Clinical Guideline / Formulary Document Pharmacy Department Medicines Management Services

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1 Clinical Guideline / Formulary Document Pharmacy Department Medicines Management Services DEMENTIA Pharmacological Treatment of Alzheimer s disease The three acetylcholinesterase (AChE) inhibitors (donepezil, galantamine and rivastigmine) are recommended options for mild to moderate Alzheimer s disease. Memantine is an option for moderate Alzheimer s disease in people who are intolerant of or have a contraindication to AChE inhibitors or for severe Alzheimer s disease. Prescribers should only start treatment with donepezil, galantamine, rivastigmine or memantine on the advice of a clinician who has the necessary knowledge and skills. This could include: secondary care medical specialists such as psychiatrists, geriatricians and neurologists other healthcare professionals such as GPs, nurse consultants and advanced nurse practitioners with specialist expertise in diagnosing and treating Alzheimer's disease. Any relevant physical, sensory or learning disabilities, or communication difficulties should be considered to ensure equality of access to treatment for service users from different ethnic groups and cultural backgrounds. Prescribers should discuss treatment options, benefits and risks with the service user and/or carer and seek carers views on the service user s condition at baseline. If prescribing an AChE inhibitor, treatment should normally be started with a drug with the lowest acquisition cost (taking into account required daily dose and the price per dose once shared care has started). However, an alternative AChE inhibitor could be prescribed if considered appropriate taking into account the adverse effect profile, expectations around adherence, medical comorbidity, the possibility of drug interactions, pharmaceutical and dosing profiles. When using pharmacological treatments in dementia, low initial doses and gradual dose increments are necessary. Monitor closely for any adverse drug reactions and review treatment if side effects are severe or intolerable (see Appendix 1). Further information on contraindications, cautions, interactions and side effects is available from manufacturer summaries of product characteristics available at: or the BNF. Carer views on the service user s condition at follow up should be considered. The decision whether to continue treatment with AChE inhibitors is highly patientspecific. NICE advises that treatment should be continued only when it is considered to be having a worthwhile effect on cognitive, global, functional and behavioural symptoms. Carer views on the service user s condition at follow up should be considered. Service users who continue on pharmacological treatments for dementia should be reviewed regularly using cognitive, global, functional and behavioural assessment. Prescribing, supply and treatment review should follow locally agreed arrangements. See Pan Mersey website for more information. Investigations / Screening Investigations are usually done in primary care, for suspected dementia. They include: Full blood count, ESR, urea and electrolytes, calcium, glucose, liver function tests, thyroid function tests; serum vitamin B12/folate levels, and iron studies, if indicated Other investigations include - midstream urine culture, chest x-ray, brain imaging and electrocardiography (ECG) if cardiovascular problems suspected Dementia Next Review: Jan

2 Other Dementias There is limited evidence on the treatment of non-alzheimer s dementias. NICE dementia guidance advises that if the underlying neurochemical deficit is similar, irrespective of the aetiology of the cognitive impairment, then it is possible that acetylcholinesterase inhibitors or memantine would produce a similar symptomatic effect in other types of dementia. It is therefore important to establish as far as possible from the evidence available whether there is a significant clinical improvement to be gained by treatment with AChE inhibitors or memantine in the other forms of dementia. Do not use acetylcholinesterase inhibitors in mild cognitive impairment. The potential benefits are unlikely to outweigh the increased risks of adverse events. NICE does not recommend the routine use of cholinesterase inhibitors or memantine for cognitive decline in vascular dementia. Mixed dementia should be managed according to what is considered the predominant cause of their dementia. Avoid use of antipsychotics in people with Parkinsons Disease dementia (PDD) or Dementia with Lewy Bodies [DLB]. People with DLB who have non cognitive symptoms causing significant distress to the individual, or leading to behaviour that challenges, should be offered an acetylcholinesterase inhibitor Behavioural and Psychological Symptoms of Dementia (BPSD) Behavioural and psychological symptoms of dementia include a range of non-cognitive symptoms, such as apathy, anxiety, depression, agitation, aggression, delusions and hallucinations, wandering, incontinence, altered eating habits, sexual disinhibition, shouting, hoarding, repeated questioning and sleep disturbances. Antipsychotics are sometimes prescribed for BPSD but produce only limited benefits and are associated with an increased risk of stroke and mortality, as well as other serious adverse events such as sedation, extrapyramidal side effects, dehydration, falls, chest infections and accelerated cognitive decline. Reducing inappropriate prescribing of antipsychotic medication for people with dementia is an urgent national priority. In cases of dementia associated with severe behavioural disturbance that requires urgent treatment (if violence, aggression and extreme agitation threaten the safety of the patient or others), an antipsychotic drug or a benzodiazepine may be given. The management of BPSD is discussed further below. Relevant NICE Guidance Dementia: supporting people with dementia and their carers in health and social care. NICE clinical guideline 42. November Last updated: September Available from: NICE TA217: Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. March Last updated May 2016 Available at: NICE Dementia quality standard [QS1]. June Related NICE quality standards Dementia Next Review: Jan

