Getting Over the ADHD Treatment Hurdles

An Information Session for Pharmacists

Leslie JocelynMD FRCPC Pediatrics & Psychiatry

Developmental Pediatrician

Child & Adolescent Psychiatrist

February 2, 2010

Disclosures and Acknowledgment

Speakers Bureau : Janssen, Lilly, Purdue, Shire

Research Grants : Janssen

Advisory Board: Lilly, Purdue, Shire

Thanks to Jill Bojarski and Purdue Canada for their financial support of this evenings program

This presentation is for educational purposes only. The opinions expressed in this

presentation are not necessarily those of the sponsor and neither product

descriptions nor opinions expressed should be attributed to the sponsor. The

sponsor does not recommend any use of its products that is inconsistent with the

product monograph

Objectives: At the conclusion of this program the

pharmacist will be able to clear the following hurdles:

1. Recognize the symptoms of ADHD across the lifespan

2. Outline the evidence for a biological etiology for ADHD

3. Communicate the importance of ADHD treatment to

parents.

4. Appreciate what factors influence choice of medication

5. Serve as a valuable and informed resource for patients

with ADHD and their families.

How many times a week do parents ask you “Does my child really need ADHD medication?”

A. No one ever asks me that

B. Once a week

C. Five times a week

D. Ten times a week

E. Virtually every parent asks this

Reluctant parents seem most concerned about?

A. Safety of the med (i.e. serious side effect)

B. General concerns about giving medication to children

C. Belief treatment should be limited to “school time”

D. The stigma of ADHD

E. The cost of medication

F. Potential for addiction

Making the diagnosis across the lifespan

Hurdle # 1

What should an assessment for ADHD consist of ?

Physical

Exam

AssessmentLearning

Testsprn

Mental Status Exam

Rating Scales

DSM 1V Diagnosis ADHD Based on Type of Symptoms

Inattentive Type

Hyperactive/Impulsive Type

DSM 1V Criteria continued

Duration of 6+ months

Not due to developmental delay

Onset before age 7 yrs

2+ settings (home, school, social)

Impairment in function

Not due to another mental D/O

Adapted from American Psychiatric

Association, DSM-IV TR, 2000.

Prevalence of ADHD

The most common psychiatric diagnosis in children and adolescents

• Affects 8 – 10% of males < 18 years old *

• Affects 3 – 4 % of females < 18 years old *

You’ll see it even in adults

• 80% remain symptomatic into adolescence

• 60% remain symptomatic into adulthood

• 4.4% adults meet full DSM 1V criteria

*CADDRA guidelines 2008 (Canadian ADHD Resource Alliance)

ADHD Symptoms Change Over the Life Span

Inattention

Time

Hyperactivity

Impulsivity

Persistence greatest in those with symptomatic parent, co-morbidity & social adversity.

Biederman J. et al. Am J Psychiatry. 2000 May;157(5):816-8.

•Lack attention to details

•Avoids paperwork / paralyzing procrastination

•Starts but does not finish projects

•Poor time management

•Changes gear in middle of tasks

•Misses appointments or late

•Careless mistakes

•Difficulty sustaining attention

•No follow-through

•Can’t organize

•Easily distractible

•Forgetful

•Can’t sit through meetings

•Can’t wait in line, tolerate frustration

•Drives too fast

•Talks excessively,

•Makes inappropriate comments

•Interrupts

•Squirming, fidgeting

•Can’t wait turn

•On the go/driven by motor

•Blurts out answers

Hurdle #2

ADHD is a Real Diagnosis

What’s the

evidence to

support a biologic

basis for ADHD ?

Willerman, 1973

Goodman, 1989

Gillis, 1992

Edelbrock, 1992

Schmitz, 1995

Thapar, 1995

Gjone, 1996

Silberg, 1996

Sherman, 1997

Levy, 1997

Nadder, 1998

Hudziak, 2000

0 0.2 0.4 0.6 0.8 1

HeightBreast cancer Asthma Schizophrenia

ADHD is InheritedAverage genetic contribution to ADHD

0 means no genetic effect1 means 100% due to genetics

ADHD

ADHD: MRI Studies

Swanson JM et al. Lancet. 1998;351:429–433. Castellanos FX et al. Arch Gen Psychiatry. 2001;58:289–295.

Corpus

Callosum

Cerebellum

Frontal lobes

Several brain areas

are 10% smaller in

patients with ADHD

compared to

controls

Bush G et al. Biol Psychiatry. 1999;45:1542-1552.

1 x 10 -3

1 x-2y = +21 mm

Normal Controls

1 x 10 -2

1 x 10 -3

y = +21 mm

ADHD

Dorsal Anterior Cingulate Cortex (Cognitive

Division) Fails to Activate in ADHD on fMRI Study

During Stroop Test

PET Scans show Global and Regional glucose Metabolism Reduced in Adults with ADHD

Global & regional glucose consumption reduced in

ADHD

Increased glucose consumption with Ritalin

Zametkin AJ et al, N Eng J Med1990;323:1361-6

Hurdle # 3

The Consequences of Not Treating

Side effects of the

ADHD meds are well

know but are the

consequences of not

treating ADHD as

well appreciated ?

