Attention Deficit Hyperactivity Disorder

Attention Deficit Hyperactivity

Disorder

Spring 2015 Continuing Education John Erramouspe, PharmD, MS

Idaho State University College of Pharmacy

208-282-3019

I have no relevant financial interests

with respect to this subject

Learning Objectives for

Pharmacists and Prescribers

• Describe the diagnosis, core symptoms and common comorbid conditions of ADHD

• Recommend appropriate pharmacologic treatments for ADHD, including dosage form selection for

patients having problems with symptom control

• Recommend strategies for minimizing side effects of stimulant and non-stimulant ADHD medications

Learning Objectives for

Technicians and Nurses

• Identify which ADHD medications are classified as stimulants and which ones as non-stimulants • Recognize some common ADHD medications by

their brand and generic names

• List two advantages and two disadvantages of

stimulants as compared with non-stimulants in the treatment of ADHD

ADHD is a disorder of childhood and

adolecence that resolves by adulthood.

1. True

2. False

Childhood Medication Use for ADHD

• 2010: Prescriptions for ADHD drugs - 51½ million

Total sales of ADHD drugs - $7.42 billion (↑ of 83% from $4.05 billion in 2006)

• Psychoactive Medication Use

Regular education - 1 to 2%

Elementary school - up to 5% Special education - about 25%

INCIDENCE OF ADHD MEDICATION USE BY STATE & REGION 2012

ADHD - Epidemiology

• Approximately 7% of school age children • Effects of Age and Gender

– Children: Males > Females (~ 3:1) – Adolescence: Males = Females

– Young Adults: Females > Males

• Genetic predisposition

Adult ADHD

• Approximately 1.7 million patients (20 – 64 yrs)

took ADHD prescriptions in 2005 • up to 60% persistence from childhood to adult

• prevalence estimated at about 4%

• Inattention ~ 90% Hyperactivity/Impulsivity ~50% • Other Associated Problems 

social marital academic career

anxiety depression smoking substance abuse • FDA adult approved: Adderall, Concerta, Vyvanse,

ADHD - Etiology

Core Symptoms/Types of ADHD

1. Hyperactivity-Impulsivity

2. Inattention

3. Combined type

Diagnosis of ADHD

• >6 symptoms present for >6 months of either

1) inattention or 2) hyperactivity-impulsivity • symptoms present before 12 yrs

• impairment >2 settings

• clear evidence symptoms interfere with social, school, or work functioning • symptoms not better explained by schizophrenia or another

psychotic/mental disorder (e.g. mood, depressive, bipolar, anxiety, dissociative, or personality disorder, substance abuse)

Differentiation of Possible coexisting

problems/disorders with ADHD

• Oppositional defiant disorder (ODD) • Conduct disorder • Aggression • Depression • Anxiety • Tics • Bipolar • Mental handicap • Psychosis

Adolescents with ADHD and Comorbid

Oppositional Defiance with Aggression

Should Not Be Treated with Stimulants

.

1. True

2. False

Differentiation of Possible Coexisting

Problems with ADHD and Selection of

Possible Initial Drug Therapy

• Oppositional defiant disorder  stimulant* • Conduct disorder  stimulant*

• Anxiety† _{/ Depression (mild or moderate)}  _stimulant

• Depression (severe) Antidepressant (e.g. SSRI)‡

*If severe aggression coexists add mood stabilizer (e.g. divalproex or lithium)

followed by ₂-agonist. If symptoms still persist, may use atypical antipsychotic

†_{if severe anxiety remains, a SSRI may be added}

‡_{try an alternative antidepressant (e.g. SSRI or bupropion) before finally adding}

Differentiation of Possible Coexisting

Problems with ADHD and Selection of

Possible Initial Drug Therapy

• Tics  stimulants (trial of at least 2 stimulants)‡

• Bipolar  mood stabilizer (e.g. anticonvulsant or lithium)

• Psychosis  atypical antipsychotic

‡ if tics still remain problematic clonidine or guanfacine can then be added or used to replace stimulant

ADHD – Nonpharmacologic

Therapy

ADHD - Drug Treatment

I. Stimulants

II. Non-Stimulants

• Antidepressants (TCAs, Bupropion and SNRIs) • Alpha-2 Adrenergic Agonists (Clonidine and

Guanfacine) • Atomoxetine

Preschool children with ADHD should not

be treated with:

1. Stimulants

2. Behavioral therapy

3. Stimulants or

Behavioral therapy

4. None of the above

AAP Subcommittee on ADHD Clinical

Practice Guideline (2011)*

1. Behavior therapy plus FDA Approved ADHD Med (Stimulant, Atomoxetine, Guanfacine ER, or

Clonidine ER)

*AAP: Subcommittee on ADHD Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents. Pediatrics 2011;128:1007-1022.