3 Dementia Prescribing Support Documentation for Primary Care Pan Mersey Area Prescribing Committee, DRUGS FOR DEMENTIA: INFORMATION FOR PRIMARY CARE Pan Mersey Area Prescribing Committee, Request by Specialist Clinician to the patient s GP to discharge a patient from secondary care services Pan Mersey Area Prescribing Committee, Request by Specialist Clinician to the patient s GP to take over the prescribing from secondary care services Dementia Next Review: Jan

4 Alzheimer s Disease - Pharmacological Management of Cognitive Symptoms First Line: Relative Cost Notes Acetylcholinesterase Inhibitors (AChEIs) Donepezil Tablets Brand Orodispersible tablets Oral solution Galantamine Tabs Brand Oral solution - Only dementia specialists in consultation with service user/carer should initiate treatment. Appropriate AChEI should be selected following consideration of cost, adverse effects, drug interactions, other conditions, expectations around concordance, and dosing profiles. Switching between agents may considered in cases of non-response or intolerance Continue AChEI only if benefits on cognitive, global, functional and behavioural symptoms - - Both 5mg and 10mg are effective doses. Elimination half-life is long at about 70 hours Oral solution and modified release preparations are available. Reductions in dose may be necessary in hepatic or renal impairment Rivastigmine Caps Brand Liquid Patches - Oral solution and patch also available; also licenced for mild to moderately severe dementia in idiopathic Parkinson's disease; Gastrointestinal side effects appear more frequent with rivastigmine. Patch may be appropriate in those unable to tolerate side effects of oral rivastigmine but application site reactions (erythema, pruritus, rash, vesicles) can occur Second Line: Relative Cost Notes Alternative AChEI - If initial AChEI not tolerated or not effective, switch to another AChEI not already tried. Memantine Tabs Branded Liquid - Recommended for moderate Alzheimer s disease in people who are intolerant of or have a contraindication to AChEIs or in severe Alzheimer s disease Only specialists in the care of people with dementia (in consultation with service user/carer) should initiate treatment. Dementia Next Review: Jan

5 Alzheimer s Disease - Pharmacological Management of Cognitive Symptoms -Continued Third Line: Relative Cost Notes Memantine + AChEI - There is growing evidence of additional clinical efficacy. Consultant initiation only. Monitoring and continual review of clinical benefit essential. Not Recommended Relative Cost Notes Vitamin E Ginkgo biloba Souvenaid Limited data available - difficult to determine evidence of clinical benefit Dementia Next Review: Jan

6 Other Dementias - Pharmacological Management of Cognitive Symptoms Mild Cognitive Relative Cost Notes Impairment AChEIs - Do not use acetylcholinesterase inhibitors for mild cognitive impairment because any potential benefits are unlikely to outweigh the increased risk of side effects Vascular Dementia Relative Cost Notes AChEIs Memantine - - DLB or PDD Relative Cost Notes AChEIs Memantine - - Mixed Dementia Relative Cost Notes AChEIs Memantine - - AChEIs and memantine are not licensed for the treatment of vascular dementia and should not be routinely prescribed for cognitive decline in vascular dementia Specialists may carefully consider exceptional use on a case-by-case basis (off-label use). People with mixed VaD and Alzheimer s may benefit. Further studies are needed to establish the role of AChEIs and memantine Use of AChE inhibitors may be considered in Parkinson s disease Dementia (PDD) or dementia with Lewy Bodies (DLB) on a case-by-case basis. BAP guidelines (2017) state that there is evidence to support treatment with rivastigmine and donepezil in Lewy Body Dementia and possible improvement with memantine. Rivastigmine is the only AChEI licensed for symptomatic treatment of mild to moderately severe dementia in idiopathic Parkinson's disease Memantine has not been widely investigated for use in DLB NICE advises that people with mixed dementia should be managed according to what is considered the predominant cause of their dementia. Dementia Next Review: Jan