How to Help Parents Understand the Need for ADHD Treatment

1. De-stigmatize ADHD

2. Emphasize the risks associated with

non-treatment

3. Emphasize the protective effect treatment

can have

4. Reassure that the abuse potential for most

ADHD medications is low

5. Address specific concerns about the safety

of a medication

Treatment: The ADHD Tool Belt

1. Education

Verbal, written, local & web info

www.caddra.ca

2.Behavioral/Environmental

ChangesClassroom interventions

Behavioral interventions

3. MedicationsEffective and safe

Treat the core symptoms

If you only have a hammer you better hope you only need a nail

0% 10% 20% 30% 40% 50% 60%

Fired from job

Incarcerated

Arrested

Serious car accident

Accident prone

Substance abuse

STD

Teen pregnancy

< high school

Repeat a grade

Subjects (%)

ADHD

Normal

1. Barkley. Attention-deficit hyperactivity disorder. A handbook for diagnosis and treatment, 1998; 2. Barkley et al. JAACAP 1990; 3. Biederman et al. Arch Gen Psych1996; 4. Weiss et al. JAACAP 1985; 5. Satterfield, Schell. JAACAP 1997; 6. Biederman et al. Am J Psych 1995.

Functional Impairment in Untreated ADHD vs Controls

3x

9x

4x

3x

4x

11x

2x

Stimulants Protect Against Psychiatric Disorders in Youth with

ADHD. A 10 yr Follow up study

Case-control study of male children aged 6-18 with ADHD

Disorder P value

Major depression <0.001

Conduct disorder <0.001

Multiple (≥2) anxiety disorder <0.001

Oppositional defiant disorder <0.001

Bipolar disorder 0.063

Repeated a grade in school <0.001

Biederman J, et al. Pediatrics 2009;124(1):71-8

ADHD and Driving: A Dangerous Mix

• MVAs are #1 cause of death in teens

• ADHD increases the risk. (1)

• Adolescents with ADHD:

• 2-4 x more car accidents ( 2-4)

• 3 x more injuries (3)

• 4 x more at fault (2)

• 6-8 x more license suspensions (2,3)

• Meds decrease risk for MVAs (4,6)

1.National Highway Traffic Safety Administration, Ann Emerg Med 1997:29:546-9.

2. Barkley RA, Pediatrics1993:92:212-218. 3. Barkley RA, Pediatrics 1996:98:1069-1095.

4. Cox DJ, J Nerv Ment Dis 2000:188:230-234. 5. Neda-Rajas, JAACAP 1997:36:515-32

6. Cox DJ, JAACAP.2004:43(3):269-75

Do Stimulants Increase Risk of Later Drug Abuse?

NOMedication treatment of ADHD decreases drug use by teens with ADHD by 6 times

Wilens et al. Pediatrics 2003;111:179-185

Things to keep in mind if you’re concerned about abuse of ADHD medication...

1. These meds have approval from Health Canada.

2. Some ADHD medications can only be abused if

they are snorted or injected. There is no risk if

they are taken orally.

3. Other ADHD medications haven’t shown any

ability to give a high, even if injected or snorted.

4. Short acting meds are more likely to be abused

5. Diversion is most common in patients with

substance use disorders/conduct disorder

Choosing a Medication

Factors That Influence Choice of Medicationfor A Specific Patient

Medical Considerations

• Treatment guidelines

• Urgency of treatment

• Duration of effect

• Patient preference

• Co-morbid symptoms

• Previous treatment success

• History of drug abuse (individual or family)

Pliszka SR, et al. J Am Acad Child Adolesc Psychiatry 2006;45(6):642-57.

Practical Considerations

• Adherence

• Stigma

• Cost / insurance

• Administration:

• By parent

• By teacher

COMORBIDITY: The Rule not the Exception in ADHD

ADHD andOppositional

Defiant Disorder

ADHD only

n = 579 Does not include 30-40% with LDs

Jensen P, et al. Arch Gen Psychiatry 1999;56:1073-1086. MTA study

*Note that the total is greater than 100% due to listing some patients with more than one diagnosis

ADHD and Oppositional Defiant Disorder

ADHD only

n = 579 Does not include 30-40% with LDs

ADHD and anxiety /mood disorders

ADHD and Conduct Disorder

ADHD and tics

Medication Guidelines

CADDRA

Guidelines

2008

www.caddra.ca

Canadian ADHD Resource Alliance

1st line 2nd line 3rd line

2008 CADDRA Guidelines Medication Treatment of ADHD

"Off label"

if drugs fail

Imipramine

Wellbutrin®

Short Acting

Dexedrine®

Dex-Spansules®

Ritalin IR®

Ritalin SR®

Long Acting

Adderall

XR®

Biphentin ®

Concerta ®

Strattera ®

All trade-marks mentioned in this presentation are the property of their respective owners.

