Sara J.D. Bork, PharmD, MBA - PowerPoint Presentation

Sara J.D. Bork, PharmD, MBAApril 14th, 2016 SCHEDULE II: ATTENTION-DEFICIT / HYPERACTIVITY DISORDER(ADHD)

Speaker DisclosuresSara Bork does not have any actual or potential conflicts of interest in relation to this program Editorial advisors and ACPE administrator disclosuresNo actual or potential conflicts of interest in relation to this program are reported.Disclosures

Compare characteristics of Attention-Deficit/Hyperactivity Disorder in children, adolescents and adults Provide an overview of the current American Academy of Pediatrics Clinical Practice Guideline for the Diagnosis, Evaluation, and Treatment of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents and application in select clinical practice scenariosDifferentiate pharmacologic treatment options for Attention-Deficit/Hyperactivity Disorder in children, adolescents and adultsObjectives

Define Attention Deficit / Hyperactivity Disorders (ADHD) Prevalence of ADHDDifferentiation of child, adolescent and adult ADHDAAP Practice Guidelines Medication Treatment Methylphenidate Dextroamphetamine Dexmethylphenidate Lisdexamfetamine AtomoxetineClonidineGuanfacine In Preparation for today…

ATTENTION-DEFICIT / HYPERACTIVITY DISORDER (ADHD)

Attention-deficit / hyperactivity disorder (ADHD) is a disorder that manifests with persistent symptoms of inattention and/or hyperactivity-impulsivity. These symptoms affect academic, occupational, and social functioning. ADHD DSM-IV-TR. 4 th Edition, 2000.

Timeline CDC. ADHD: Data & Statistics. http://www.cdc.gov/ncbddd/adhd/data.html

ADHD in children 5 – 17 years: 9% ADHD in children 12 – 17 years: 3 million children Males 12.3%: Females 5.5% Studies of ADHD in childhood suggest persistence of ADHDInto adolescence: 75%Into adulthood: 50%Prevalence of ADHD Curr Opin Pediatr 2014;26:119-129.

Prevalence of ADHD Diagnosis CDC. ADHD: Data & Statistics. http://www.cdc.gov/ncbddd/adhd/data.html

Prevalence of ADHD TREATMENTCDC. ADHD: Data & Statistics. http://www.cdc.gov/ncbddd/adhd/data.html

ADHD in Texas CDC. ADHD: Data & Statistics. http://www.cdc.gov/ncbddd/adhd/data.html

ADHD in Texas CDC. ADHD: Data & Statistics. http://www.cdc.gov/ncbddd/adhd/data.html

N Engl J Med 2014;370(9):838-846.

N Engl J Med 2013;369(20):1935-1944.

The primary care clinician should initiate an evaluation for ADHD for any child 4 through 18 years of age who presents with academic or behavioral problems and symptoms of inattention, hyperactivity, or impulsivity (quality of evidence B/strong recommendation). AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

Pediatrics 2011;128(5):SI1-SI21.

Assessment of ADHD J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-921.

To make a diagnosis of ADHD, the primary care clinician should determine that Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria have been met (including documentation of impairment in more than 1 major setting); information should be obtained primarily from reports from parents or guardians, teachers, and other school and mental health clinicians involved in the child’s care. The primary care clinician should also rule out any alternative cause (quality of evidence B/strong recommendation).AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

N Engl J Med 2014;370(9):838-846.

Inattention N Engl J Med 2013;369(20):1935-1944.

Hyperactivity / Impulsivity N Engl J Med 2013;369(20):1935-1944.

Symptoms of ADHD Pediatrics 2011;128(5):SI1-SI21.

Combined presentation Both inattention and hyperactivity / impulsivity criteria have been present for the past 6 monthsPredominantly inattentive presentationInattention criteria are met but criteria for hyperactivity and impulsivity are not metPredominantly hyperactive and impulsive presentation H yperactivity / impulsivity criteria are met and criteria for inattention are not metDiagnosisN Engl J Med 2013;369(20):1935-1944.

