Bro Taf Localities Drugs & Therapeutics Committee SHARED CARE Drugs: Acetylcholinesterase inhibitors - Donepezil, Rivastigmine and Galantamine (Cardiff and Vale and Cwm Taf) Protocol No. CV 52 N-methyl-D-aspartate (NMDA) Receptor Antagonist Memantine (CWM TAF ONLY) Indication: Acetylcholinesterase Inhibitors (donepezil, rivastigmine, galantamine) used in the treatment of mild and moderate Alzheimer s disease (AD) and rivastigmine for symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson s disease. N- methyl-d-aspartate (NMDA) receptor antagonist (memantine) used in the management of moderate Alzheimer s disease (AD) in people unable to take/tolerate Acetylcholinesterase inhibitors and as an option for managing severe Alzheimer s disease (Cwm Taf only). General Guidance This protocol sets out details for the shared care of patients taking the anticholinesterases donepezil, rivastigmine and galantamine and the NMDA receptor antagonist memantine and should be read in conjunction with the General Guidelines for Shared Care. Sharing of care requires communication between the specialist, GP and patient/carer. The intention to share care should be explained to the patient by the doctor initiating treatment. The doctor who prescribes the medication legally assumes responsibility for the drug and the consequences of its use. Prescribers have a duty to keep themselves informed about the medicines they prescribe, their appropriateness, effectiveness and cost. They should also keep up to date with the relevant guidance on the use of the medicines and on the management of the patient s condition. Background Donepezil, galantamine and rivastigmine (acetylcholinesterase inhibitors) are recommended as options for managing mild to moderate Alzheimer s disease. All three increase the concentration of acetylcholine at sites of neurotransmission while galantamine also modulates activity at nicotine receptors. Rivastigmine is also licensed for mild to moderately severe dementia in patients with idiopathic Parkinson s disease. Memantine (For use in Cwm Taf only) is an NMDA receptor antagonist which blocks the effects of pathologically elevated levels of glutamate that may lead to neuronal dysfunction and is used where Acetylcholinesterase inhibitors are not suitable / tolerated or as an option for managing severe Alzheimer s disease. When using assessment scales to determine the severity of Alzheimer s disease, physical, sensory or learning disabilities or communication difficulties (e.g. patients not fluent in the language in which the test is administered) or level of education that could affect the results, should be taken into account. Appropriate adjustments should be made.
The aims of treatment are to promote independence, maintain function and treat symptoms including cognitive, non-cognitive (hallucinations, delusions, anxiety, marked agitation and associated aggressive behaviour), behavioural and psychological symptoms. Treatment should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional or behavioural symptoms. Carer s views on the patient s condition at baseline and follow-up should be sought. (NICE Technology Appraisal Guidance 217, March 2011) Dose regimens Donepezil 5mg at bedtime, increased after at least 4 weeks to 10mg if necessary. Rivastigmine 1.5mg twice daily titrated in steps of 1.5mg twice daily at intervals of at least 2 weeks according to tolerance up to a maximum of 6mg twice daily. If treatment is interrupted for more than several days it should be reinitiated at 1.5mg twice daily and re-titrated. A transdermal preparation is commonly prescribed - initially 4.6mg patch daily, that can be increased to 9.5mg patch daily after 4 weeks. Galantamine the XL formulation commonly prescribed is given initially at 8 mg once daily for 4 weeks and then increased to 16 mg once daily for at least 4 weeks. Maintenance treatment is 16 24 mg once daily depending on tolerance and benefits. An older tablet formulation and a liquid preparation are also available to be given twice a day. Memantine 5mg once daily increased in steps of 5mg at weekly intervals up to a maximum of 20mg once daily. Responsibilities A. Consultant responsibilities 1. Assessment of the patient to include cognitive, global and behavioural function and abilities in terms of activities of daily living. Carers views of the patient s condition at baseline will also be sought. 2. When treatment is considered to be appropriate and following full discussion with the patient (and/or carer) of benefits and risks, initiate treatment with donepezil, rivastigmine, galantamine or memantine and send Shared Care request form with Shared Care Protocol to GP. 3. When a GP positive response to Shared Care has been received and once patient is stable on a maintenance dose of medication, send a letter to GP handing over the Shared Care of the patient to the GP asking them to continue treatment, with an outline of follow up arrangements for continued monitoring by specialist services. 4. Provide written and verbal information to patient and carer about drug treatment, to facilitate concordance with medication. 5. Advise the GP on dose changes required, continuing, or stopping drug therapy as appropriate. 6. Respond promptly to any request from GP for advice or a request to review the patient. 7. Patients who continue on treatment should be reviewed regularly (at least annually) using cognitive, global, functional and behavioural assessment