7 Pharmacological Treatments for Alzheimer s Disease Drug Dose Contraindications and Cautions Key adverse effects and Interactions Donepezil (Aricept Eisai/Pfizer and nonproprietary formulation) - 5mg and 10mg film coated tablets - 5mg and 10mg orodispersible tablets 1mg/1ml Oral solution Licenced Indication Symptomatic treatment of mild to moderately severe Alzheimer's dementia Initially 5mg once daily at bedtime; increased after 1 month to a maximum of 10 mg once daily, if appropriate and tolerated **Lower doses required in those with renal and hepatic disease; or Slower titration, if initial side effects, as follows: Donepezil: 5mg OD for 6weeks; then double to 10mg OD for 6 weeks. Contra-indications - Hypersensitivity to donepezil - Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucosegalactose malabsorption Precautions Cardiovascular conditions e.g. sick sinus syndrome, sinoatrial or atrioventricular block, or other conduction defects - cardiac monitoring required. Gastrointestinal e.g ulcers, concurrent NSAIDs, undiagnosed nausea and vomiting; Genitourinary Risk of bladder outflow obstructions. Neurological Cerebrovascular disease; convulsions Pulmonary Conditions e.g. asthma or chronic obstructive pulmonary disease. Adverse effects - Very Common: nausea diarrhoea hallucinations headache. - Common: common cold, anorexia, agitation, aggressive behavior, dizziness, syncope, insomnia, abnormal dreams and nightmares, vomiting abdominal disturbances, muscle cramps, rash, pruritus, fatigue, urinary incontinence, pain. - Uncommon: seizures, bradycardia, gastro-intestinal haemorrhage, gastric and duodenal ulcers. - Rare sinoatrial block, AV block, hepatitis, extrapyramidal symptoms; potential for bladder outflow obstruction, rhabdomyolysis and neuroleptic malignant syndrome. Pharmacokinetic Interactions -Ketoconazole, quinidine, itraconazole and erythromycin, and CYP2D6 inhibitors, such as quinidine, fluoxetine, fluvoxamine, and paroxetine could inhibit the metabolism of donepezil Increased side effects possible - Enzyme inducers, such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the levels of donepezil - Can interact with concomitant inhibitors of acetylcholinesterase, agonists or antagonists of the cholinergic system - avoid. - Beta blockers that significantly reduce the heart rate and can cause bradycardia and hypotension. - Antipsychotics, increased risk of NMS. Dementia Next Review: Jan

8 Pharmacological Treatments for Alzheimer s Disease Drug Dose Contraindications and Cautions Key adverse effects and Interactions Galantamine (Reminyl, Shire and non-proprietary) - 8mg and 12mg tablets - 4mg/mL oral solution - 8mg, 16mg and 24mg modifiedrelease capsules Licenced Indication Symptomatic treatment of mild to moderately severe dementia of the Alzheimer type. Modified release capsules Initially 8mg once daily for 4 weeks; increased to 16mg once daily for at least 4 weeks. Maintenance treatment 16 24mg once daily according to clinical benefit and tolerability Tablet and liquid preparation Initially 4 mg twice daily for 4 weeks increased to 8 mg twice daily for 4 weeks; maintenance 8 12 mg twice daily Hepatic impairment - For immediate-release preparations in moderate impairment, initially 4 mg once daily (preferably in the morning) for at least 7 days, then 4 mg twice daily for at least 4 weeks; max. 8 mg twice daily; - For modified-release preparations in moderate impairment, initially 8 mg on alternate days (preferably in the morning) for 7 days, then 8 mg once daily for 4 weeks; max. 16 mg daily; Contra-indications - Hypersensitivity to galantamine or to any of the excipients. - severe renal impairment - Severe hepatic impairment Precautions Genitourinary risk of bladder outflow obstructions Cardiac disorders - 'sick sinus syndrome' or other supraventricular cardiac conduction disturbances -Use with medicinal products that significantly reduce heart rate concomitantly, such as digoxin and beta blockers -Uncorrected electrolyte disturbance. Patients with/or at risk of developing cardiovascular diseases. Gastrointestinal - peptic ulcers; concurrent non-steroidal anti-inflammatory drugs - Gastrointestinal obstruction or recovering from gastrointestinal surgery Neurological - may worsen Parkinsonian symptoms; has potential to cause seizures. Respiratory - history of severe asthma or obstructive pulmonary disease or active pulmonary infections. Adverse effects - Very Common: vomiting and nausea. - Common: anorexia, decreased appetite (weight loss), hallucinations, depression, syncope, dizziness, tremor, headache, somnolence, lethargy, bradycardia, hypertension, abdominal pain, diarrhoea, dyspepsia, sweating, muscle spasm, asthenia and falls. - Uncommon: dehydration, visual and auditory hallucinations, paraesthesia, hypersomnia, blurred vision, tinnitus, hypotension, flushing, muscular weakness, hepatic enzymes increased, retching, firstdegree AV block, sinus bradycardia, palpitations, supraventricular extrasystoles. - Rare: hepatitis, exacerbation of Parkinson s disease, seizures and serious skin reactions (Stevens-Johnson syndrome and acute generalized exanthematous pustulosis). Interactions - Food slows the absorption rate but not extent but food reduces side effects -Ketoconazole, quinidine, itraconazole and erythromycin, and quinidine, fluoxetine, fluvoxamine, and paroxetine could inhibit the metabolism of donepezil Increased side effects possible - Do not give with other cholinomimetics (e.g. donepezil, neostigmine, pyridostigmine, rivastigmine) - can antagonise the effect of anticholinergics - Interaction possible with drugs that significantly reduce the heart rate such as digoxin, beta-blockers, certain calcium-channel blockers and amiodarone. Caution with drugs that can cause torsades de pointes Dementia Next Review: Jan

