP I accept my responsibilities as outlined in the enclosed guideline. YES/NO Signed GP Date: 9

10 Local Salford Service Variations Appendix 2 Diagnosis and Early Intervention for Mild to Moderate Dementias Including Treatment with Antidementia Drugs. 1. Referrals to the Memory Clinic 1.1 Referrals may be received from a variety of sources; mainly from Primary Care, but many are received from Social Services, CMHT s, Neurology, Department of Health Care for the Elderly, General Psychiatry services and other secondary care sources. Prior to referral, the referring agent should explain the reason for the referral to the patient and carer as appropriate with a brief description of the service to which they are being referred. 1.2 The Memory Clinic accepts referrals of individuals of all ages with possible mild to moderate dementia requiring assessment, diagnosis and consideration for treatment in keeping with the recommendations of the National Dementia Strategy: This may include individuals with mild cognitive impairment, some of whom will later progress to dementia (see NICE, NDS). 1.3 The service does not see urgent referrals or people whose main presenting problems include significant challenging behaviours, major mood disorder or psychotic symptoms. Referrals of people with these problems should be addressed initially to the Older People s CMHT single point of entry (Tel: ), or A and E in an emergency. 1.4 If major physical investigations are in progress consider delaying referral until stable/consult clinic for advice. 1.5 Referrals should include the following information (see standard referral form attached) Demographic data Brief history of presenting problem Dementia screening test results (see below) Information about recent physical assessment Blood pressure Medical history and current medication Use of compliance aids ECG if possible/available Recent hospital correspondence/test results if relevant Information about smoking and alcohol intake (and other substance misuse if relevant) Contact details for patient and main carer Risks Whether it is reasonable to ask patient to attend a clinic 1.6 Dementia screening tests Full Blood count Biochemical profile (include U and E s and LFT s) Thyroid function Serum B12 and folate Syphilis serology if applicable Lipid profile Cognitive screening (eg AMTS etc) 2.0 Specialist Service Responsibilities Undertake a comprehensive assessment of people newly presenting with possible mild to moderate dementia including domiciliary assessment when appropriate Arrange, undertake or refer for specialist investigations as appropriate, for example: 10

11 o Neuroimaging MRI, SPECT, CT o Psychometric assessment Sensitive delivery of diagnosis Formulate an appropriate care plan involving other agencies as necessary Provide information and support including adjustment to diagnosis, advice around secondary prevention and management of condition to patients and carers Advice about psychosocial management of cognitive impairments Occupational Therapy interventions Recommend medication based on cost effectiveness, individual patient tolerance, simplicity of dosage regime, licensed indication, ability to swallow, side effect profile etc. Provide information for GP to initiate or continue medication where appropriate Monitor effects of medication and associated side effects. This takes place in accordance with NICE guidance utilising a local protocol and takes place at least 6 monthly, in some cases by telephone. Inform G.P. of any change in medication including drug titration schedules or if medication is to be stopped. Signpost patients to other services where appropriate Inform G.P. of patient s progress. Liaison with o Primary Care o Social Services o Age Concern/local voluntary agencies o CMHT o Cerebral Function Unit o Other agencies as relevant e.g. Court of Protection, DVLA, Police If and when dementia becomes severe, review and discontinue medication as appropriate, provide support and further signposting to services as needed. Educational Role Within available resources, memory clinic staff will contribute to educational programmes for a variety of agencies and including service users and carers. Research, evaluation and audit Memory Clinics will participate in well-designed research projects and continuously evaluate and audit services. Approaches will assess patient and carer experience will be incorporated on a regular basis. 3. Written information provided to patient 3.1 Information leaflets about the Memory Assessment and Treatment Service are provided with appointment details and may be provided to primary care if requested. 3.2 Information leaflets are available about all 3 cholinesterase inhibitors and are provided to patients and carers as appropriate. 3.3 Information leaflet on memantine are provided to patients and carers as appropriate All patients and carers receive information about their diagnoses, implications and proposed management. After initial face-to-face discussion, this may be provided in the form of standardised leaflets or individualised written material or a combination of both. This includes as appropriate, Information about driving in dementia, Issues relevant to mental capacity including o Lasting Power Of Attorney o Advance Directives Information about local support services for service users and carers. Other sources of relevant information such as web sites. 4. General Practitioner and Primary Care Services Refer to service according to guidance in paragraph 1.5 Initiate and continue regular prescriptions for cholinesterase inhibitors as per guidance from specialist services/secondary care. Be aware of side effects and common drug interactions Provide regular health checks including where relevant the review of clients with vascular dementia or mixed dementia and provision of advice about lifestyle. 11

12 Inform specialist services of any relevant physical health problems at the earliest opportunity. If patient suffers any adverse reaction, GP should liaise with secondary care/specialist services. If patient develops bradycardia with symptoms, such as light-headedness or syncope, stop the drug and notify Memory Clinic. If patient develops bradycardia without symptoms and if the rate is persistently less than 50, stop the drug and notify Clinic, if rate is 50-60, continue drug and notify Memory Clinic. If patient develops second or third degree AV block, stop drug, consider referral to cardiology and notify memory clinic. Back-up care available to GP from Hospital, including emergency contact procedures and help line numbers. Salford Memory Assessment and Treatment Service The Memory Clinic is not an emergency service, so there is no out of hours arrangement at present. During the day there is an answer phone system when administrative staff are not available. During the working day there is an emergency Duty System for the Department of Psychiatry of Later Life based at Humphrey Booth Resource Centre, and accessed via ). Emergencies out of hours should be referred to the Out of Hours GP service or A&E. 12