Donepezil, Galantamine, Rivastigmine and Memantine ESCA: For treatment of Alzheimer's disease AREAS OF RESPONSIBILITY FOR THE SHARING OF CARE This shared care agreement outlines suggested ways in which the responsibilities for managing the prescribing of Donepezil, Galantamine, Rivastigmine and Memantine for Alzheimer s disease can be shared between the specialist and general practitioner (GP). GPs are invited to participate. If GPs are not confident to undertake these roles, then they are under no obligation to do so. In such an event, the total clinical responsibility for the patient for the diagnosed condition remains with the specialist. If a specialist asks the GP to prescribe this drug, the GP should reply to this request as soon as practicable. Sharing of care assumes communication between the specialist, GP and patient. The intention to share care should be explained to the patient by the doctor initiating treatment. It is important that patients are consulted about treatment and are in agreement with it. Patients with Alzheimer s disease are under regular specialist follow-up, which provides an opportunity to discuss drug therapy. The doctor who prescribes the medication legally assumes clinical responsibility for the drug and the consequences of its use. RESPONSIBILITIES and ROLES Specialist responsibilities This is an NHS Suffolk document that has been adopted by the WSCCG.
1 Confirm diagnosis of Alzheimer s disease. 2 Ask the GP whether he or she is willing to participate in shared care after a 16 week stabilisation period and discuss the agreement with the patient and carer. 3 Discuss benefits, side effects and prescribing guidelines of treatment with the patient and carer. The patient and carer should be prepared for any sudden deterioration that may occur when the drug is stopped. Ascertain willingness by the patient to take their medication and co-operation (within the bounds of their illness) with the assessment of their illness before treatment is initiated. Assurance of compliance may need to come from either the carer or care worker. 4 Assess donepezil, galantamine, rivastigmine or memantine dosage with particular reference to effectiveness in Alzheimer s disease. 5 Initiate donepezil, galantamine, rivastigmine or memantine treatment. 6 Communicate any changes in treatment with the GP promptly. 7 Monitor response to treatment. Treatment should only be continued where there has been an improvement or no deterioration in MMSE score or with evidence of global improvement on behavioural and/or functional assessment. An assessment of compliance should also be made at this stage. 8 Monitor cognition, behaviour and function unless the GP has agreed to do so. Advise the GP on frequency of monitoring & what to do when the parameters change. 9 An assessment by a hospital specialist will take place 6 months after the GP has agreed to prescribe. Continued assessment will be offered where the client and or their family have specific needs. 10 If necessary, supervise the withdrawal of treatment and provide supporting advice to the patient and carer. 11 Ensure clear back-up arrangements exist for GPs, including direct telephone helpline for advice and support. 12 Report adverse events to the CSM. www.mhra.gov.uk/safetyinformation/reportingsafetyproblems/index.htm General Practitioner responsibilities 1 After the four-month stabilisation period, any GP who is willing to accept the shared care agreement will notify the hospital specialist in writing, without undue delay, of their acceptance. 2 Prescribe donepezil, galantamine, rivastigmine or memantine at the dose advised by the specialist. 3 Receive and follow specialist advice on any changes in treatment. 4 Monitor the patient s general health and well being and liaise with the carer or care-worker as appropriate. 5 Seek specialist advice if the patient experiences adverse reaction/interaction or (for donepezil, galantamine or rivastigmine) MMSE drops below 10/30. 6 Refer back to specialist in the event of deteriorating clinical condition. 7 Report adverse events to specialist and CSM. www.mhra.gov.uk/safetyinformation/reportingsafetyproblems/index.htm 8 Keep mental health teams appraised of progress as appropriate and contact the specialist staff if there are any concerns or consider that the medication should be stopped. 9 If therapy has to be stopped, the specialist service must be contacted ASAP. Patient/Carer role 1 Report any adverse effects to the specialist or GP whilst taking donepezil, galantamine or rivastigmine. 2 Share any concerns in relation to treatment with donepezil, galantamine, rivastigmine or memantine with the specialist or GP. 3 Report to the specialist or GP if he or she does not have a clear understanding of their treatment. 4 Notify specialist services if the medication is stopped. BACK-UP ADVICE AND SUPPORT Suffolk Mental Health Partnership Trust Contact details Telephone No. Bleep: Fax: Email address: Specialist doctor Dr Gillian Collighan (East) Dr Anna King (East) Dr Sylvia Ferrera (West) Dr Ruth Chipperfield (West) Dr Judy Rubinsztein (West) Specialist nurse Annie Atkinson (East) Jane Polley (East) David Jarrold (West) 01473 891891 01473 329876 01284 713680 01284 712575 01284 713664 01473 329874 01473 329866 01284 748516 Gillian.collighan@smhp.nhs.uk Anna.king@smhp.nhs.uk Sylvia.ferrera@smhp.nhs.uk Ruth.chipperfield@smhp.nhs.uk Judy.rubinsztein@smhp.nhs.uk Annie.atkinson@smhp.nhs.uk Jane.polley@smhp.nhs.uk David.jarrold@smhp.nhs.uk