9 Pharmacological Treatments for Alzheimer s Disease Drug Dose Contraindications and Cautions Rivastigmine (Exelon, Novartis and non-proprietary) - 1.5mg, 3mg, 4.5mg and 6mg capsules - 2mg/mL oral solution - 4.6mg/24 hours, 9.5mg/24 hours and 13.3mg/24 hours patches See BNF for dose equivalences and conversions Licenced Indications - Symptomatic treatment of mild to moderately severe Alzheimer's dementia. - Symptomatic treatment of mild to moderately severe dementia in patients with idiopathic Parkinson's disease. Capsules and oral solution Initially 1.5mg twice daily, with morning and evening meals ; may be increased in steps of 1.5mg twice daily at intervals of at least 2 weeks according to tolerance up to a maximum dose of 6mg twice daily Patches Initially a 4.6mg patch per day. This can be increased to a 9.5-mg patch per day after at least 4 weeks. After a further 6 months if well tolerated and cognitive deterioration or functional decline are demonstrated, the dose can be increased to 13.3 mg/24 hours patch daily Replace patch with a new one after 24 hours If treatment is interrupted for more than several days, re-initiate with 4.6 mg/24 h patch or Slower titration, if initial side effects, as follows: Rivastigmine: 1.5 mg bd for 4 weeks, followed by 1.5mg 3 mg for 4 weeks and finally 3 mg bd for 4 weeks Contraindications - Hypersensitivity to the active substance, other carbamate derivatives or to any of the excipients used in the formulation, Previous allergic contact dermatitis with rivastigmine patch - Severe liver impairment. Precautions Gastrointestinal - ulcers or history of ulcers. It may cause increased gastric acid secretions. Cardiovascular - in patients with sick sinus syndrome or conduction defects (sinoatrial block, atrioventricular block) Respiratory - history of asthma or obstructive pulmonary disease. Genitourinary urinary obstruction; risk of bladder outflow obstructions Neurological - cerebrovascular disease; seizures One of the excipients in Exelon oral solution is sodium benzoate. Benzoic acid is a mild irritant to the skin, eyes and mucous membrane. Key adverse effects and Interactions Adverse effects - Very Common: anorexia, dizziness, nausea, vomiting, diarrhoea, malaise, restlessness, fatigue, - Common: confusion, agitation, headache, somnolence, tremor, abdominal pain, sweating - Uncommon: insomnia, depression, syncope, weight loss (monitor body weight) - Rare: seizures, angina pectoris, gastric and duodenal ulcers, rash, - Very rare: urinary infection, hallucinations, extrapyramidal symptoms (and worsening of Parkinson s disease), bradycardia, atrial fibrillation, AV block, hypertension, gastro-intestinal haemorrhage, pancreatitis, Application site skin reactions with patch (e.g. erythema, application site pruritus, application site oedema, application site dermatitis, application site irritation), asthenic conditions (e.g. fatigue, asthenia), pyrexia, weight decreased Note -Adverse reactions may respond to omitting one or more doses or dose reduction -Transdermal patches may be less likely to cause gastro-intestinal disturbance Interactions - Caution is recommended when selecting anaesthetic agents. - Should not be given concomitantly with other cholinomimetic - Might interfere with the activity of anticholinergic medicinal products Dementia Next Review: Jan

