Clinical Guideline / Formulary Document Pharmacy Department Medicines Management Services

Clinical Guideline / Formulary Document Pharmacy Department Medicines Management Services ATTENTION DEFICIT HYPERACTIVITY DISORDER [ADHD] Introduction Attention Deficit Hyperactivity Disorder (ADHD) is a neurodevelopmental condition characterised by persistent and pervasive pattern of inattention and/or hyperactivity and impulsiveness which can persist from childhood into adulthood and cause clinically significant impairments. Current management of ADHD includes a range of behavioural, social, psychological and pharmacological interventions and dietary advice. Pharmacological Treatment Drug treatment is not recommended as the first-line treatment for children and young people with ADHD but should be reserved for children and young people with severe symptoms or for those with moderate levels of impairment who have refused non-drug interventions, or whose symptoms have not responded sufficiently to educational interventions or group psychological treatment. Young people continuing ADHD treatment into adulthood should be assessed to establish the need for continuing pharmacological treatment. Pharmacological treatments for ADHD in adults and young people should be initiated only under the guidance of a specialist with expertise in ADHD, ideally as part of a multidisciplinary team; following thorough assessment and as part of a comprehensive treatment programme that addresses psychological, behavioural, educational and occupational needs. People with ADHD and concurrent substance misuse should be managed by specialists with expertise in both areas. Adults with ADHD should be offered pharmacological therapy as first-line treatment unless psychological approaches are preferred. Before initiating drug treatment, the diagnosis should be confirmed and a full assessment of ADHD and associated comorbidities done according to current national guidelines. Careful titration, monitoring and management of drug side effects is required. Cognitive behavioural therapy (CBT) may be considered when the service user has made an informed choice not to have drug treatment or drug treatment is partially effective or ineffective or if service user is intolerant to ADHD medications. Prescribing Advice Stimulant medications are the first-choice pharmacological treatments for ADHD in children, young people and adults. Methylphenidate and dexamfetamine are licensed for the treatment of ADHD in children and adolescents. Initiation in adults is off-label although treatment regimes are similar. Lisdexamfetamine (prodrug of dexamfetamine) may be prescribed by specialists only for ADHD in children aged 6 years and over when response to previous methylphenidate treatment is clinically inadequate. Atomoxetine is licensed for the treatment of ADHD in children of 6 years and older, in adolescents and in adults as part of a comprehensive treatment programme. The choice of pharmacological treatment depends on a range of factors such as the presence of coexisting conditions, treatment side effects, risk of diversion and/or misuse or factors that may affect adherence and service user preference. If there is a choice of more than 1 appropriate drug, the product with the lowest cost (taking into account the cost per dose and number of daily doses) should be prescribed. Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 1

Prescribing Advice continued When prescribing medication off-label, it is the responsibility of the prescriber to determine the clinical need of the patient and the suitability of using medication outside its authorised indications. Informed consent should be obtained and documented. Before treatment, adults with ADHD should be offered written information about their condition and its assessment, potential benefits and adverse effects of medications, available services, psychological support and self-help. During the titration phase, doses should be gradually increased with monitoring until there is no further clinical improvement and side effects are tolerable. Consider dose reduction if side effects become troublesome. Dose titration should be slower if tics or seizures are present. Suspected side effects should be documented and reported via the Yellow Card Scheme, as appropriate. Following titration and dose stabilisation by a specialist (usually over 4 6 weeks), continued prescribing and monitoring may be transferred to GPs, under local shared care arrangements. If there is an adequate response, pharmacological treatment for ADHD should be continued for as long as it is clinically effective. If continued for more than a year, treatment should be monitored and reviewed annually as below. Methylphenidate should be stopped if there is no improvement in symptoms after appropriate adjustments in dosage over one month. It also needs to be stopped from time to time in those who do respond, to assess the patient's condition. Antipsychotics should not be used for treatment of ADHD in young people and adults. NB: Stimulants are controlled drugs and have the potential for misuse and diversion. The requirements of controlled drug legislation with respect to prescribing and supply of stimulants should be followed. Assessments and Monitoring NICE recommends that before starting drug treatment for adults with ADHD, a full assessment should be completed. This should include: full mental health and social assessment full history and physical examination, including: assessment of history of exercise syncope, undue breathlessness and other cardiovascular symptoms heart rate and blood pressure (plotted on a centile chart) weight and height family history of cardiac disease and examination of the cardiovascular system. an ECG if there is past medical or family history of serious cardiac disease, a history of sudden death in young family members or abnormal findings on cardiac examination risk assessment for substance misuse and drug diversion (when prescribing psychostimulants) Drug treatment should be reviewed annually. This should include: a comprehensive assessment of clinical need, benefits and side effects, taking into account the views of the person and, those of a spouse, partner, parent, close friends or carers wherever possible, and considering how these accounts may differ the effect of missed doses the effect of planned dose reductions taking into account brief periods of no treatment the preferred pattern of use coexisting conditions, with the person treated or referred if necessary the need for psychological, social and occupational support for the person and carer(s) Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 2

