FDA Pediatric Advisory Committee June 30, 2005 Marsha D. Rappley, MD

Managing Children and Adolescents with ADHD in Primary Care Source of referrals Issues in diagnosis Treatment options **Medications in treatment of ADHD** Choice of medication Establishing an effective dose Monitoring for effectiveness and side effects

Source of referrals Most children and adolescents with ADHD are managed in primary care –ADHD is one of the most common reasons for an office visit for school aged children –Stimulant medications are among the 10 most frequently prescribed medications for children Referrals –Self referrals from the primary care practice –Referrals from schools –Referrals to pediatrics from family practice

Diagnostic issues Guidelines –American Academy of Pediatrics Adopted by American Academy of Family Physicians –American Academy of Child and Adolescent Psychiatry –European groups as well

Common to these guidelines Comprehensive history Information from important domains of the child’s life –More than one source –Typically parents, school and child or teen Use of standardized checklists Allows comparisons of behavior to children of same age Asses for co-existing conditions

Common to these guidelines ADHD as chronic health condition Establishment of treatment goals Medication with stimulants to manage symptoms Behavior therapy for parent-child conflict, oppositional behavior; psychological therapy for co-existing conditions Taken together, these guidelines establish a standard of care

Considering treatment for ADHD Inattention: Medication –Methylphenidate –Dextroamphetamine products (including mixed salts) –Atomoxetine –Bupropion Hyperactivity and Impulsivity: Medication Oppositional behavior: Med + Counseling Parent child conflict: Med + Counseling

Considering medications Stimulants first line –Most effective: 68-80% –3-4% experience side effects causing discontinuation of medications –Provide targeted coverage –Available as generic –Products with duration 2 -4 hr, 4 – 8 hr, 8 – 12 hr

Considering medications Atomoxetine second line –Effective 50 – 60% –Similar side effects to stimulants –Provides 24 hour coverage –1-3 weeks to reach effect Bupropion –Fewer studies, more serious side effects –Role of antidepressant effect –24 hour coverage with twice daily dosing –3-4 weeks to reach effect

Choosing a medication Stimulant usually chosen for most children and teens –MPH and DEX have similar profiles –DEX slightly more side effects, which are mild –Mixed salt preparation (Adderall®) Recent withdrawal of long acting product in Canada Warning of use in children with cardiac conditions Parent may have preference

Setting target outcomes Measurable desired outcomes are preferred –Inattention Work completion, time on homework, spelling tests, timed math tests, fluidity of thinking and writing (copying from the board, note taking) –Hyperactivity and impulsivity Calls from school, episodes of detention, participation in activities without disruption (cub scouts, sports)

Setting target outcomes Quality of relationships –Peers: teasing, friendship, time in play –Teachers: decreasing negative, increasing positive interactions, engagement in learning activities –Parents: decreasing negative, increasing positive interactions, time for affection and support –Siblings: decreasing negative, increasing positive interactions, decreasing reactivity,

Setting target outcomes Severe ADHD: safety concerns may be priority Treatment goals that make sense to the child Treatment goals that make sense to the parents

Choosing an initial medication First decision: longer or shorter acting? –Should relate to target goals –Long acting obviates need for mid school day dose Especially important with older school aged and teens –Short acting allows targeting times of day May be important for younger child in half day of school –If target goal is school related only and parents are tolerant of behaviors at home

Choosing an initial product Largely dictated by insurance coverage –Many cover at least one long acting preparation Cost difference between generic shorter duration and name brand long acting may be > $100/mo, depending on dose.