In the evaluation of a child for ADHD, the primary care clinician should include assessment for other conditions that might coexist with ADHD, including emotional or behavioral (e.g., anxiety, depressive, oppositional defiant, and conduct disorders), developmental (e.g., learning and language disorders or other neurodevelopmental disorders), and physical (e.g., tics, sleep apnea) conditions (quality of evidence B/strong recommendation). AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

Comorbidities of ADHD CDC. ADHD: Other Concerns and Conditions. http://www.cdc.gov/ncbddd/adhd/conditions.html

The primary care clinician should recognize ADHD as a chronic condition and, therefore, consider children and adolescents with ADHD as children and youth with special health care needs. Management of children and youth with special health care needs should follow the principles of the chronic care model and the medical home (quality of evidence B/strong recommendation). AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

Pediatrics 2011;128(5):SI1-SI21.

Recommendations for treatment of children and youth with ADHD vary depending on the patient’s age: For preschool-aged children (4–5 years of age), the primary care clinician should prescribe evidence-based parent- and/or teacher-administered behavior therapy as the first line of treatment (quality of evidence A/strong recommendation) AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

Recommendations for treatment of children and youth with ADHD vary depending on the patient’s age: And may prescribe methylphenidate if the behavior interventions do not provide significant improvement and there is moderate-to severe continuing disturbance in the child’s function. In areas where evidence-based behavioral treatments are not available, the clinician needs to weigh the risks of starting medication at an early age against the harm of delaying diagnosis and treatment (quality of evidence B/recommendation). AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

Recommendations for treatment of children and youth with ADHD vary depending on the patient’s age: For elementary school–aged children (6–11 years of age), the primary care clinician should prescribe US Food and Drug Administration–approved medications for ADHD (quality of evidence A/strong recommendation) and/or evidence-based parent and/or teacher-administered behavior therapy as treatment for ADHD, preferably both (quality of evidence B/strong recommendation). AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

Recommendations for treatment of children and youth with ADHD vary depending on the patient’s age: The evidence is particularly strong for stimulant medications and sufficient but less strong for atomoxetine, extended-release guanfacine, and extended-release clonidine (in that order) (quality of evidence A/strong recommendation).AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

Recommendations for treatment of children and youth with ADHD vary depending on the patient’s age: For adolescents (12–18 years of age), the primary care clinician should prescribe Food and Drug Administration–approved medications for ADHD with the assent of the adolescent (quality of evidence A/strong recommendation) and may prescribe behavior therapy as treatment for ADHD (quality of evidence C/recommendation), preferably both. AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

AAP guidelines recommend Behavioral Modification Training (BMT) as first line for children 4-6 years Combination of behavioral therapies with medication is considered most effective therapy for children > 6 yearsNonpharmacologic Options Pediatrics 2011;128(5):1007-1022.

N Engl J Med 2014;370(9):838-846.

10-20 weekly sessions (1 to 2 hours) during which time parents: are given information about the nature of ADHDlearn to attend more carefully to their child’s misbehavior and to when their child compliesestablish a home token economyuse time out effectively manage noncompliant behaviors in public settings use a daily school report card anticipate future misconduct Behavioral Parent Training J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-928.

Create a routineGet organizedAvoid distractions Limit choices Change your interactions with your child Use goals and rewards Discipline effectivelyHelp your child discover a talentBehavioral Therapy: At Home CDC. ADHD: Treatment. http://www.cdc.gov/ncbddd/adhd/treatment.html

Use a homework folder for communicationsMake assignments clearGive positive reinforcementBe sensitive to self-esteem issues Involve the school counselor or psychologist Behavioral Therapy: In the Classroom CDC. ADHD: Treatment. http://www.cdc.gov/ncbddd/adhd/treatment.html

Behavioral Therapy: Techniques Pediatrics 2001:108(4);1033-1044.

The Texas Children's Medication Algorithm ProjectRevision of the algorithm for pharmacotherapy of attention-deficit/hyperactivity disorder. (2006) American Academy of Child Adolescent Psychiatry (2007) American Academy of Pediatrics (2011) All recommend a stimulant as first line Guidelines for Treatment J Am Acad Child Adolesc Psychiatry. 2007;46(7):894-928. Pediatrics 2011;128(5):1007-1022. J Am Acad Child Adolesc Psychiatry. 2006;45(6):642-57.

Ann Pharmacother. 2014;48(2):209-25 .

Texas CMAP Algorithm: Comorbidities J Am Acad Child Adolesc Psychiatry. 2006 Jun;45(6):642-57.

TREATMENT

Psychoeducation Education on signs and symptoms of ADHDEducation on the misconceptions about ADHD and its treatment Psychotherapy Behavioral parent therapy Behavioral classroom management Behavioral peer interventions Medications StimulantsNon-Stimulants Treatment: Individualize therapy N Engl J Med 2014;370(9):838-846.