During treatment, monitor weight at 3 and 6 months from initiation and every 6 months thereafter. Strategies to reduce weight loss should be recorded in the care plan. Monitor heart rate and blood pressure at each dose change and routinely every 3 months; Reduce dose if clinically significant changes are noted. Relevant NICE Guidance NICE clinical guideline CG72. Attention deficit hyperactivity disorder. Diagnosis and management of ADHD in children, young people and adults. September 2008. Available at: http://www.nice.org.uk/guidance/cg72. Technology Appraisal 98 Methylphenidate, atomoxetine and dexamfetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents (including a review of guidance TA13). March 2006. Available at: http://www.nice.org.uk/guidance/ta98. NICE quality standards [QS39]. Attention deficit hyperactivity disorder. http://www.nice.org.uk/guidance/qs39. NICE Pathways. Attention deficit hyperactivity disorder. http://pathways.nice.org.uk/pathways/attention-deficit-hyperactivity-disorder. Local Shared Care Agreements SHARED CARE AGREEMENT between Mersey Care NHS Trust and Liverpool CCG Methylphenidate (Ritalin, Equasym, Concerta XL, Medikinet ) and Atomoxetine (Strattera ) in the Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Adults 16 Years or older. Date Prepared: January 2013 Date for Review: April 2016 http://www.panmerseyapc.nhs.uk/shared_care/documents/sc2.pdf Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 3

Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Adults First Line: Relative Cost Notes Methylphenidate immediate release (IR) or modified release (M/R) (Schedule 2 controlled drug) Off-label for initiation in adults with ADHD Second Line: Relative Cost Notes Some formulations may be used as continuation treatment of ADHD in adolescents and adults. Dose titrated against symptoms and side effects over a 4 6 week period (see Appendix 2). Optimal doses and adequate therapeutic trial (6 weeks) are important to maximise response. Discontinue if there is no response after 1 month. Monitor, discuss and record side effects at each review or dose change. M/R preparations may improve adherence and limit misuse or diversion but are not bioequivalent. May affect performance of skilled tasks (e.g. driving); effects of alcohol may be unpredictable. Monitor weight at 3 and 6 months from initiation and every 6 months thereafter; if weight loss occurs, advise that medication should be taken with or after food and provide appropriate dietary advice. Heart rate and blood pressure should be monitored at each dose change and routinely every 3 months; reduce dose if clinically significant changes noted and refer to a physician. Discontinue treatment if psychotic symptoms emerge and carry out a full psychiatric assessment If anxiety symptoms develop, reduce dose, add antidepressants or switch to atomoxetine. If tics emerge, reduce dose or consider switching treatment to atomoxetine or stop treatment Atomoxetine Should be preferred if there are any contraindications to stimulant treatment; when treatment with methylphenidate has been ineffective, or not tolerated, in the presence of anxiety disorders or severe tics, or when there is a risk of misuse or diversion. Check history of cardiac problems or any significant cardiovascular concerns and carry out relevant investigations including ECG before starting treatment, as appropriate. Initial dose according to body weight, increased after 7 days to maintenance dose (see Appendix 2) Response to treatment should be assessed over the first 12 weeks. Monitor, discuss and record symptoms and side effects e.g. agitation, irritability, anxiety, suicidal thinking, self-harming and unusual changes in behaviour, particularly at initiation and after each dose change. Liver damage is a rare and idiosyncratic side effect of atomoxetine. Advise that this usually presents as abdominal pain, unexplained nausea, malaise, darkening of the urine or jaundice. Monitor for sexual dysfunction and dysmenorrhoea as side effects of atomoxetine Monitor weight at 3 and 6 months after initiation and every 6 months thereafter. If weight loss occurs, advise taking medication with or after food and provide appropriate dietary advice. Monitor heart rate and blood pressure at each dose change and routinely every 3 months; Reduce dose if clinically significant changes noted and refer to a physician. Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 4