10 Pharmacological Treatments for Alzheimer s Disease Drug Dose Contraindications and Cautions Memantine (Ebixa, Lundbeck and non-proprietary) 5mg, 10mg, 15mg, 20mg Initiation pack - 10mg and 20mg scored tablets - 5mg/actuation (10mg/mL) oral drops Licenced Indications Treatment of patients with moderate to severe Alzheimer's disease. Initially 5mg once daily and then increased in steps of 5mg at weekly intervals to a maximum of 20mg daily; max 20mg/day Can be taken with or without food Beware of the mechanism by which each product delivers the required dose. There is a risk of confusion between doses delivered by the pump device compared with doses delivered by the dropper Contraindications - Hypersensitivity to the active substance or to any of the excipients Precautions -Epilepsy or history of convulsions or predisposing factors for epilepsy - Recent myocardial infarction, uncompensated congestive heart failure (NYHA III-IV), or uncontrolled hypertension. - Severe hepatic impairment - Renal impairment when egfr less than 5 ml/minute/1.73 m 2 - Lactation and pregnancy. The oral solution contains sorbitol. Key adverse effects and Interactions Adverse effects - Common: drug hypersensitivity, somnolence, dizziness, hypertension, constipation, dyspnoea, headache, - Uncommon: fatigue, fungal infection, confusion, hallucinations, gait abnormal, cardiac failure, Venous thrombosis / thromboembolism - Very rare: seizures, post-marketing reports of depression, suicidal ideation and suicide. Interactions ** Amantadine, ketamine, or dextromethorphan may increase both the incidence and severity of adverse effects and should be avoided. - Memantine may alter the effects of the antispasmodics baclofen and dantrolene. - The effects of L-dopa, dopaminergic agonists, and anticholinergics may be enhanced by concomitant treatment with memantine - The clearance of memantine is reduced under alkaline urine conditions. Drastic changes in diet and drugs such as carbonic anhydrase inhibitors and sodium bicarbonate should be used with caution and careful monitoring. - Possible international normalized ratio (INR) increases with warfarin For further information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (emc) ( or the British National Formulary (BNF) ( Dementia Next Review: Jan

11 Managing BPSD (in line with NICE/SCIE Dementia guideline CG42) Conduct a comprehensive assessment to identify factors that generate or aggravate BPSD. These factors can include physical health problems, infection, pain or discomfort, alcohol, constipation, depression, sleep disturbance, medication side effects, psychosocial factors, environment or personal beliefs. Identify factors that improve BPSD e.g. music, dance, aromatherapy, cognitive stimulation, massage, multisensory stimulation, exercise, creative therapies, animal assisted therapies, environment. Involve the person/carers/staff in developing a person-centred care plan to address individual needs. Record the plan in the case notes and review it regularly. Challenging behaviours may be a way of communicating an unmet need. Treat any underlying contributory problems (e.g. infection, pain, drug side effects) Be alert for and treat any coexisting emotional disorders (e.g. depression and/or anxiety and sleep disturbances) For mild to moderate BPSD, watchful waiting or non-pharmacological interventions (psychological, social, behavioural & environmental) should be tried first. Consider available options and tailor activities to individual preferences, skills and abilities. The causes of any disturbed behaviour in patients with dementia should be reviewed and managed before initiating pharmacologic treatment. Pharmacological treatment should only be initiated by dementia specialists: Consultant Psychiatrists, Neurologists, Psycho-geriatricians, Geriatricians and their Specialist Registrars, Non-Medical Prescribers and GPs with a special interest in dementia; documenting the reasons (target symptoms) for use of any pharmacological interventions and discuss risks and benefits. Pharmacological interventions, often in conjunction with non-pharmacological interventions, should only be used in cases of severe distress or when there is immediate risk of harm to the service user and/or others. Be aware that there is limited evidence for pharmacological management of BPSD. Avoid prescribing medications with anticholinergic effects because they can worsen cognition. Starting doses of medication should be low and titration gradual. The lowest possible effective dose should be used for the shortest possible time. Dementia specialists should consider antipsychotics for BPSD only if there are severe non-cognitive symptoms (psychosis and/or agitated behaviour causing significant distress) or immediate risk of harm to the person with dementia or others. The decision to prescribe antipsychotics should be taken on an individual basis after careful consideration of cerebrovascular risk factors and full discussion with the service user, relatives and/or carers about antipsychotic risks and benefits Prescriptions for antipsychotics should be time limited and reviewed against target symptoms and side effects (3 monthly or according to clinical need). Monitor for benefits and side effects at 6 and/or 12 weeks and 3 monthly thereafter. At each review, consider reducing or gradual withdrawal of antipsychotic treatment Only risperidone is licenced for the short-term treatment (up to 6 weeks) of persistent aggression with moderate to severe Alzheimer's dementia unresponsive to non-pharmacological approaches and when there is a risk of harm to self/others. Dementia Next Review: Jan

