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 johnerra@pharmacy.isu.edu

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 (adapted from Turning Attention to ADHD, Express Scripts Report, Mar 2014)

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 Continues into adolescence and adulthood

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, Strattera

ADHD - Etiology Unknown Genetic Environmental Role of neurotransmitters Dopamine Norepinephrine

Core Symptoms/Types of ADHD 1. Hyperactivity-Impulsivity 2. Inattention 3. Combined type 4. Not Otherwise Specified

Diagnosis of ADHD per DSM-V (2013) >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) no exclusion for autism (both can co-occur)

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 a stimulant

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 Education Behavioral modification/therapy Special education Psychological therapies

ADHD - Drug Treatment I. Stimulants II. Non-Stimulants Antidepressants (TCAs, Bupropion and SNRIs) Alpha-2 Adrenergic Agonists (Clonidine and Guanfacine) Atomoxetine Antipsychotics?

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)* 4 to 5 yrs (Preschool) 1. Behavior therapy 2. add Methylphenidate 6 to 18 yrs 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 legal restrictions

Stimulants for ADHD Amphetamine + Dextroamphetamine(Adderall ) Dexmethylphenidate (Focalin )* Dextroamphetamine (Dexedrine, Zenzedi )* Lisdexamfetamine (Vyvanse ) Methylphenidate (Ritalin, Methylin, Metadate, Concerta, Quillivant XR, Daytrana)* Methamphetamine (Desoxyn )* *generics exist for selected dosage formulations

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 serotonin from presynaptic neuron

Side Effects of Methylphenidate Most common: stomach pain, nausea, loss of appetite, insomnia, headache, irritability Less common: dizziness, rash, heart rate or systolic blood pressure, mood alterations, nervousness Rare: tics, slowing of height velocity, priapism

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 add clonidine, guanfacine, TCA, antihistamine, melatonin

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 dose or switch to longer-acting stimulant

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

Stimulant General Potency Ratio Approximate Methylphenidate 2 Dexmethylphenidate (Focalin ) 1 Amphetamine Mixture (Adderall ) 1 Dextroamphetamine (Dexedrine ) 1 Lisdexamfetamine (Vyvanse ) 2.5 Equivalent Dose (mg)

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 *generics exist for selected dosage formulations

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 ascending pattern (i.e. early & then gradual release)

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 bimodal pattern (i.e. early & late release)

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) IR = immediate release ER = extended release pk1 = time in hrs to 1 st peak pk2 = time in hrs to 2 nd peak

Generics for Concerta- FDA Alert Nov 2014 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 brands made by Janssen Pharmaceutical & identical)

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) 10 30 mg patch once daily for 9 hrs

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 Refill record

The use of stimulants in adolescents with ADHD predisposes them to drug abuse later in life. 1. True 2. False

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 disease exacerbation, federal law prohibition)

Non-Stimulant Medication for ADHD Antidepressants Tricyclic Bupropion SNRIs Alpha-2 Adrenergic Agonists - Clonidine - Guanfacine Atomoxetine Antipsychotics?

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 )* *generics exist for selected dosage formulations

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 Doses used: 50-200 mg/d in ADHD

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 regular-release* extended-release - Kapvay Guanfacine regular-release* extended-release - Intuniv *generic availability

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 Taper slowly

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 *2015 PrescriptionBlueBook.com

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 *2015 PrescriptionBlueBook.com

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/maximum dose: 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 *2015 PrescriptionBlueBook.com

Typical Antipsychotics Thioridazine (Mellaril)* Chlorpromazine (Thorazine)* Haloperidol (Haldol)* Atypical Risperidone (Risperdal)* most studied Quetiapine (Seroquel)* Aripiprazole (Abilify) Ziprasidone (Geodon)* *generics exist for selected dosage formulations

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 Pharmacists and Prescribers

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 4. impairment in > 2 settings

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 extendedacting stimulant formulation if rebound symptoms occur at 5 pm