Stimulants

• At least 80% (and up to 95%) of patients will respond to one of the stimulant drugs when they are tried in a systematic way

• Parent’s concerns must be addressed

– potential for addiction (all in schedule II) – growth concerns

Stimulants for ADHD

• Amphetamine + Dextroamphetamine(Adderall®)* • Dexmethylphenidate (Focalin®)*

• Dextroamphetamine (Dexedrine®, Zenzedi®)* • Lisdexamfetamine (Vyvanse®)

• Methylphenidate (Ritalin®, Methylin®,

Metadate®, Concerta®, Quillivant XR, Daytrana)*

• Methamphetamine (Desoxyn®)*

Mechanism of Action of Stimulants

• Inhibits reuptake of dopamine and norepinephrine

• Dextroamphetamine and amphetamine also

– inhibits monoamine oxidase and

– at higher doses results in release of dopamine and

Side Effects of Methylphenidate

Most common:

appetite, insomnia, headache, irritability

Less common:

 systolic blood pressure, mood alterations, nervousness

Rare side effects from

too high of a dose of methylphenidate

• delirium • confusion • muscle twitch • tremors • sweating • vomiting • difficulty breathing • dysphoria • zombie-like state

Management of Stimulant Side Effects

• Loss of appetite, nausea, stomachache, weight loss

–  dose or switch from extended-acting to short-acting or intermediate-acting stimulant

– administer with small meal or snack when stimulant effects are low

– consider cyproheptadine at bedtime

– caloric-enhanced supplements

– if severe, consider drug holiday or different medication

• Insomnia, nightmares

– administer earlier in the day and stop giving in the afternoon or evening

–  dose or switch from extended-acting to short-acting or intermediate-acting stimulant

Management of Stimulant Side Effects

• Headache

– divide dose

– administer with food

– add an analgesic (e.g. acetaminophen or ibuprofen)

• Anxiety

– titrate slowly –  dose

– add anxiolytic

• Dizziness

– check blood pressure

– encourage drinking of fluids

Management of Stimulant Side Effects

• Rebound (medication’s beneficial effects wear off too rapidly)

– give doses more frequently (overlap)

– switch to or add a longer-acting stimulant

– add or switch to a different type of medication, e.g. clonidine, atomoxetine, bupropion

• Irritability

– Assess at what time this is occurring in relation to dosing (i.e. determine if drug-induced)

If related to peak:  dose or try longer-acting stimulant

If related to trough/withdrawal: change to longer-acting stimulant

– Evaluate for coexisting problems and treat if present

– add or switch to a different type of medication, e.g. mood stabilizers like lithium or anticonvulsants, antidepressants

Management of Stimulant Side Effects

• Growth impairment

– try not giving the stimulant on weekend and during vacations from school “drug holidays”

– if severe, switch to nonstimulant treatment

• Depression/sadness, moodiness, agitation, dazed or

withdrawn behavior

– Treat any coexisting problems

–  dose or switch to longer-acting stimulant

– add or switch to a different type of medication, e.g. mood stabilizers like lithium or anticonvulsants, antidepressants

General Potency Ratio

Approximate

Stimulant Equivalent Dose (mg)

Methylphenidate 2

Dexmethylphenidate (Focalin®) 1 Amphetamine Mixture (Adderall®) 1 Dextroamphetamine (Dexedrine ®) 1 Lisdexamfetamine (Vyvanse®) 2.5

Stimulant - Precautions

• generally similar amongst amphetamines and methylphenidate • tic syndrome

• seizures

• cardiovascular disease • hyperthyroidism

• moderate to severe hypertension • glaucoma

Short-Acting, Rapid Onset Stimulant Dosage

Forms and Prescribing Schedules

Methylphenidate, both d,l* & d* (3-5 hr duration)

• Ritalin/Metadate/Methylin (2.5, 5, & 10 mg reg/chew tab; 20 mg tab; 5mg/5ml and 10mg/5ml soln) 2.5 – 20 mg bid to tid

• Focalin (2.5, 5, & 10 mg tab) 2.5 – 10 mg bid

Dextroamphetamine* (4-6 hr duration)

• Dexedrine/Zenzedi (2.5, 5, 7.5, 10, 15, 20, & 30 mg tab) 5 – 15 mg bid or 5 – 10 mg tid

Intermediate-Acting, Slower Onset Stimulant

Dosage Forms and Prescribing Schedules

Methylphenidate* (3-8 hr duration)