Treatment of Attention Deficit Hyperactivity Disorder (ADHD) in Adults continued Second Line: Relative Cost Notes Alternative stimulants Dexamfetamine (Schedule 2 controlled drug) Lisdexamfetamine (Schedule 2 controlled drug) Other agents (Off-label use) Not currently licensed for the treatment of ADHD in adults. NICE advises use of dexamfetamine for refractory attention deficit hyperactivity disorder, if symptoms unresponsive to a maximum tolerated dose of methylphenidate or atomoxetine. Dose titrated to response over 4-6 weeks and given in divided doses see Appendix 1. Maintenance dose given in 2 4 divided doses Caution is required when prescribing to those likely to be at risk of stimulant misuse or diversion. Monitoring and management of side effects, as for methylphenidate (see above) It may be used as continuation ADHD treatment in adolescents and adults. Specialist only; Branded product so expensive; Can be initiated at 30mg daily with increases of 20mg at weekly intervals up to a maximum of 70mg. Lower abuse potential but may be less well tolerated than methylphenidate Relative Cost Black Triangle Product report all adverse effects to https://yellowcard.mhra.gov.uk/ Notes Reserve for individuals who fail to respond to, or are intolerant of stimulants or atomoxetine Antidepressants - Limited evidence of effect for imipramine, venlafaxine and reboxetine; reboxetine preferred Also useful if anxiety symptoms are precipitated by stimulant Clonidine Limited evidence; common adverse effects of clonidine include sedation and reduced heart rate. cardiovascular examination and ECG should be carried out before starting treatment with clonidine Bupropion Limited evidence that use reduces symptoms but high risk of side effects; consider previous history of bipolar disorder and epilepsy; seek specialist advice Melatonin M/R May reduce sleep onset insomnia and improve duration of sleep in ADHD; side effects headache, dizziness and abdominal pain Not Recommended Relative Notes Cost Modafinil Limited evidence; Use now restricted to narcolepsy only due to safety concerns Antipsychotics - oral - There is no evidence that antipsychotics are of value in treatment of the symptoms of ADHD Omega 3 fatty acids There is no consistent evidence of effect Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 5

Treatment Resistant Attention Deficit Hyperactivity Disorder in Adults Strategy Relative Cost Notes Dose escalation - Increase dose of stimulant or atomoxetine; if improvement is only temporary, do not continue increasing the dose. Consider group or individual cognitive behavioural therapy (CBT) Switching - Seek specialist advice. Change the preparation or try alternative stimulant eg dexamfetamine. Change timing of administration. Consider alternative medication such as atomoxetine; or bupropion, clonidine or imipramine (consultant only).try alternative psychological interventions Combinations - Combinations of medications (eg atomoxetine and a stimulant) may be tried by ADHD specialists. Risk of psychosis and movement disorders Adding clonidine to existing stimulant therapy was associated with an increase in moderate to severe side effects, most notably sedation and drowsiness Treatment Resistant Attention Deficit Hyperactivity Disorder in Adults - Managing Co-morbid Conditions Condition Relative Cost Notes Depression - Treat depression with SSRIs first; atomoxetine or reboxetine preferred; check interactions and monitor side effects; CBT may be helpful. Anxiety/Agitation - Treat anxiety first; anxiety symptoms, may be precipitated by stimulants. Lower doses of stimulant medication and/or combined treatment with an antidepressant licenced for anxiety can be helpful. Monitor effect Psychotic Disorders - Use atomoxetine and antipsychotic medication; carefully monitor if using stimulants with antipsychotics Sleep Disorders - Sleep hygiene and behavioural therapy; adjust dose eg reduce evening dose of stimulant or administer earlier in the afternoon OR switch smimulants. Consider changing to atomoxetine. If hypnotic required, use zolpidem or consider off-label use of melatonin m/r (consultant initiation only). Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 6