Ensure safety of the patient Develop a therapeutic relationshipChange the patient’s behavior / symptoms Improve written and verbal communication Improve academic performance Decrease disruptive behaviors Improve self-esteem Reduce requirement of supervision Enhance safetyGoals of Treatment Ped in Review. 2003:24(3);92-98.

The primary care clinician should titrate doses of medication for ADHD to achieve maximum benefit with minimum adverse effects (quality of evidence B/strong recommendation). AAP Practice Guidelines Pediatrics 2011;128(5):1007-1022.

PHARMACOLOGIC TREATMENT

1930-40’s Benzedrine and desoxyn become first agents 1950’s Introduction of methylphenidate or amphetamine 1970’s Introduction of pemoline (Cylert®) and dextroamphetamine ( Dexedrine®) 1980’s Sustained release methylphenidate 1990’s Multiple formulations of methylphenidate become available (Methadate ER®, Concerta®, and Methylin ER®) 2000’s More formulations of methylphenidate become available (Focalin®, Adderall XR®, Methadate CD®, Ritalin LA®, Methylin®, Focalin XR®, Daytrana®) as well as lisdexamfetamine (Vyvanse®) Release of non-stimulants atomoxetine (Strattera®), guanfacine (Intuniv®), and clonidine (Kapway®) Treatment Pipeline CDC. ADHD: Data & Statistics. http://www.cdc.gov/ncbddd/adhd/data.html

Pediatrics 2011;128(5):SI1-SI21.

N Engl J Med 2014;370(9):838-846.

Mechanism of Action (MOA) Inhibit the reuptake of dopamine (DA) and norepinephrine (NE)Inhibit monoamine oxidase, which is responsible for metabolizing DA and NE (amphetamine > methylphenidate) Amphetamine: Releases stored neurotransmitters at the presynaptic terminal Stimulants Ann Pharmacother. 2014;48(2):209-25.

Medication DoseDuration of Effect Methylphenidate Concerta® 18 mg/DAY (MAX: 72 mg) 12 hours Methylin®5 mg two to three times a day (MAX: 60 mg) 3-5 hours Daytrana® 10 mg (apply for 9 hours) (MAX: 30 mg) 11-12 hours Ritalin® 5 mg two to three times a day (MAX: 60 mg) 3-5 hours Ritalin LA® 20 mg/DAY (MAX: 60 mg) 6-8 hours Ritalin SR® 20 mg once to twice daily (MAX: 60 mg) 2-6 hours Metadate CD® 20 mg/DAY (MAX: 60 mg) 6-8 hours Quillivant XR® 20 mg/DAY (MAX: 60 mg) 12 hours Dexmethylphenidate Focalin® 2.5 mg twice daily (MAX: 60 mg) 3-5 hours Focalin XR® 5 mg/DAY (MAX: 20 mg) 8-12 hours Stimulants DSM-IV-TR. 4 th Edition, 2000.

Medication DoseDuration of Effect Mixed amphetamine salts Adderall® 2.5-5 mg once to twice daily (MAX: 40 mg) 6 hoursAdderall XR®5 mg/DAY (MAX: 40 mg) 10 hours Dextroamphetamine Dexedrine® 2.5 mg two to three times a day (MAX: 40 mg) 4-6 hours Dexedrine Spansule® 5 mg once to twice daily (MAX: 40 mg) >6 hours Lisdexamfetamine (Vyvanse®) 20 mg/DAY (MAX: 70 mg) 10-12 hours Stimulants DSM-IV-TR. 4 th Edition, 2000. Side effects: Headache, abdominal pain, decreased appetite, delayed onset of sleep