Hospital Pharmacy dept SMHP Clinical Pharmacist 01473 329798 (East) West Suffolk Hospital 01284 713232 (West) Medicines Information 01284 713109 01284 713000 01284 druginfo@wsh.nhs.uk bleep 984 713918 SUPPORTING INFORMATION Therapeutic review This shared care is based on revised guidance given by the National Institute for Clinical Excellence in March 2011. (Donepezil, Rivastigmine and Galantamine (review) and Memantine for the treatment of Alzheimer s disease. Available at NICE website: www.nice.org.uk ). In summary, the review advises that donepezil, galantamine and rivastigmine are recommended as options for the treatment of mild to moderate Alzheimer s disease. Memantine is recommended as an option for people with moderately severe to severe Alzheimer s disease. A recommendation was made that if GPs were to be asked to supply these drugs, prescribing should be undertaken under a shared care document. The guidance did not assess the benefits of these drugs in non- Alzheimer dementias (such as dementia with Lewy bodies). Therefore this shared care guideline does not cover the treatment of these forms of dementia. A brief summary of Alzheimer s disease and its treatment Alzheimer s disease (AD) is the most common form of dementia although there are difficulties both with the diagnosis and with classification of the stages of the disease making exact patient numbers difficult to predict. It has been estimated that 26% of women and 21% of men over 85 years of age have some form of dementia, of which a little more than half have AD. Measurement tools for AD are imprecise but for cognitive outcome, MMSE (Mini Mental State Examination) scored out of 30 (best) and ADAS-cog (Alzheimer s disease Assessment Scale cognitive subscale) are commonly used. There are a number of other measures, which are primarily research tools. Mild AD is usually associated with an MMSE of 21 to 26. Moderate with an MMSE of 10-20 and severe AD with an MMSE of less than 10. As AD progresses, acetylcholine (a neuronal transmitter) is produced in diminishing quantities. Donepezil, Galantamine and Rivastigmine all inhibit acetylcholinesterase, the enzyme that metabolises acetylcholine.
Memantine has a different mode of action. Memantine belongs to a group of medicines called NMDAreceptor antagonists. Memantine acts on these NMDA-receptors improving the transmission of nerve signals and the memory These drugs do not prevent the eventual outcome of the dementing process but merely postpone the onset of more severe impairment in a proportion of patients. Initial referrals under these guidelines may come from either GPs or another hospital specialist The referring doctor should screen the patient to exclude reversible causes of dementia. Recommended tests for screening dementia: FBC, Serum B12 & folate, U&Es, glucose, LFTs, TFT Ca 2+ (consider gamma GT if? alcohol problems, ESR/CRP, VDRL/TPHA, syphilis EIA), Where indicated urinalysis for Glucose/infection Referral should be made to the specialist memory clinics Donepezil, Galantamine or Rivastigmine (chosen according to specialist preference/experience), will be considered for patients whose mini mental state examination (MMSE) is between 10 and 26 (mild to moderate Alzheimer s disease). NOTE: The accuracy of the MMSE may vary for several reasons: for example, English as a foreign language, educational attainment, and sensory impairment. It may not be the most significant parameter in assessment for all individuals. In these circumstances, the clinician should have the flexibility to prescribe outside the score of 10-26. A patient with Alzheimer s disease may be offered one of the other two drugs if the first is not tolerated or due to lack of clinical efficacy. Memantine will be considered for patients with moderate to severe Alzheimer s disease or for those with mild to moderate disease for whom acetylcholinesterases are contraindicated. Dosage and Administration Summary prescribing information for guidance only; please refer to the full SPC (available at www.medicines.org.uk, local specialist or medicines information centre. Stopping Treatment Treatment should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional or behavioural symptoms Patients who continue on treatment should be reviewed regularly using cognitive, global,functional and behavioural assessment. Treatment should be reviewed by an appropriate specialist team. Carers views on the patient s condition at follow-up should be sought.