Choosing an initial dose Aim for lowest dose likely to be effective –In past, starting routinely at very low dose, but safety at effective doses established with large randomized controlled studies Younger child, slight child, primarily inattentive: lower dose to start Older, or symptoms more severe: moderate doses to start

Doses DEX higher potency than MPH Dosing Intervals –Short acting: 2 to 4 doses per day –Longer acting 1 dose per day Or 7 am dose long acting and 5pm dose short acting of same medication –Ex: Concerta® or Ritalin LA® in am and generic MPH in late afternoon

Doses Lower doses, per dose –Short acting 5 – 10 mg. MPH, 5 mg. DEX –Longer acting 10 – 27 mg. MPH; 5 – 10 mg DEX Moderate doses, per dose –Short acting 20 mg. MPH, 10 – 20 mg. DEX –Longer acting 39 – 54 mg MPH; 30 – 40 mg. DEX

Doses Higher doses –Short acting > 20 mg per dose MPH or DEX Or > 60 mg per day MPH or DEX –Long acting > 72 mg per dose MPH, > 40 mg DEX > 54 mg in younger child MPH, > 30 mg DEX Higher doses used in more severe cases Guidelines: titrate to benefit without side effects

Monitoring medication Optimal frequency of follow up is not well studied Many recommend follow up visits every 3 to 4 months once dose is established Allows monitoring effectiveness Allows monitoring side effects

Monitoring medication If intervals longer than every 4 months –Potential for med to be continued when not effective –Potential for med to be prematurely discontinued or other meds selected, which might have more side effects –Potential for mild side effects to be unnecessarily tolerated for most of school year

Monitoring medication Very young children and those with co- existing conditions need visits every 3 months when stable –More difficult diagnostic challenge –Greater possibility of developmental progress in symptoms for very young child –More side effects in younger children –Distinct possibility of under treated co-existing condition –Possibility of co-existing condition primary, rather than ADHD

Monitoring for side effects At all visits –Blood pressure, pulse, height, weight Appetite, headache, abdominal pain, sleep Tics, mood changes, irritability “Rebound” phenomena Most side effects are responsive to changes in dose or timing

Appetite suppression Expected in perhaps 80% patients For most children and families, awareness of need to provide good caloric intake prevents or solves problem Problem is more pronounced in younger children

Appetite suppression Some children must find their own food and fail to gain weight on stimulants Some families are rigid about food and mealtime and children fail to gain on stimulants Some children fail to gain weight and this is not apparent until height is affected –Illustrates importance of follow up visits

Headache and “stomach ache” These may respond to taking medication with food Many kids, all ages, go to school without breakfast, are not hungry at lunch due to medication, and experience headaches, abdominal pain and mood changes May occur in first few days of medication, but usually not severe enough to interrupt activities

Delayed sleep onset Important to establish baseline sleep patterns Recent research indicates difficulty with sleep onset may be associated with disorder rather than medication Other research indicates medication Usually responsive to timing of last dose

Onset of tics, tic disorder Important to note baseline behaviors, mannerisms, family history of tics Tics may not be recognized as such by patient, family or teacher Not contraindication to treatment with stimulants

Mood changes, irritability Unusual for this to occur at reasonable doses Some children sensitive to this effect for one of the stimulants, but not the other If other reasons cannot be found (such as new custody arrangements, loss of pet), this may be reason to change medication Not a fair trade off –child may be more attentive and focused but feels unhappy or dysphoric

“Rebound” phenomena Some researchers say this doesn’t exist Search for other causes of increased irritability toward end of school day or afternoon –Not eating, siblings home alone May be responsive to lowering dose over day, with short acting –20 mg 7am, 20 mg. 11am, 10 mg. 3pm.

Need to change dose A dose may be effective for 1 to 2 years, and then need adjusting A dose is not necessarily increased every year Summers, holidays, weekends off? –Depends on target outcomes –May be management of poor weight gain

How long to treat? Double blind controlled study not often done clinically –Cumbersome placebo production, hard to mask the product –Expensive – not covered by insurance Adolescents often want to stop med Patient learns to use med for targeted outcomes and takes that skill into young adult years

More than one medication for ADHD? Uncomplicated ADHD does not require more than one medication Most common rationale for more than one medication –Severe and disabling symptoms –Safety issues –Co-existing conditions Depression, tic disorder, obsessive compulsive disorder

Challenges of managing more than one medication Lack of guidance Difficulty discerning which needs to be adjusted Difficulty anticipating drug interactions Stimulants often among those used in combination pharmacotherapy