MEDICINES MANAGEMENT FOR ADULT ADHD GLOUCESTERSHIRE PATHWAY. Before commencing treatment measure weight, blood pressure and heart rate.

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1 MEDICINES MANAGEMENT FOR ADULT ADHD GLOUCESTERSHIRE PATHWAY ADULT ADHD MEDICATION TITRATION SCHEDULE Before commencing treatment measure weight, blood pressure and heart rate. CONCERTA XL Check heart rate/ blood pressure 3-5 days every time after increasing dose Week 1 Start on 18 mg daily Week 2 Increase to 36 mg daily Week 3 Increase to 54 mg daily (36 mg +18 mg) Week 4 Increase to 72 mg daily (36 mg x2) Exceptionally Increase to 108 mg daily (54 mg x2) (36 mg x3) (27 mg x4) EQUASYM XL Check heart rate/ blood pressure 3-5 days every time after increasing dose Week 1 Start on 10 mg daily Week 2 Increase to 20 mg daily Week 3 Increase to 30 mg daily Week 4 Increase to 40 mg daily Week 4 Increase to 60 mg daily MEDIKINET XL Check heart rate/ blood pressure 3-5 days every time after increasing dose Week 1 Start on 10 mg daily Week 2 Increase to 20 mg daily Week 3 Increase to 30 mg daily Week 4 Increase to 40 mg daily Week 4 Increase to 60 mg daily Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 1

2 DEXAMFETAMINE Only licensed refractory cases and children Higher risk of diversion due to its recreational purpose LISDEXAMFETAMINE Check heart rate/ blood pressure 3-5 days every time after increasing dose Week 1 Start on 30 mg daily Week 2 Increase to 50 mg daily Week 3 Increase to 70 mg daily ATOMOXETINE Check heart rate/ blood pressure 3-5 days every time after increasing dose Week 1 Start on 10 mg daily Week 2 Increase to 20 mg daily Week 3 Increase to 40 mg daily Week 4 Increase to 60 mg daily Week 4 Increase to 80 mg daily APPROXIMATE EQUIVALENT DOSAGE METHYLPHENIDATE (mg) Ritalin Concerta XL Equasym XL Medikenet XL * 30* 30* *do not increase dosage above the equivalent of Concerta XL 36 mg OD without a review with a specialist to assess tolerability and clinical response Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 2

3 SIDE EFFECT RATING SCALE WEEK number: Headaches Abdominal pain Insomnia Palpitations Nervousness Chest pain Short of breath Loss of appetite Weight loss Dizziness Vomiting Nausea Diarrhoea Dry eyes/ mouth Runny nose Sore throat Cough Urinary frequency Sweating Thirsty Mood swings anger Irritability Aggressiveness Talkativeness Depression Hallucinations Anxiety Fatigue Tics Suicide ideation Not at all Sometimes Often All the time Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 3

4 GUIDELINES (1) NICE (2008) and BAP (2006) Guidelines are the UK main professional bodies who systematically review there is sufficient evidence and/or experience of using the medicine to demonstrate safety and efficacy (2). NICE recommends that treatment should be initiated by a specialist and following titration and dose stabilisation, prescribing and monitoring should be carried out under locally agreed shared care arrangements with Primary Care. Gloucestershire CGC advocates the same approach with some variance (3). NICE recommends medication as first line in A-ADHD; therapy should be available as alternative to drugs (4). INITIATION NICE recommends measuring blood pressure, heart rate and weight pre-treatment (5). Personal and family history of cardiovascular events (sudden death in young relatives, exercise syncope, breathless, hypertension) may require further investigations such as blood tests, ECG and examination by specialist before starting stimulant treatment. Dose should be titrated against symptoms and side effects over 4 6 weeks. During the titration phase, every time dose has been increased record on a centile chart blood pressure and heart rate and routinely every 3 months once the dose is stabilised. Weight should be measured every time dose has been increased and routinely every 6 months once the dose is stabilised. Atomoxetine has a warning regarding to potential liver damage. History of alcohol abuse or liver disease should raise extra concerns and monitoring liver function. MAINTENANCE (6) (7) NICE does not recommend Methylphenidate immediate release (IR) drugs for adults. ADHD is a 24/7 disorder and patients struggle complying with a divided dose regimen. Methylphenidate extended release (ER) formulation - once a day- is more frequently used in children and adults (8) Dexamfetamine is listed in the BNF for refractory ADHD, that is, patients who have not responded to Methylphenidate. Guidelines recommend that it should not be used as a first line due to misuse risk. Lisdexamfetamine (Elvanse ) is an amphetamine launched in UK in April It is designed to avoid multiple dosing and minimise abuse risk (9). Atomoxetine is a Norepinephrine Reuptake Inhibitor (10). Modafinil is an unlicensed medication used to treat ADHD. This medication has become very popular. It is easily obtained on-line because it is not a controlled substance (11). Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 4