Appendix 1 Strengths and Release Profiles for Different Formulations of Methylphenidate Methylphenidate generic and Ritalin, or Medikinet (Immediate Release IR) Concerta XL Modified release (M/R) Drug Name and Brand Equasym XL Modified release (M/R) Medikinet XL Modified release (M/R) Strengths 5mg, 10mg, 20mg 18mg, 27mg, 36mg, 54mg 10 mg, 20 mg, 30 mg 10 mg, 20 mg, 30 mg, 40 mg Product details IR 3-4 hours duration M/R 10-12 hours duration M/R up to 8 hours duration M/R Up to 8 hours duration Release profile Peak plasma Concentration in 1-2 hours. 22% IR: 78% MR Initial peak plasma concentration in 1-2 hours. Second peak at 6-8 hours Formulation tablet Capsule shaped tablet containing two layers of drug. Outer layer (overcoat) released first, followed by gradual release of drug from inner core. Empty tablet shell excreted Administration details Tablets can be halved Tablet must be swallowed whole, not chewed, crushed or broken 30% IR: 70% MR Initial peak plasma concentration in 1-2 hours. Second peak at 4.5 hours Capsule containing two types of pellets/beads which allow immediate release of drug, followed by gradual release over the day. Capsule may be opened and contents mixed with soft foods.(stability unknown) Contents must be swallowed whole, not chewed, crushed or broken. 50% IR:50% MR Initial peak plasma concentration in 1-2 hours. Second phase of drug release 3 hours later resulting in a 3-4 hour plateau Capsule containing two types of pellets/beads which Allows immediate release of drug, followed by gradual release over the day. Capsule may be opened and contents mixed with soft foods.(stability unknown) Contents must be swallowed whole not chewed, crushed or broken. Ingestion with high fat content food delays absorption by approximately 1.5 hours. Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 7