8. Agree to review and monitor patients already on acetylcholinesterase inhibitors or memantine who come into Cardiff and Vale or Cwm Taf from other areas, using the same shared care principles outlined above. B. General practitioner responsibilities 1. Within one week of receipt, return the completed Shared Care request form to indicate whether or not willing to undertake Shared Care. 2. Prescribe maintenance doses of donepezil, rivastigmine, galantamine or memantine if considered appropriate and as advised by consultant as part of the Shared Care agreement. 3. Monitor the general health and well being of the patient. 4. Refer to consultant if advice required on dose changes, continuing, or stopping drug therapy or any other drug-related issues of concern. 5. Report possible adverse effects of therapy to the consultant. 6. Prescribe acetylcholinesterase inhibitors or memantine for patients already taking them who move into Cardiff and Vale or Cwm Taf, whilst seeking information from previous prescriber where possible and referring to specialists for review and monitoring. C. Patient (carer) responsibilities 1. Consent to treatment with donepezil, rivastigmine, galantamine or memantine. 2. Attend appointments made with specialist centre and GP. 3. Report any side effects to the specialist or GP whilst taking donepezil, rivastigmine, galantamine or memantine. Monitoring Before treatment Diagnosis of Alzheimer s disease should follow a full assessment by an appropriate specialist in keeping with NICE Guidelines (CG42 Dementia). Before initiating treatment there should be an assessment of cognition, global function, activities of daily living and behaviour. During treatment Patients who continue on treatment should be reviewed regularly (at least annually) using cognitive, global, functional and behavioural assessment. Carers views on the patient s condition at follow-up should be sought. Treatment should be continued while the patient is showing worthwhile effects. Treatment should be discontinued if the patient is experiencing significant side effects and also when the patient has reached the terminal phase of their illness (where all medicines should be reviewed) Adverse effects Donepezil Common undesirable effects include diarrhoea, muscle cramps, fatigue, nausea, vomiting and insomnia. Other possible side effects reported include headache, pain, common cold, dizziness, anorexia, syncope, rash, pruritis, urinary incontinence, fatigue There have also been reports of psychiatric disturbances, including hallucinations, agitation and aggressive behaviour, which resolved on dose reduction or discontinuation of treatment. However, these symptoms may also sometimes respond to treatment with an anticholinesterase drug. Rivastigmine
Common undesirable effects are mainly gastrointestinal including nausea and vomiting loss of appetite and diarrhoea. Other possible side effects include abdominal pain, agitation, confusion, dyspepsia, headache, increased sweating, malaise, weight loss, tremor, somnolence, fatigue, asthenia. Adverse effects such as nausea, vomiting and abdominal pain may respond to the omission of one or more doses. If adverse effects persist, the daily dose should be reduced to the previous well-tolerated dose. Rivastigmine patch is associated with fewer gastrointestinal effects than the oral preparation, but the patch may be associated with skin irritation and local allergic reactions. Galantamine Common undesirable effects include nausea and vomiting. Other possible side effects include anorexia, weight decrease, confusion, depression, dizziness, somnolence, syncope, tremor, abdominal pain, diarrhoea, dyspepsia, asthenia, fatigue, fever, headache, malaise, fall, injury, insomnia, rhinitis, urinary tract infection. Memantine Common undesirable effects include dizziness, headache, constipation, somnolence, dyspnoea and hypertension. Contraindications Cautions Known hypersensitivity to any of the drugs or excipients (All) Severe liver impairment (Donepezil, Rivastigmine and Galantamine) Severe renal impairment (Galantamine) For Acetylcholinesterase inhibitors Sick Sinus Syndrome or conduction defects e.g. sino-atrial block, atrioventricular block Current or previous history of gastric or duodenal ulcers or patients predisposed to these conditions (e.g. taking non-steroidal anti-inflammatory drugs) History of urinary obstruction Asthmatic patients or those with obstructive pulmonary disease Epilepsy or a history of seizures (seizure activity may also be a manifestation of Alzheimer s disease) May exacerbate or induce worsening of extrapyramidal symptoms Mild and moderate hepatic impairment - titrate according to individual tolerability. Lower dose may be sufficient For Memantine Epilepsy, former history of convulsions or patients with predisposing factors for epilepsy. Drug interactions Acetylcholinesterase inhibitors Anticholinergics e.g procyclidine, benztropine, benzhexol, orphenadrineantagonism of effects Non- depolarising muscle relaxants- antagonism of effect
Memantine Drugs which reduce heart rate e.g. digoxin, betablockers additive effect. Inhibitors of Cytochrome P450 3A4 and 2D6- may increase the levels of anticholinesterases (consider dose reductions) Examples include erythromycin, ketoconazole, itraconazole, fluoxetine, paroxetine, quinidine, ritonavir. Suxamethonium anticholinesterases likely to exaggerate succinylcholine type muscle relaxation during anaesthesia. Other anticholinesterases e.g. neostigmine, pyridostigmine, carbechol, bethanechol, distigmine, pilocarpine and carbachol eye drops, edrophonium additive effects-avoid concomitant use. Ketamine increased risk of cns toxicity (avoid concomitant use) Dextromethorphan increased risk of cns toxicity (avoid concomitant use) Dopaminergics and Selegiline enhanced effect Amantadine increased risk of cns toxicity (avoid concomitant use) L-dopa, dopaminergic agonists, and anticholinergics effects may be enhanced. Barbiturates and antipsychotics effects may be reduced. Dantrolene or baclofen, effects may be modified and a dosage adjustment may be necessary. 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 of the memantine or the other medications listed. Hydrochlorothiazide (HCT) There may be a possibility of reduced serum level of hydrochlorothiazide when memantine is co-administered with HCT or any combination containing HCT. Warfarin although no causal relationship has been established there have been isolated cases of raised INR therefore close monitoring is advised. Contact information Prof. Antony Bayer Memory Team, Academic Centre, University Hospital Llandough, Penarth CF64 2XX. Tel No.02920 716977. Fax 02920 704244. Email memory.team@wales.nhs.uk Dr V M Aziz, Consultant Psychiatrist, Cwm Taf HB, Mental Health Unit, Ysbyty Cwm Cynon, New Road, Mountain Ash. RCT CF45 4BZ. Tel No. 01443 715124. Email victor.aziz@wales.nhs.uk. Approved July 2012 (updated March 2013) Date of review July 2015