12 Managing BPSD (in line with NICE/SCIE Dementia guideline CG42) - Continued Avoid antipsychotics in people with Parkinson s Disease/Lewy Body dementia wherever possible; there is a high risk of severe neuroleptic sensitivity reactions (such as severe extrapyramidal symptoms; or acute, severe physical deterioration). Where antipsychotics are already prescribed for BPSD, all healthcare professionals should question the need for long-term use. Antipsychotics must be reviewed, and where appropriate, discontinued (gradually) in discussion with relevant colleagues, unless the service user still has severe symptoms, or previous discontinuation caused symptoms to return. Dementia specialists should review antipsychotic treatments on transfer or discharge from hospital to another setting Dementia specialists may consider using acetylcholinesterase inhibitors or memantine for BPSD in dementia, where appropriate (see tables below) Dementia Next Review: Jan

13 Dementia: Pharmacological Management of Non-Cognitive Symptoms Managing Comorbid Conditions Schizophrenia/Mania Relative Cost Notes Antipsychotics e.g. Risperidone Olanzapine Quetiapine Aripiprazole Amisulpride Haloperidol Branded/Liquids/MR/ Orodispersible forms - Depression+/-Anxiety Relative Cost Notes SSRIs Citalopram (liquid) Sertraline Mirtazapine Tabs/orodispersible Liquid () Benzodiazepines liquids Sleep Disorders Price Band Notes Zopiclone (3.75mg) Liquid Zolpidem (5mg) Comorbid psychosis/mania should be managed appropriately; as per appropriate guidelines Low doses are preferred in older adults with dementia (e.g. half of normal elderly dose) Warning: The risk of cerebrovascular adverse events, such as stroke or transient ischaemic attack (TIA), may be raised as much as three-fold in older adults with dementia prescribed an antipsychotic; mortality is also raised. The balance of risks and benefits associated with antipsychotics in dementia should be carefully assessed particularly where there is a previous history of stroke or TIA, hypertension, atrial fibrillation and heart valve disorders. Consideration should also be given to other risk factors for cerebrovascular disease including smoking, high BMI, immobility, diabetes and hypercholesterolaemia and dyslipidaemia. Be aware of an increased risk of severe extrapyramidal side effects in DLB/PDD Document all discussions about risks and benefits with the service user, relatives and/or carers SSRIs preferred because they are better tolerated than other antidepressants; mirtazapine is an alternative; These drugs have a low likelihood of drug interactions. Caution: QT prolongation with citalopram Avoid tricyclic antidepressants due to risk of daytime sedation, tolerance, rebound insomnia, confusion and worsened cognition, falls, disinhibition, and delirium; If a tricylic is indicated, low dose trazodone may be considered Before starting antidepressant, discuss the delayed onset of action, side effects and discontinuation reactions and the importance of adherence with the service user and/or carer. Short-term use only for severe cases; risk of dependence, tolerance, sedation, worsening cognition, delirium, falls, disinhibiting effects and in some cases, respiratory depression. Promote good sleep hygiene; Use drug treatment for a short-term only when sleep disturbances is the main problem and other approaches have failed. Do not use antihistamines or benzodiazepine due to cognitive side effects, confusion, falls or delirium Dementia Next Review: Jan