Appendix 2 Doses and Side Effects of Drugs Used for ADHD Treatment Drug Name(s) Strengths Methylphenidate (Schedule 2 controlled drug) Immediate-release (IR) tablets (5mg, 10mg, 20mg) Not licensed in adults Ritalin (10mg) Medikinet (5mg, 10mg, 20mg) Off-label for use adults with ADHD. Modified-release (M/R) Concerta XL tablets (18mg, 27mg, 36mg) may be continued in adulthood if symptoms persist Medikinet XL Capsules (10mg, 20mg, 30mg, 40mg) may be continued in adulthood if symptoms persist Equasym XL Capsules (10mg, 20mg, 30mg) Not licensed in adults Dose May be given before breakfast and lunch. A later dose may be considered if the effect wears off in the evening causing rebound hyperactivity. In adults (>18 years) 5 mg up three times a day (as an immediate-release preparation), increased if necessary by 5 to 10 mg at weekly intervals to a maximum of 60 mg daily in divided doses (equivalent doses for M/R preparations). The dose should be titrated against symptoms and side effects over 4 6 weeks to a suitable maintenance dose. Up to 100mg daily may be given under specialist supervision. Modified-release preparations refer to BNF for specific advice on dosage for each brand M/R tablets must be swallowed whole, not chewed, crushed or broken. Modified release preparations of methylphenidate should be prescribed by brand name, as the different preparations are not interchangeable. Safety Precautions and Adverse Effects Contraindications and Cautions Hypersensitivity, glaucoma, phaechromocytoma, hyperthyroidism or thyrotoxicosis, preexisting cardiovascular or cerebrovascular disorders, vasculitis, pregnancy and breastfeeding; severe depression, anorexic disorders, suicidal tendencies, psychotic symptoms, severe mood disorders, bipolar mania, schizophrenia, psychopathic/ borderline personality disorder. Diagnosis or history of severe and episodic (Type 1) Bipolar (affective) disorder (that is not well controlled) Also monitor for psychiatric disorders; anxiety or agitation; tics or a family history of Tourette syndrome; drug or alcohol dependence; epilepsy (discontinue if increased seizure frequency); susceptibility to angle-closure glaucoma; avoid abrupt withdrawal. Should not be used in combination with or within 2 weeks of monoamine oxidase inhibitors Side effects Side effects include reduced appetite and weight, sleep disturbance, headaches, palpitations, nervousness, dysphoria, dry mouth, tachycardia, palpitations, increased blood pressure and heart rate (consider discontinuation or dose reduction), pruritis and rash; nasopharingitis, abdominal pain, diarrhoea, nausea and vomiting (may be alleviated by taking with food); dysphoria and agitation (may respond to dose reduction); psychotic reactions, such as hallucinations and delusional thinking; Tics; mania, seizures, and stroke have occurred, as has muscle damage with associated rhabdomyolysis and renal complications; syncope of cardiac origin requires specialist advice; blood dyscrasias (blood counts should be monitored periodically during prolonged therapy). Weight should be monitored during treatment with methylphenidate. Misuse of stimulants of the central nervous system may be associated with sudden death and other serious cardiovascular adverse events Methylphenidate can impair cognitive function and affect the person s ability to drive. Potential interaction with warfarin, antidepressants, antipsychotics, anticonvulsants, clonidine, alcohol and other sympathomimetics. Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 8

Appendix 2 continued Doses and Side Effects of Drugs Used for ADHD Treatment Drug Name Strengths Atomoxetine Strattera (Eli Lilly) 10mg, 18mg, 25mg, 40mg, 60mg or 80mg hard capsules. Indicated for the treatment of ADHD in children of 6 years and older, adolescents and adults as part of a comprehensive treatment programme. Dose Total daily dose may be administered as a single daily dose in the morning, with or without food or as equally divided doses in the morning and late afternoon or early evening. Adults (>18years) Starting dose (Maintain for at least 7 days) Maintenance dose <70kg 0.5mg/kg/day 1.2mg/kg/day >70kg 40mg/day 80mg to 100mg/day 120mg/day or (1.8mg/kg/day in patients <70kg) may be necessary in cases of poor response. A trial of 6 weeks on a maintenance dose should be allowed to evaluate the full effectiveness of atomoxetine. Dose should be reduced in liver failure (refer to BNF) Safety Precautions and Adverse Effects Contraindications and Cautions Contraindicated in hypersensitivity, closed angle glaucoma, severe cardiovascular or cerebrovascular disorders, pheochromocytoma, pregnancy and breast feeding Should not be used in combination with or within 2 weeks of monoamine oxidase inhibitors Prior to prescribing, take an appropriate medical history and assess baseline cardiovascular status, blood pressure and heart rate Caution in cardiovascular disease, cardiac abnormalities or other serious heart problems, QT prolongation, seizures, cerebrovascular disease, liver disease, aggressive behaviour, emotional lability, and prior history of psychotic illness or mania, suicidal ideation May affect performance of skilled tasks (e.g. driving); effects of alcohol unpredictable Side effects Headache, abdominal pain, decreased appetite and weight loss are most common; others - dyspepsia, nausea and vomiting, abdominal pain, anorexia and weight loss, fatigue, sleep disturbances, dizziness, cough, sinusitis or rhinorrhoea, urinary hesitancy or retention, sexual dysfunction, rashes, increased sweating, hot flushes, irritability, psychotic or manic symptoms (such as hallucinations, delusional thinking, mania, or agitation) and aggressive behaviour, hostility, or emotional lability; there have also been rare reports of severe hepatotoxicity - discontinue if jaundice or markedly increased liver enzyme values; increases in blood pressure and heart rate and orthostatic hypotension and syncope have been reported. Suicidal behaviour reported - monitor for signs of agitation, irritability, suicidal thought and self-harm and unusual changes in behaviour, particularly during the initial months of treatment or dose change; Seizures possible caution advised or avoid use. Check interactions with antidepressants, antipsychotics, CYP450 inhibitors etc. Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 9