• Metadate ER & Methylin ER (10 & 20 mg tab) 20-40mg q day or 40mg am + 20mg early pm

Dextroamphetamine +/- Amphetamine* (6-8 hr) • Adderall (5, 7.5, 10, 12.5, 15, 20 & 30 mg tab) • Dexedrine† (5, 10 & 15 mg cap)

5-30 mg q day or 5-15 mg bid

*generics exist for selected dosage formulations

Extended-Acting, Rapid Onset Stimulant Dosage Forms and Prescribing Schedules

Methylphenidate* (8–12hrs)

• Concerta†_{(18, 27, 36 & 54 mg tab; 72mg (2x36mg)} • Metadate CD‡ _{(10, 20, 30, 40, 50 & 60 mg cap)} • Ritalin LA‡ _{(10, 20, 30 & 40 mg cap)}

18–72 mg q day

• Quillivant XR‡ _{(25mg/5ml susp)} 20-60 mg q day

Amphetamine + Dextroamphetamine* (10-12hrs) • Adderall XR‡ _{(5, 10, 15, 20, 25 & 30 mg cap)}

10–30 mg q day

*generics exist for selected dosage formulations

†_{ascending pattern (i.e. early & then continuous release)} ‡_{bimodal pattern (i.e. early & late release)}

Extended-Acting, Rapid Onset Stimulant Dosage Forms and Prescribing Schedules - continued

Dexmethylphenidate* (4-11hrs)

• Focalin XR‡ _{(5, 10, 15, 20, 25, 30, 35 & 40mg cap)} 5 – 40 mg q day

*generics exist for selected dosage formulations

Pharmacokinetics/Pharmacodynamics of Tabular & Capsular Extended Release Stimulant Formulations

Frequency of Stimulant Regular-Release

Formulation Onset(hrs) Mimicked Duration(hrs) IR:ER(pk1/pk2)

Methylphenidate

Concerta 0.5-2 tid 12 n/a

Metadate CD 0.5-2 bid 6-8 30:70 (1.5/4.5) Ritalin LA 0.5-3 bid 6-8 50:50 (1-3/6)

Dexmethylphenidate

Focalin XR >0.5 bid 12 50:50 (1.5/6.5)

Mixed Amphetamine Salts

Adderall XR 1-2 bid 10-12 50:50 (1-3/4-6)

Generics for Concerta

FDA Alert

• Mallinckrodt Pharmaceuticals & Kudco generics of Concerta may deliver methylphenidate at a slower release rate than the intended 10 to 12 hrs

• Therapeutic equivalence rating change: AB → BX • Still approved & can be prescribed, but no longer

automatically substitutable by pharmacy

• 6 months for inequivalent generics to confirm bioequivalence or remove product

• Actavis generic of Concerta not affected (both

Extended-Acting, Delayed Onset/Peak

Stimulant Dosage Forms and

Prescribing Schedules

Lisdexamfetamine (10 - 12 hrs)

• Vyvanse (20, 30, 40, 50, 60 & 70 mg cap) 30 – 70 mg q day

Methylphenidate Transdermal System (10 hrs) • Daytrana (10, 15, 20 & 30 mg patches)

Stimulant Monitoring Parameters

• Baseline

– height, weight, BP, pulse – LFTs

– eating and sleeping pattern

– monitoring parameters for comorbidities

– ECG (selective cardiac testing for patients with known cardiac disease per history or physical exam)

• Response to treatment

– parent & teacher behavior rating scales • Medication adherence

The use of stimulants in adolescents with

ADHD predisposes them to drug abuse

later in life.

1. True

Abuse and Misuse of Stimulants

Euphoria abuse potential: Methylphenidate: least Dextroamphetamine +/- Amphetamine: most

• Person abusing often not the patient and route for hardcore abuse generally not oral, rather IV or inhaled • Most of the extended-release stimulant dosage forms are

difficult to abuse (e.g. snort or use IV) and not often found in the possession of people arrested for abuse

Misuse purpose:  energy, stay awake, finish tasks

• reported  in adolescents, college students, young adults • Pharmacists role: Watch for signs of diversion (eg. frequent early refill requests) and Warn of potential dangers (comorbid

Non-Stimulant Medication for ADHD

• Antidepressants

– Tricyclic – Bupropion – SNRIs

• Alpha-2 Adrenergic Agonists

- Clonidine - Guanfacine

• Atomoxetine

Antidepressants

• 2nd line therapy

– Use after 2 to 3 different stimulants have been tried in

a systematic way

• Good if specific comorbid condition (eg depression, anxiety, tics, addictive tendencies)