5 ADVERSE EFFECTS/ RISK (12) Most patients tolerate these medications very well. The majority of side effects are dose-related: some of the commonest are migraine, abdominal pain, weight loss, nervousness and insomnia. Patients receive a checklist of common adverse effect for their weekly self-monitoring during the titration phase. They should contact their GP if there is anything unusual and/or an adverse effect becomes intolerable. If a patient during titration shows alarming increase of blood pressure (15-20 mmhg) and heart rate (20 bpm) and/or notices chest pain, short of breath and faint, medication needs to be stopped immediately. An ECG can be done in the local surgery and a Cardiology referral may be considered These drugs also can exacerbate or produce de novo tics, depression, anxiety, mania and psychosis. PREGNANCY ADVICE (13) ADHD can increase the risk of antenatal and postnatal depression. FDA classifies ADHD drugs under the pregnancy category C. Patients should be closely monitored throughout their pregnancy and postnatal period by Midwives/ Obstetrics team in collaboration with the Local Recovery/PMHS. Contact UK Teratology Information Service (UKTIS: ) for an updated information. REGULATIONS (14) The prescribing doctor should provide a letter to their patient with patient s name, date of birth, address, country of destination, date of departure, date of return and details of the drug including name, strength, form and total quantity to be taken out of the country. Patients are responsible to check if the destination country has different laws regarding to stimulant medication to avoid unnecessary and serious consequences. Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 5

6 NOTES 1 ADHD is a chronic and evolving medical condition; Adult ADHD (A-ADHD) is the continuation of a childhood disorder. A-ADHD pharmacological treatments are stimulant medication (Dexamphetamine and Methylphenidate) and non-stimulant medication (Atomoxetine). These drugs can be combined in exceptional cases. There are also other medications used in ADHD: Clonidine, Guanfacine, Bupropion, Venlafaxine, Modafinil and Imipramine. Antipsychotic drugs are occasionally used to treat children with co-morbid conditions but not ADHD per se. 2 NICE uses expert opinion, consensus and other lower level of EBM and also its recommendations have also been influenced by economic parameters 3 The Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for licensed medicines, they determine what makes acceptable standard in efficacy, safety and quality. There is a common mistake to use indistinguishably off label and unlicensed use of drugs. Methylphenidate and Dexamphetamine are only licensed to treat children, it means their use in newly diagnosed Adult is off-label, and for example ADHD treatment with Clonidine is unlicensed. Some drugs have an extended label that means adult patients whose treatment has been initiated during childhood can continue their treatment. In June 2013, the MHRA has licensed Atomoxetine to begin treatment of ADHD in adult patients, but only when pre-existing symptoms (and impairments in different settings) during childhood (< 7 years old) can be confirmed by a third party. If taken rigorously, undoubtedly this clause limits considerably the group of suitable patients. The GMC has recently changed its language; only the word unlicensed is used: Good practice in prescribing and managing medicines and devices (2013)(see paragraphs regarding to prescribing unlicensed medicines for use outside the terms of their approval and also see paragraphs regarding Information for patients about the licence for their medicines) 4 NICE does not specify what intervention. Research in this field is very promising. Specific- ADHD therapy is not available in Gloucestershire. 5 Medication may increase blood pressure < 5 mm Hg and/ or heart rate < 10 bpm. 6 My recommendation is to start ADHD drugs very slowly; patients taking stimulant medication may feel a marked difference in behaviour and symptoms after a few days. For simplicity I will refer to Concerta XL as example because it is the most used stimulant preparation in the county, I do not recommend any commercial brand. Once the patient is taking Concerta XL 36 mg daily for at least three months, patients will make an appointment to review efficacy, side effects and compliance. 7 NICE does not suggest that adults require higher doses than children. There is a debate about the optimal dose to treat ADHD in adults. Studies have produced very disparate results regarding effect size (efficacy) and dose response effects, Faraone (2004) calculated a size effect of 0.9, however Koesters meta-analysis (2008) found a much smaller size effect of The Amphetamines Cochrane Review of Castells (2011) did not find a dose-response effect. Cools and D Esposito (2011) argued that stimulant medication may be more effective in small doses (inverted- U shaped dopamine activity) and that higher doses hinder the overall cognitive performance of the individual. The final dose will be determined by individual s responses. Patients and professionals must keep in mind that it is possible that a symptom may be responding well but the associated impairment remains unaltered. That means that increasing the dose may not produce any benefit and the response has reached its plateau. Treatment choice and dose can be strongly influenced by a co- Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 6