METHYLPHENIDATE

Ritalin IR®, Methylin®Initial dose: 2.5-5 mg/DAY (MAX: 60 mg/DAY) Peak: ~2 hours with a duration: 3-6 hours Divide doses 2-3 times/DAY (breakfast, lunch) Immediate Release Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Ritalin SR®, Metadate ER®, Methylin ER®Initial dosing should be with Immediate Release formulations Switch to equivalent dosing (IR = SR) SR Peak: 4-7 hours with duration: 8 hours Sustained-Release Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Ritalin LA®, Metadate CD® Biphasic release simulates twice daily dosing1st peak = ~2 hours 2 nd peak = 6 hours Duration: ~ 8 hours IR:ER Metadate CD® = 30:70Ritalin LA® = 50:50Sustained-Release (Bi-phasic) Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Quillivant XR® Powder suspension for reconstitutionShake well Room temperature (4 months)Final Concentration = 25 mg/5 mL Peak: ~4 hours IR:ER (20:80) Extended-Release Suspension Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Concerta® Dosing: 18-72 mg/DAYTri-phasic release stimulates three times daily dosing 1 st peak = 1-2 hours Slow increase over next 3-4 hours Time to peak: 6-8 hours Slow declineDuration: 12 hoursAdjust doses weeklyOsmotic controlled-release oral delivery system Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Tablet Dose Initial Dose Extended Dose 18 mg 4 mg 14 mg 27 mg 6 mg21 mg36 mg 8 mg 28 mg 54 mg 12 mg 42 mg 72 mg 16 mg 56 mg Osmotic controlled-release oral delivery system

Immediate Release Sustained ReleaseOROS 5 mg two to three times a day 20 mg once daily 18 mg once daily 10 mg two to three times a day40 mg once daily36 mg once daily15 mg two to three times a day 60 mg once daily 54 mg once daily 20 mg three times a day 72 mg once daily Dose Conversions: Methylphenidate Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Daytrana® Dosage Forms: 10, 15, 20, and 30 mgApply patch for 9 hoursOnset: ~2 hoursPeak: 7.5-10.5 hoursResidual effects: 3 hours after removal Transdermal Patch Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Transdermal Patch Application Alternate hip daily Avoid waist line Try rotating areas Clean, dry, non-oily, intact skin Apply pressure for 30 seconds Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Methylphenidate Patch Drug Delivery Rate (mg/hr) Methylphenidate PO Equivalent (mg/DAY) 10 1.1 15 151.6522.520 2.2 30 30 3.3 45 Transdermal Conversions Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

DEXMETHYLPHENIDATE

Dexmethylphenidate Focalin IR®2.5 mg twice daily (MAX: 60 mg)Dosage may be adjusted in increments of 2.5-5 mg at weekly intervals (MAX dose: 20 mg/DAY) Doses should be taken at least 4 hours apart Peak: 1-1.5 hours Duration: 6 hours Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Dexmethylphenidate Focalin XR® 5 mg/DAY (MAX: 40 mg) Dosage may be adjusted in increments of 5 mg/DAY at weekly intervals (MAX dose: 30 mg/Day) Onset of Action: ~0.5 hours Peak: 1 st : 1.5 hours (1-4 hours) 2 nd: 6.5 hours (4.5-7 hours) Duration: 12 hours Biphasic release IR:ER = 50:50 Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Conversion to dexmethylphenidate from methylphenidate Immediate release: Initial: Half the total daily dose of racemic methylphenidate (maximum dexmethylphenidate dose: 20 mg/day)Extended release: Initial: Half the total daily dose of racemic methylphenidate (maximum dexmethylphenidate dose: 40 mg/day)Conversion from dexmethylphenidate immediate release to dexmethylphenidate extended release When changing from Focalin® tablets to Focalin® XR capsules, patients may be switched to the same daily dose using Focalin® XR (maximum dose: 40 mg/day) Dose reductions and discontinuation Reduce dose or discontinue in patients with paradoxical aggravation of symptoms. Discontinue if no improvement is seen after one month of treatment. Dexmethylphenidate: Conversions Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

DEXTROAMPHETAMINE

Dexedrine® 5 mg/DAY (MAX: 20 mg) Duration: 4-6 hoursDextroamphetamine Dexedrine Spansules (SR)® 5 mg once daily (MAX: 15 mg) Duration: 6-10 hours Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Vyvanse® Amphetamine pro-drugLess potential for abuseDose: 20-70 mg/DAYDuration: 8-12 hours Capsules can be opened, dissolved in water and taken immediately Lisdexamfetamine Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