• Not FDA approved for this indication • Less effective in improving attention

Other Antidepressants

• Bupropion (Wellbutrin®_{, Budeprion}®_)*

• Venlafaxine (Effexor®_)*

Bupropion (Wellbutrin

,

Budeprion

, generics)

• Weakly inhibits norepinephrine, dopamine, and serotonin reuptake • May be useful with comorbid conduct disorders • ADRs:  seizure threshold

• May  risk of tics

Venlafaxine (Effexor

_{, generics)}

• Inhibits reuptake of serotonin, norepinephrine & dopamine (weakly)

• Small, open labeled trials in children,

adolescents, and adults with ADHD limits role • Black box warning (like all antidepressants) on risk of suicidal ideation

Alpha-2 Adrenergic Agonists

• Clonidine

• Guanfacine

Alpha-2 Adrenergic Agonists

• Effective in trials (about a 70% response rate) • Works best in children with:

– high motor activity

– aggression/conduct disorder – poor response to stimulants

– problematic side effects from stimulants – tics

Clonidine RR - Dosing

• Initial:0.05 mg hs (½ of a 0.1 mg tab) • Available in 0.1, 0.2, and 0.3mg tablets

• Titrate by ¼ - ½ of a 0.1mg tab q 2-5 days • Typical dose range: 0.1 mg TID-QID

• Max daily dose: 0.4 mg • ADR: sedation

Clonidine ER (Kapvay

) - Dosing

• Initial: 0.1 mg once daily at bedtime • Available in 0.1 mg tablets

(0.2 mg tablet strength discontinued) • Titrate by 0.1mg/day at weekly intervals

• Typical dose range: 0.1 to 0.2mg BID (am & hs) • Max daily dose: 0.4 mg

• ADR: sedation

• Taper slowly (<0.1 mg q 3 to 7 days) • Cost*: $4.26 per 0.1mg

Guanfacine

 t½ and ↓ sedation relative to clonidine Regular-release tablet (Tenex, generics) • Cost*: $0.27/1mg tab, $0.41/2mg tab

• Initial dose: 0.5 mg hs; titrate by 0.5 mg q 3-14 days • Typical dose range: 1mg bid to tid

Extended-release tablet (Intuniv)

• Cost*: $8.44 per 1, 2, 3, or 4 mg tab

• Initial dose: 1 mg once daily; titrate by <1mg per wk Max dose for both RR & ER tablets: 4 mg/day

Atomoxetine (Strattera

, generic)

- norepinephrine reuptake inhibitor, not a controlled substance - capsules: 10, 18, 25, 40, 60, 80 and 100mg

-children/adolescent dosing (<70kg)

initial/target/maximumdose: 0.5/1.2/1.4 mg/kg/day (100mg max)

 dose after 3-day minimum (4wks if on strong CYP2D6 inhibit)

-frequency of administration single dose q am

twice daily dose (am & late afternoon/early evening)

-high acquisition cost ($7.21-$8.46 cost/cap depending on strength*)

- patient counseling/warnings: liver dysfunction & suicidal ideation

Antipsychotics

• Risperidone (Risperdal)* – most studied • Quetiapine (Seroquel)*

• Aripiprazole (Abilify) • Ziprasidone (Geodon)*

Assessment Questions for

Technicians and Nurses

An FDA-approved non-stimulant for both

pediatric and adult patients with ADHD?

1. Strattera®

2. Vyvanse®

3. Adderall®

4. Concerta®

Which of the following generic names is

associated with the correct brand name?

1. clonidine = Intuniv

2. dextroamphetamine = Ritalin 3. dexmethylphenidate = Adderall 4. methylphenidate = Concerta

An advantage of stimulants relative to

non-stimulants in the treatment of ADHD?

1. lack of potential for abuse

2. persistence of efficacy despite missing a single daily dose

3. greater efficacy

4. lack of an effect on growth velocity

Assessment Questions for

Criteria for the diagnosis of ADHD

(per DSM-V)

does not include:

1. a positive response to a stimulant

2. symptoms of inattention or hyperactivity-impulsivity

3. presence of symptoms before 12 years of age

What single daily stimulant would be preferred to cover the entire daily activities of a child with

ADHD, including both early morning and afternoon classes plus after-school activities?

1. Vyvanse® 2. Adderall® 3. Concerta® 4. Focalin®

A management strategy for minimizing the negative effects of stimulant medication might include:

1. a dose increase in headache occurs 2. administering an Adderall XR®

dose later in the day in case of bedtime insomnia

3. changing to a longer-acting

stimulant in the morning if loss of appetite occurs at lunch and dinner 4. switching to a morning

extended-acting stimulant formulation if