Appendix 2 continued Doses and Side Effects of Drugs Used for ADHD Treatment Drug Proprietary Name(s) (Strengths) Dexamfetamine (Schedule 2 controlled drug) Dexedrine Off licence in adults Lisdexamfetamine (Schedule 2 controlled drug) Elvanse 30mg, 50mg, 70mg capsules, hard. Shire Pharmaceuticals Limited In adolescents whose symptoms persist into adulthood and who have shown clear benefit from treatment, it may be appropriate to continue treatment into adulthood. Dose In adults (>18 years), 5 mg twice daily, increased according to response to a maximum of 60 mg daily Initially 30 mg taken once daily in the morning, increased by 20 mg increments, at approximately weekly intervals to a maximum recommended dose of 70 mg/day; higher doses have not been studied. Dose adjustment may be required in the elderly Safety Precautions and Adverse Effects Contraindications and Cautions as for methylphenidate decreased appetite and weight; aggression, agitation, liable affect, mood swings, and depression; dizziness, dyskinesia, psychomotor hyperactivity, insomnia, night terrors, nervousness, restlessness, euphoria, fatigue, depression confusion, irritability, and headache; hypertension, tachycardia, cardiomyopathy, and myocardial infarction; dry mouth, diarrhoea, abdominal cramps, nausea, vomiting, and ischaemic colitis; sexual dysfunction; renal impairment; mydriasis; psychotic reactions (hallucinations, delusions, mania); very rarely, rhabdomyolysis, angle-closure glaucoma and sudden death Contraindications and Cautions hypersensitivity to sympathomimetic amines or relevant excipients; concomitant use of monoamine oxidase inhibitors (MAOI) or within 14 days of MAOI; hyperthyroidism or thyrotoxicosis; agitated states; symptomatic cardiovascular disease; moderate to severe hypertension; advanced arteriosclerosis; glaucoma; prescribe cautiously to people with a history of substance abuse or dependence; Cardiomyopathy has been reported with chronic amfetamine use; may exacerbate or induce psychosis and mania; stimulants may lower the seizure threshold Side effects Common adverse effects include nausea, vomiting, diarrhoea, decreased appetite, dry mouth, and abdominal cramps; aggression, headache, dizziness, drowsiness, sleep disturbances, and tics; weight loss and growth restriction; mydriasis, rash. Less common adverse effects include tachycardia, palpitations, hypertension, and cardiomyopathy; anxiety, paranoia, depression, dysphoria, depression, mania, hallucinations, and seizures; sexual dysfunction. Rarely, angle-closure glaucoma. For detailed information on contraindications, cautions, drug interactions, and adverse effects, see the electronic Medicines Compendium (emc) (http://emc.medicines.org.uk ) or the British National Formulary (BNF at https://www.medicinescomplete.com/mc/bnf/current/). Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 10

Appendix 3 Stimulant Dose Equivalents Methylphenidate is not licensed for use in adults with attention deficit hyperactivity disorder (ADHD) and hyperkinetic disorders (HKD). Manufacturers state that the maximum daily dose is 60 mg per day for Ritalin, Equasym and Medikinet. For Concerta XL the maximum dose is 54mg. However, NICE guidelines defines that methylphenidate can be use in adults with ADHD and the dose should be increased according to response up to a maximum of 100 mg/day [CG72 2008]. For Equasym XL and Medikinet XL brands, methylphenidate IR tablets are equipotent. So, the dose can be prescribed on a 1:1 basis. Modifiedrelease preparations should usually be given as a single dose in the morning and no more than twice daily. For Concerta XL, the manufacturer only provides the dose equivalents for those who are currently taking methylphenidate three times daily at doses of 15 to 45 mg/day. Doses of modified release preparations may vary according to brand chosen. See table below. Stimulant Dose Equivalents Methylphenidate IR Concerta XL Equasym XL Medikinet XL (in divided doses) 5 mg - - - 10 mg - 10 mg 10 mg 15 mg 18 mg once daily - - 20 mg 20 mg 20 mg 30 mg 36 mg once daily 30 mg 30 mg - - 40 mg 45 mg 54 mg once daily - - 60 mg 72 (*Licensed up to 54 mg) 60 mg - * Adapted from NICE ADHD guidelines. Direct conversions for doses beyond maximum licensed doses are not provided in the literature. Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 11