7 morbid condition frequently paired with ADHD. Castells Cochrane review (2011) observed that ADHD patients with comorbid Substance Misuse Disorder showed poor response to stimulant treatment; Castells actually questioned the efficacy of stimulants in this particular group. 8 There are three commercial brands: Concerta XL, Equasym XL and Medikinet XL. These products have some subtle differences and occasionally patients will respond better to one of them. See the table below: CONCERTA XL MEDIKINET XL EQUASYM XL IR/ ER percentage 22/78 50/50 30/70 Release profile 1-2 hours max action Second peak 6-8 hours later 30 min max action Second peak 3-4 hours later 1.5 hours max action Second peak 6 hours later Duration of action Up to 12 hours Up to 7 hours Up to 8 hours Administration Capsules must be Capsules must be Capsules must be swallowed whole swallowed whole swallowed whole or opened and or opened and sprinkled sprinkled IR MPH equivalent TDS BD BD (IR immediate release, ER extended release, MPH methylphenidate) 9 It is approved by the MHRA for treatment of ADHD in children aged 6 years & over when response to previous Methylphenidate treatment is considered clinically inadequate. It was first licenced in USA by FDA in July 2007, for treating ADHD in children aged 6 to 12 years. It is not licensed to treat newly diagnosed adults. Lisdexamfetamine is not a controlled substance yet and is under revision of the Misuse of Drugs Act (1971). 10 BNF advises to commence on 40 mg a day and after one week following monitoring up to 80 mg OD or twice a day if the patient complains of side effects. I strongly recommend starting very slowly at 10 mg weekly steps up to 80 mg a day to minimise side effects and increase chance of compliance. Atomoxetine has a response latency of at least 6-8 weeks, similar to SSRIs. Slower titration will increase the time gap. 11 This medication is also quite popular among students, academics and professionals as a cognitive enhancer. MHRA only approves this drug for the treatment of narcolepsy. Recent search in the Gloucestershire pharmacy database (epact) shows that the amount of prescribed Modafinil by Primary Care is well above of the prevalence of narcolepsy in the county, suggesting that this drug is being used unlicensed. This finding needs further analysis. 12 Methylphenidate was first licensed by the FDA in 1955 for treating hyperactivity. ADHD drugs have been used for more than five decades; surprisingly most studies evaluating treatment do not pass beyond seven weeks. Patients must be informed that there is a lack of knowledge in the longterm safety and effectiveness of this medication. Guidelines do not mention the duration of the treatment. Some patients may need treatment indefinitely. Drug Analysis Prints (DAPs) contain complete listings of all suspected adverse drug reactions or side effects, which have been reported to the MHRA, via the Yellow Card Scheme. This includes all Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 7

8 reports received from healthcare professionals, members of the public and pharmaceutical companies. Gould (2009) observed an increased risk of stroke, heart attack and sudden cardiac death in children and young adults (2-24 years) taking ADHD drugs. However, in 2011 the FDA disputed the association of serious cardiovascular events with ADHD drug use.. Schelleman (2012) found that initiation of methylphenidate was associated with a 1.8-fold increase in risk of sudden death or ventricular arrhythmia. Nevertheless the FDA strongly advise monitoring BP/HR and indicate stimulants should generally not be used in patients with serious heart problems, or for those that an increase in blood pressure or heart rate would be problematic. There are not similar studies done in an adult population % of USA college students are misusing stimulants according to Smith and Farah (2011) Students use this medication as a cognitive enhancer rather than for recreational purposes. Extended release preparations are specifically designed to reduce the risk of abuse for recreational purposes. However be alert because the phenomenon of globalisation means that someone at the other end of the world may find a method to overcome the drug manufacturer design efforts to reduce such risk and the knowledge can be easily disseminated through internet. (Google search of how to abuse Concerta produces 1,760,000 results in less than a second). Clinical studies of Atomoxetine suggested that some children and teenagers may experience suicidal thoughts during the titration phase. Although no suicides occurred in these studies, 4 out of every 1000 patients developed suicidal thoughts. Stimulants can also induce suicidal ideation. There are no similar studies carried out with older adults. DAP accumulative data available from MHRA, Yellow Card Scheme website. METHYLPHENIDATE 1 ATOMOXETINE 2 Completed suicide 5 2 Intentional self-injury 4 19 Self-injurious behaviour 3 11 Self-injurious ideation 2 8 Suicidal behaviour - 3 Suicidal ideation Suicide attempt Period covered: 01-Jul-1963 to 09-Jul Earliest reaction date: 09-Oct-1964 (DAP) 2 Period covered: 01-Jul-1963 to 09-Jul Earliest reaction date: 13-Oct-2003 (DAP) 13 Leigh and Milgrom (2008) identify some perinatal affective disorder risk factors such as low income, lower educational attainment, history of depression, concomitant anxiety, low self-esteem, low social support, negative cognitive attribution style. ADHD Patients scored high in all of these risk factors. Category C means that animal reproduction shows some effects on the foetus. There are no adequate controlled studies on humans, but potential benefits may warrant the use of drug in pregnant women. Extra knowledge in humans is acquired from studies on drug abuse population. It is important to say that the available data suggest there is no increase in the risk of malformation when these drugs are used at therapeutic doses. Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 8