Donepezil (Aricept ) Pharmacology Specific and reversible inhibitor of acetylcholinesterase Preparations available 5mg and 10mg tablets and orodispersible tablets. Licensed indications symptomatic treatment of mild to moderately severe Alzheimer s dementia Recommended dosage and administration 5mg once daily in the evening for at least one month, increasing after assessment to a maximum of 10mg once daily Contra-indications pregnancy and breast feeding Cautions - sick sinus syndrome and other supraventricular abnormalities, pts at risk of peptic ulcers, asthma, obstructive airway disease. Monitoring as per NICE guidance Drug interactions neuromuscular blocking agents, drugs with anticholinergic action, drugs that interact with P450 isoenzymes (such as quinidine, ketoconazole, itraconazole, erythromycin, rifampicin, phenytoin and carbamazepine (mainly in vitro studies). Adverse effects most commonly diarrhoea, muscle cramps, fatigue, nausea, vomiting, and insomnia Prescribing costs see table 1
Galantamine (Reminyl ) Pharmacology Competitive and reversible inhibitor of acetylcholinesterase, and also an enhancer of the intrinsic action of acetylcholine on nicotinic receptors. Preparations available 4mg, 8mg and 12mg galantamine tablets or modidified release capsules Licensed indications symptomatic treatment of mild to moderately severe dementia of the Alzheimer type Recommended dosage and administration Administer twice daily, preferably with morning and evening meals. Recommended starting dose is 4mg twice daily for four weeks, then maintenance with 8mg twice daily increasing after four weeks up to 12mg twice daily if required. Contra-indications severe hepatic or severe renal failure (as no safety data exists) Precautions sick sinus syndrome, supraventricular cardiac conduction abnormalities, patients at increased risk of peptic ulcers, severe asthma or obstructive pulmonary disease, urinary outflow obstruction, galactose intolerance. Pregnancy and lactation. Monitoring see NICE guidance Drug interactions cholinomimetic agents and muscle relaxants, paroxetine, ketoconazole, erythromycin, quinidine, fluoxetine, fluvoxamine, ritonavir all making side effects more likely Adverse effects Most commonly nausea, vomiting, diarrhoea, abdominal pain, dyspepsia, anorexia, fatigue, dizziness, headache, somnolence and weight decrease. Prescribing costs see table 1
Rivastigmine (Exelon ) Pharmacology rivastigmine is an acetylcholinesterase inhibitor Preparations available 1.5mg, 3mg, 4.5mg and 6mg hard capsules and patch 9.5 mg/24 h Licensed indications Symptomatic treatment of mild to moderately severe Alzheimer s disease Recommended dosage and administration Administer twice daily with morning and evening meals. The capsules should be swallowed whole. The initial starting dose is 1.5mg twice daily. If this dose is well tolerated after a minimum of two weeks the dose may be increased to 3mg twice daily. Subsequent increases up to 4.5mg twice daily then 6mg twice daily may be considered after a further two weeks. The maximum daily dose is 6mg twice daily. Contra-indications severe liver impairment (no studies in these patients) Precautions sick sinus syndrome or conduction defects, patients at increased risk from peptic ulcer disease, patients with a history of asthma or obstructive pulmonary disease. Patients predisposed to urinary obstruction or seizures. Monitoring see NICE guidance Drug interactions succinylcholine-type muscle relaxants, other cholinomimetic drugs and anticholinergic medications. No other significant drug interactions have been observed. Adverse effects Asthenia, anorexia, dizziness, nausea, somnolence and vomiting. Female patients were found to be more susceptible to nausea, vomiting, loss of appetite and weight loss. Prescribing costs see table 1 Side Effects All suspected reactions (including those considered not to be serious and even where the causal link is uncertain) should be reported to