14 Dementia: Pharmacological Management of Non-Cognitive Symptoms BPSD* Antipsychotics Relative Cost Notes Antipsychotics For non severe BPSD, use non-pharmacological interventions or watchful waiting e.g. Manage factors that generate or aggravate symptoms, including any comorbid symptoms Antipsychotics should only be used for BPSD or behaviour that challenges if there is severe Risperidone distress and/or agitation OR an immediate risk of harm to the service user and others mg/day Antipsychotics produce small reduction in neuropsychiatric symptoms of dementia (psychosis, (max 2mg) aggression and agitation) but increase the risk of cerebrovascular adverse events and death. Other antipsychotic side effects include tardive dyskinesia, neuroleptic malignant syndrome, weight gain, Olanzapine hyperlipidaemia, diabetes mellitus, sedation, falls, Parkinsonism, and worsening of cognition mg/day Do not prescribe antipsychotics for mild-moderate BPSD risks outweigh any benefits (max 10mg) Consultants or trainees after discussion with consultants may initiate antipsychotics for severe BPSD after reviewing and managing the causes of disturbed behaviour (non-pharmacological Quetiapine management plus treatment of comorbidities) mg/day Assess risk factors and discuss benefits and risks of antipsychotic fully with service user or carer (max 150mg/day) Risperidone is the only antipsychotic licenced for short term treatment (up to 6 weeks) of persistent aggression in moderate to severe Alzheimer's dementia unresponsive to non-pharmacological Aripiprazole 5mg/day approaches and when there is a risk of harm to self or others. NB: Warnings regarding risks of Max 10mg/day antipsychotics in dementia also apply to risperidone. Antipsychotic dose should be initially low and the dose gradually titrated upwards Amisulpride 25-50mg/day In DLB or PDD, be aware of the risk of severe adverse effects e.g. development or worsening of (max 150mg) extrapyramidal side effects; or acute, severe physical deterioration) Low dose quetiapine appears to be better tolerated in DLB or PDD but monitor for side effects Branded/Liquids/MR/ - Target symptoms should be clearly defined and documented and progress reviewed regularly. Orodispersible forms Monitor for changes in cognition and antipsychotic side effects Treatment should be time-limited and regularly reviewed (at least every 3 months or according to clinical need). More frequent monitoring may be required during titration At each review, consider reduction of dose or gradual discontinuation of treatment * BPSD includes symptoms such as agitation, aggression, extreme anxiety, shouting, changes in behaviour, delusions and hallucinations. Dementia Next Review: Jan

15 Dementia: Pharmacological Management of Non-Cognitive Symptoms BPSD* AChEIs and Memantine Relative Cost Notes Donepezil Galantamine Rivastigmine Liquids; patches branded; orodispersible formulations Memantine Liquid; branded - - AChEIs may have a beneficial effect on behavioural and psychological symptoms of dementia if symptoms are causing severe distress or leading to challenging behaviour NICE advises that the following can be considered for an acetylcholinesterase inhibitor: people with DLB who have non-cognitive symptoms causing significant distress or leading to behaviour that challenges or people with mild, moderate or severe Alzheimer s disease who have non-cognitive symptoms and/or behaviour that challenges causing significant distress or potential harm to the individual if: a non-pharmacological approach is inappropriate or has been ineffective, and antipsychotic drugs are inappropriate or have been ineffective AChEIs should not routinely be used for non-cognitive symptoms or behaviour that challenges in vascular dementia Memantine may be beneficial in people with moderate to severe behavioural symptoms (agitation, aggression and/or psychotic symptoms) where: non-pharmacological interventions are ineffective or inappropriate where the severity of risk does not require use of antipsychotic medication where treatment with antipsychotics is not tolerated or contraindicated where longer term management is required The evidence for memantine for severe agitation is still developing Dementia Next Review: Jan

16 Dementia: Pharmacological Management of Non-Cognitive Symptoms BPSD* Antidepressants Relative Cost Notes SSRIs Citalopram (liquid) Sertraline () SSRIs may be useful for behaviours that suggest underlying depression or anxiety Citalopram limited evidence for agitation in people with Alzheimer s disease. Consider also if depression+/- anxiety; use lower starting doses and small and gradual dose increases necessary; Caution citalopram can cause dose-dependent QT prolongation Sertraline 50mg/day (max 200mg) useful if anxiety is a concern. May be useful where depression and anxiety and sleep problems are a concern Mirtazapine Liquid/Orodispersible Trazodone (liquid) () Trazodone may be useful when behaviour accompanied by depressive/anxiety symptoms Dementia: Pharmacological Management of Non-Cognitive Symptoms BPSD* Other agents Relative Cost Notes Mood stabilisers - NICE found conflicting results about the efficacy of carbamazepine for managing aggression, agitation and behavioural disturbances in people with dementia. Low doses of carbamazepine (200mg/day max 600mg) have been tried as a controlled therapeutic trial when other measures are ineffective. Carbamazepine may improve agitation and aggression but be aware of the risk of side effects and drug interactions. Routine use not recommended. NICE found valproate preparations are no more effective than placebo for treating agitation or behavioural disturbances in people with dementia. Benzodiazepines e.g. Lorazepam; diazepam, clonazepam Liquids Not routinely recommended except for short-term/prn use only in severe cases when anxiety or agitation is prominent and other approaches have failed. Adverse effects can include dependence, tolerance, sedation, worsening cognition, delirium, increased risk of falls, disinhibiting effects and in some cases, respiratory depression or worsening of breathing disorders Dementia Next Review: Jan