References 1. NICE clinical guideline CG72. Attention deficit hyperactivity disorder. Diagnosis and management of ADHD in children, young people and adults. Available at: http://www.nice.org.uk/guidance/cg72 2. Technology Appraisal 98 Methylphenidate, atomoxetine and dexamfetamine for attention deficit hyperactivity disorder (ADHD) in children and adolescents (including a review of guidance TA13). http://www.nice.org.uk/ta98 3. Consensus Group. Evidence-based guidelines for the pharmacological management of attention deficit hyperactivity disorder: Update on recommendations from the British Association for Psychopharmacology.. J Psychopharmacol. Feb 2014: 1-25 http://www.bap.org.uk/pdfs/adhd_guidelines.pdf. 4. NICE. Attention deficit hyperactivity disorder Evidence Update July 2013 https://www.evidence.nhs.uk/evidence-update-45. 5. NICE advice [ESUOM8]. Attention deficit hyperactivity disorder in children and young people: clonidine. Published date: April 2013 http://www.nice.org.uk/advice/esuom8 6. NICE advice [ESNM19]. Attention deficit hyperactivity disorder in children and young people: lisdexamfetamine dimesylate. May 2013 http://www.nice.org.uk/advice/esnm19 7. NICE advice [ESUOM2]. Sleep disorders in children and young people with attention deficit hyperactivity disorder: melatonin January 2013. http://www.nice.org.uk/advice/esuom2 8. MHRA (2009) Methylphenidate: updated guidance on safe and effective use in ADHD. Drug Safety Update 2(8), 2-3. http://www.mhra.gov.uk/publications/safetyguidance/drugsafetyupdate/con041211 9. MHRA (2009) Atomoxetine: risk of psychotic or manic symptoms. Drug Safety Update 2(8), 4. http://www.mhra.gov.uk/publications/safetyguidance/drugsafetyupdate/con041211 10. MHRA (2012) Atomoxetine (Strattera [black triangle]): increases in blood pressure and heart rate - new contraindications, warnings, and advice for monitoring. Drug Safety update 5(6), A1. http://www.mhra.gov.uk/home/groups/dsu/documents/publication/con140708.pdf 11. Scottish Intercollegiate Guidelines Network 2009: Management of attention deficit and hyperkinetic disorders in children and young people at: http://www.sign.ac.uk/pdf/sign112.pdf. 12. Kooij et al. European consensus statement on diagnosis and treatment of adult ADHD: The European network Adult ADHD. BMC Psychiatry 2010: 10: 67 Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 12

13. NICE CKS. Attention deficit hyperactivity disorder. Last revised in May 2014 Available at: http://cks.nice.org.uk/attention-deficit-hyperactivitydisorder#!references/a45937 14. Pan Mersey Melatonin M/R statement. http://www.panmerseyapc.nhs.uk/recommendations/documents/13_24_melatonin_201303.pdf 15. Adult ADHD Self-Report Scales. Available at: http://www.hcp.med.harvard.edu/ncs/asrs.php. 16. Manufacturer summaries of product characteristics (SPCs), various. Available at: https://www.medicines.org.uk/emc/. 17. The United Kingdom Adult ADHD Network (UKAAN) at: http://ukaan.org/index.htm. 18. ADHD Consultants Mersey Care Specialist in ADHD (expert opinion). Attention Deficit Hyperactivity Disorder Next Review: Jan 2017 13