9 Similar studies on population who abuse Methylphenidate, the drug is associated with premature birth, grown retardation and neonatal withdrawal symptoms, high risk of pre-term delivery, low Apgar score and neonatal mortality. Any potential teratogenic medication should be discontinued before conception. However, pregnant women usually come for advice when they are already in the end of their first trimester. Childbearing age women in should have counselling before starting treatment. 14 Stimulants (dexamfetamine and methylphenidate) are Class B Drugs under by the Misuse of Drugs Act (1971) and Schedule 2 under the Misuse of Drugs Regulations (2001) Possession may result up to 5 years in prison, an unlimited fine or both, supply and production may result up to 14 years in prison, an unlimited fine or both. ACMD is a scientific and ethical advisory body to the Government, but only the Secretary of State has the power to modify any decision regarding to the classification of drugs. Patients travelling abroad only require a special licence if they are leaving the UK for a month or more. For shorter trips a letter from the prescribing doctor mentioning diagnosis and treatment should suffice. It may be illegal to bring such medication in to certain countries in the world. ( /licensing/personal/) Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 9

10 AVAILABLE ADHD MEDICINES ADHD DRUGS STIMULANT NON-STIMULANT METHYLPHENIDATE AMFETAMINE ATOMOXETINE UNLICENSED IMMEDIATE RELEASE (IR) EXTENDED RELEASE (XL)* IMMEDIATE RELEASE (IR) EXTENDED RELEASE (XL) MODAFINIL RITALIN CONCERTA DEXAMFETAMINE LISDEXAMFETAMINE CLONIDINE MEDIKINET GUANFACINE EQUASYM IMIPRAMINE VENLAFAXINE (*Gloucestershire PCT only recommends the use of extended release methylphenidate for Adult ADHD) Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 10

11 APPROXIMATE MEDICATION COSTS 2013 Average daily dosage Cost p.a. Ritalin 5 60 mg Concerta XL mg Equasym XL mg Medikinet XL mg Dexamfetamine mg Lisdexamfetamine mg 757 to 1,081 Atomoxetine mg 712 *Generic forms may be less expensive Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 11

12 Glossary/Abbreviations ACMD BAP CADDRA DAP FDA GMC MHRA NICE Advisory Council on the Misuse of Drugs British Association of Psychopharmacology Canadian ADD/ADHD Research Association Drug analysis print from the MHRA USA Food and Drug Administration General Medical Council Medicines and Healthcare Products Regulatory Agency National Institute of Clinical Excellence References: Castells X, Ramos-Quiroga JA, Bosch R, Nogueira M, Casas M. Amphetamines for Attention Deficit Hyperactivity Disorder (ADHD) in adults. Cochrane Database Syst Rev Jun 15 ;( 6):CD Doi: / CD pub2 Cools R, D'Esposito M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry Jun 15; 69(12):e Doi: /j.biopsych Diagnosis and management of attention-deficit/hyperactivity disorder in children, young people, and adults: summary of NICE guidance. BMJ Sep 24; 337:a1239. Doi: /bmj.a1239. Faraone SV, Spencer T, Aleardi M, Pagano C, Biederman J. Meta-analysis of the efficacy of methylphenidate for treating adult attention-deficit/hyperactivity disorder. J Clin Psychopharmacology Feb; 24(1):24-9. Gould MS at al Sudden death and use of stimulant medications in youth. Am J Psychiatry (published online June 15, 2009; doi: /appi.ajp ) Kendall T, Taylor E, Perez A, Taylor C; Guideline Development Group. British Association for Psychopharmacology 2006; Evidence based guidelines for management of Attention-Deficit/hyperactivity Disorder in Adolescents in transition to Adult Services and in Adults Koesters M, Becker T, Kilian R, Fegert JM, Weinmann S. Limits of meta-analysis: methylphenidate in the treatment of adult attention-deficit hyperactivity disorder. J Psychopharmacol Sep; 23(7): Doi: / Leigh B and Milgrom J Risk factors for antenatal depression, postnatal depression and parenting stress BMC Psychiatry 2008, 8:24 doi: / X-8-24 Schelleman H at al, Methylphenidate and risk of serious cardiovascular events in adults. Am J Psychiatry Feb;169(2): doi: /appi.ajp Written by Dr C J Pardo-Vicente Adult ADHD Specialist Consultant for the purpose of the A-ADHD pathway map of medicine for Gloucestershire Dr CJ Pardo A-ADHD Specialist Consultant for Gloucestershire August 2013 Page 12