MIXED AMPHETAMINE SALTS

Mixed Amphetamine Salts Adderall®3-5 years: 2.5 mg once daily>6 years: 5-10 mg once daily ( MAX: 40 mg) Duration: 4-6 hours Adderall XR® 10 mg/DAY (MAX: 30 mg) Duration: 10-12 hoursBiphasic release Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Contraindications and Precautions for Stimulants Seizure disordersEEG abnormalitiesCardiac abnormalities (or family history) Glaucoma Anxiety Motor tics MAO inhibitors History of drug abuse History of psychosis Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Drug holidays: Periodic discontinuation Assess the patient's requirements Decrease tolerance Limit suppression of linear growth and weightSome patients may require 3 doses/DAY for treatment of ADHD Concerta® is OROS of methylphenidate Some products contain a mixture of immediate release and extended release beads Metadate CD® is designed to release 30% of the dose immediately and 70% over an extended period Ritalin LA® is designed to release 50% of the dose immediately and 50% delayed release over time This is also enteric coated Stimulants: Clinical Pearls Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Stimulants vs. Nonstimulants

Atomoxetine (Strattera®) Clonidine ER tablets (Kapvay®)Guanfacine ER tablets (Intuniv®)Other non-FDA approved, off-label therapies: Bupropion Venlafaxine TCAs Nonstimulant Medications for ADHD Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Norepinephrine reuptake inhibitor Onset of effect: 2-4 weeks Side effectsN/V, anorexia, increased BP/HR, constipation, sedation, rare hepatotoxicity (bolded warning) Once daily WEIGHT-BASED dosing 0.5-1.4 mg/kg/DAY up to 70 kg (Target dose of 1.2-1.4 mg/kg/DAY is recommended)Start with lower dose (0.5 mg/kg/DAY) for one week and titrate up, monitoring side effectsBetter tolerated dosing when given with dinner, may decrease GI upset and daytime sedationAtomoxetine Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Pediatric: [U.S. Boxed Warning]: Use with caution in pediatric patients; may be an increased risk of suicidal ideation. Closely monitor for clinical worsening, suicidality, or unusual changes in behavior; especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The family or caregiver should be instructed to closely observe the patient and communicate condition with healthcare provider. Growth should be monitored during treatment. Height and weight gain may be reduced during the first 9 to 12 months of treatment, but should recover by 3 years of therapy. FDA: The Boxed Warning

Tell your child or teenager’s doctor if your child or teenager (or there is a family history of): Has bipolar illness (manic-depressive illness) Had suicide thoughts or actions before starting STRATTERA® The chance for suicidal thoughts and actions may be higher: Early during STRATTERA® treatment During dose adjustments Prevent suicidal thoughts and action in your child or teenager by: Paying close attention to your child or teenager’s moods, behaviors, thoughts, and feelings during STRATTERA® treatment Keeping all follow-up visits with your child or teenager’s doctor as scheduled FDA: The Boxed Warning

Anxiety Agitation Panic attacks T rouble sleeping Irritability Hostility Aggressiveness Impulsivity R estlessness M ania D epression Suicidal thoughts FDA: The Boxed Warning Watch for the following signs in your child or teenager during STRATTERA® treatment:

Alpha-adrenergic agonists Extended release formulationsApproved as monotherapy or as adjunctive therapy in ADHDImmediate release formulations Not FDA approved, but see them used Clinically useful for treating tics, hypertension, sleep problems, aggression, self-injurious behavior More effective for impulsivity and hyperactivity than for inattentiveness symptoms Clonidine / Guanfacine Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Dosing Initial dose: 0.1 mg at bedtimeAdjust daily dose in increments of 0.1 mg/DAY at weekly intervals until desired responseDoses should be taken twice a day with either an equal or higher split dosage given at bedtime Clonidine Total Daily Dose Morning Dose Bedtime Dose 0.1 mg/day 0.1 mg 0.2 mg/day 0.1 mg 0.1 mg 0.3 mg/day 0.1 mg 0.2 mg 0.4 mg/day 0.2 mg 0.2 mg Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Dosing Once daily, either in the morning or evening at approximately the same time each dayInitial dose: 1 mg/DAYAdjust dose in increments of no more than 1 mg/DAY at weekly intervalsMaintenance dose: 1-4 mg/DAY depending on clinical response and tolerability Clinical improvements: Target dose of 0.05-0.08 mg/kg/DAY, if well tolerated, titrate up to 0.12 mg/kg/DAY for max benefit Guanfacine Drug Information Handbook, Lexi-Comp. 23rd Edition. 2015.

Ann Pharmacother. 2014;48(2):209-25.

N Engl J Med 2014;370(9):838-846.

What should you ask yourself when treating ADHD? Are the medications working?Are the medications at appropriate doses?Are the medications prescribed correctly?Is the patient undergoing psychotherapy?Is the patient being compliant?Is the patient taking the medications at the correct time? Summary