the CSM. www.mhra.gov.uk/safetyinformation/reportingsafetyproblems/index.htm Monitoring Parameter Frequency of monitoring Action Cognition At initiation of treatment, at 4 months, at 10 months, and as a baseline prior to medication being stopped. Behaviour At initiation of treatment, at 4 months, at 10 months, and as a baseline prior to medication being stopped. ADL Function At initiation of treatment, at 4 months, at 10 months, and as a baseline prior to medication being stopped. Mini Mental State Examination, informant review Clinical Assessment, informant review Clinical Assessment, informant review
Memantine (Ebixa ) Pharmacology an NMDA receptor antagonist Preparations available 10mg and 20mg film coated tablets and 5mg/pump oral solution. Licensed indications Treatment of patients with moderate to severe Alzheimer's disease Recommended dosage and administration The maximum daily dose is 20 mg daily. In order to reduce the risk of undesirable effects the maintenance dose is achieved by upward titration of 5 mg per week over the first 3 weeks as follows: Week 1 (day 1 7): The patient should take one 5 mg tablet/half a 10 mg tablet/0.5 ml solution (5 mg) equivalent to one downward pump, per day for 7 days. Week 2 (day 8 14): The patient should take one 10 mg tablet/1 ml solution per day (10 mg) equivalent to two downward pumps, per day for 7 days. Week 3 (day 15 21): The patient should take one 15 mg tablet/one and a half 10 mg tablets/1.5 ml solution per day (15 mg) equivalent to three downward pumps, per day for 7 days. From Week 4 on: The patient should take one 20 mg tablet/two 10 mg tablets/2 ml solution per day (20 mg) equivalent to four downward pumps, once a day. Maintenance dose The recommended maintenance dose is 20 mg per day. A titration pack is also available Contra-indications Hypersensitivity to the active substance or to any of the excipients Cautions - Caution is recommended in patients with epilepsy, former history of convulsions or patients with predisposing factors for epilepsy. Concomitant use of N-methyl-D-aspartate (NMDA)-antagonists such as amantadine, ketamine or dextromethorphan should be avoided. These compounds act at the same receptor system as memantine, and therefore adverse drug reactions (mainly CNS-related) may be more frequent or more pronounced Monitoring as per NICE guidance Drug interactions ). Due to the pharmacological effects and the mechanism of action of memantine the following interactions may occur: The mode of action suggests that the effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with NMDA-antagonists such as memantine. The effects of barbiturates and neuroleptics may be reduced. Concomitant administration of memantine with the antispasmodic agents, dantrolene or baclofen, can modify their effects and a dosage adjustment may be necessary. Concomitant use of memantine and amantadine should be avoided, owing to the risk of pharmacotoxic psychosis. Both compounds are chemically related NMDA-antagonists. The same may be true for ketamine and dextromethorphan (see also section 4.4). There is one published case report on a possible risk also for the combination of memantine and phenytoin.
Other active substances such as such as cimetidine, ranitidine, procainamide, quinidine, quinine and nicotine that use the same renal cationic transport system as amantadine may also possibly interact with memantine leading to a potential risk of increased plasma levels. There may be a possibility of reduced serum level of hydrochlorothiazide (HCT) when memantine is coadministered with HCT or any combination with HCT. Adverse effects most commonly constipation, hypertension, dyspnoea headache, dizziness and drowsiness Prescribing costs see table below Produced by Dr R Butler, Consultant Psychiatrist, SMHPT. Dr L Head, Consultant Psychiatrist, SMHPT. D Jarrold, Lead Nurse, Mental Health in Later Life, SMHPT. E Johnston, Head of Pharmacy Services, SMHPT April 2011. Table 1