17 Dementia: Pharmacological management of violence, extreme agitation and/or aggression with risk to self and/or others First line Relative Cost Notes Oral agents Lorazepam or Haloperidol or Olanzapine Liquids, Proprietary; and orodispersible formulations Intramuscular (IM) agents Lorazepam or Haloperidol or Olanzapine - Second Line Relative Cost Notes IM haloperidol and IM lorazepam Use non-drug strategies first Follow Trust Rapid Tranquillisation procedure but be aware of the following: Treat with lowest effective doses for the shortest possible time Aim to reduce agitation and aggression without sedation Monitor BP, temperature, pulse and respiratory rate NB: Be aware that Antipsychotics are associated with an increased risk of cerebrovascular adverse events and greater mortality when used in people with dementia. No antipsychotic (with the exception of risperidone in some circumstances) is licensed in the UK for the treatment of BPSD; Other antipsychotics are prescribed off-label for this purpose. Consider if oral treatment is refused or ineffective and severe risk or extreme distress Follow recommendations in Trust Rapid Tranquillisation Policy A single IM agent should be used in preference to a combination. Monitor vital signs Blood pressure, pulse and respiratory rate should be recorded at regular intervals Monitor for dystonia and other extrapyramidal effects. If acute dystonic reactions or distressing EPSE, consider use of anticholinergic agents Monitor for deteriorating cognitive function A combination of an antipsychotic and a benzodiazepine may allows the use of lower doses of each drug Monitor dystonia and other extrapyramidal effects If side effects become distressing, especially in acute dystonic reactions, the use of anticholinergic agents should be considered. Monitor for deteriorating cognitive function Dementia Next Review: Jan

18 References 1. Dementia: supporting people with dementia and their carers in health and social care. NICE clinical guideline 42. November 2006 updated Available from: 2. NICE TA217: Donepezil, galantamine, rivastigmine and memantine for the treatment of Alzheimer's disease. (2011 updated 2016) Available at: 3. NICE quality standard. Dementia: support in health and social care (QS1): June 2010 Available at: 4. NICE quality Standard. Dementia: independence and wellbeing (QS30) April NICE advice. Key therapeutic topics. Low-dose antipsychotics in people with dementia (KTT7) January Available at: 6. NICE advice. Management of aggression, agitation and behavioural disturbances in dementia: carbamazepine (ESUOM40) March Available at: 7. NICE advice. Management of aggression, agitation and behavioural disturbances in dementia: valproate preparations (ESUOM41) March Available at: 8. BAP guidelines: Clinical practice with anti-dementia drugs: a revised (second) consensus statement from British Association for Psychopharmacology BAP guidelines: Clinical practice with anti-dementia drugs: a revised (third) consensus statement from British Association for Psychopharmacology Banerjee S. The use of antipsychotic medication for people with dementia: Time for action. A report for the Minister of State for Care Services. Department of Health, London, Available at: /dh_ pdf 11. Dementia Action Alliance and NHS Institute for Innovation and Improvement.The right prescription, a call to action on the use of antipsychotic drugs for people with dementia: American Psychiatric Association (APA). Practice guideline for the treatment of patients with Alzheimer's disease and other dementias. Arlington (VA): American Psychiatric Association (APA); Second Edition, October Dementia Next Review: Jan

19 13. Pollock et al.a double-blind comparison of citalopram and risperidone for the treatment of behavioral and psychotic symptoms associated with dementia. Am J Geriatr Psychiatry 2007;15: Jeste et al.acnp White Paper: update on the use of antipsychotic drugs in elderly persons with dementia. Neuropsychopharmacology 2008;33(5): Alzheimer s Society. Optimising Treatment and Care for people with behavioural and psychological symptoms of Dementia, A best practice guide for health and social care professionals: July Summary of Product Characteristics of various drugs are available at: Antipsychotics: initiative to reduce prescribing to older people with dementia Dementia Next Review: Jan