Reasons for using Long-acting Medication First-line

1. Improves tolerability

2. Improves compliance

3. Preserves confidentiality & avoids legal/logistic issues of taking meds at school

4. Improves function in many areas • Home life (i.e., relationships with family)

• Interaction with friends

• Extracurricular activities (e.g., sports, peer groups)

Medication Active Agent Delivery System Duration

Adderall® XRMixed-

amphetamine salts

Beaded double-

pulse delivery10-12 h

Biphentin® MethylphenidateMulti-Layer

ReleaseTM 10-12 h

Concerta® Methylphenidate

Osmostic-controlled

release oral system

(OROS®)

10-12 h

Strattera® Atomoxetine

24 hOnce at

therapeutic

dose

4-6 weeks

Sti

mu

lan

tsN

on

S

tim

ula

nts

Long-Acting ADHD Agents Currently Available

Respective Product Monographs

What portion of the parents ask you how ADHD medications work?

A. Virtually none

B. Close to 25%

C. Close to 50%

D. Close to 75%

E. Nearly all

The Long Acting

Methylphenidates

• Osmostic-controlled release

oral system (OROS®)

• 22% immediate release

• Efficacy maintained through 12

hours after dosing

• Doses: 18, 27, 36, 54 mg

• Pharmacare coverage

• Generic????

CONCERTA ® Product Monograph, Janssen-Ortho Inc, August 14, 2007

CONCERTACONCERTA**: OROS Technology : OROS Technology

to Clinical Efficacyto Clinical Efficacy

CONCERTA ®

Methylphenidate HCl

22% released

immediately-

peaks 1-2 hrs.

Second peak 1-

2 hrs later

Generic Equivalency? • Health Canada has approved an generic MPH that is being marketed as a

“long acting” stimulant medication “equivalent “ to Concerta

• When Health Canada determines whether or not 2 medications are

“equivalent” they look at Bioequivalency not Clinical Equivalency

• Health Canada uses 2 pharmacokinetic parameters of the plasma-

concentration curve to determine whether new product is bioequivalent:

• Total-area-under-the-curve (AUCo-∞ )

• Maximum-concentration (Cmax)

• If AUC and Max concentration is 80-125% of reference product the new

product meets Health Canada Criteria for Bioequivelence

Health Canada Guidance Document: Guidance for Industry, Conduct and Analysis of Bioavailability and

Bioequivalence Studies - Part B: Oral Modified Release Formulations, 1996

Cmax 4.32 ng/mlAUC 41.8ngh/ml

Cmax 3.73ng/mlCmax 3.73 ng/mlAUC 41.8ngh/ml

Pharmacokinetic Study C98-024. Methylphenidate HCl pharmacokinetics when administered as OROS®

(methylphenidate HCl), Ritalin-SR®, and Ritalin®. ALZA Corporation. May 1999

Pharmacokinetic Study C98-024. Methylphenidate HCl pharmacokinetics when administered as OROS®

(methylphenidate HCl), Ritalin-SR®, and Ritalin®. ALZA Corporation. May 1999

Pharmacokinetic Study C98-024. Methylphenidate HCl pharmacokinetics when administered as

OROS® (methylphenidate HCl), Ritalin-SR®, and Ritalin®. ALZA Corporation. May 1999

Pharmacokinetic Study C98-024. Methylphenidate HCl pharmacokinetics when administered as

OROS® (methylphenidate HCl), Ritalin-SR®, and Ritalin®. ALZA Corporation. May 1999

Bioequivalence ≠ Clinical Equivalence

Thus even though bioequivalence may be

established between a second- entry product and a

current product , it can not be assumed that the

second- entry product will provide the same clinical

benefit as the original medication

Recommend advising physician and patients if

substitution occurs so that clinical efficacy can be

monitored.

BIPHENTIN® (CR Methylphenidate MLR™)

• Multi-Layer Release (MLRTM)• Immediate-release layer (40% total MPH)

• Controlled-release layer (60% total MPH)

• Efficacy shown to last 10-12 hours

• Capsules should be swallowed whole;

contents may be sprinkled

• Patients currently receiving IR MPH may

be converted to the same daily dose of

Biphentin, as a single daily dose in AM

• Private payers or EDS

Biphentin ® Product Monograph, Purdue Pharma, June 19, 09

0

5

10

15

20

0 4 8 12 16 20 24

Time (hours)

Co

ncen

trati

on

(n

g/m

L)

Biphentin Child (fed) IR-MPH Child (fed)

Mean Dose – 38.6 mg

D Quinn, T Bode, JL Reiz, GA Donnelly, and AC Darke, 2007. "Single-dose pharmacokinetics of multilayer-release methylphenidate and immediate-release

methylphenidate in children with attention-deficit/hyperactivity disorder." J Clin Pharmacol. 47 (6): 760-66.

Biphentin® Single-Dose Plasma

Concentration Time Profile in Children

The Long Acting

Amphetami

ADDERALL XR ®(mixed salts amphetamine)

• Capsule contains beads designed

to give double-pulse delivery

• Behavioural improvements both

in morning and afternoon

assessments

• May be taken whole or sprinkled

• Single dose of Adderall XR

provided comparable plasma [ ]’s

to IR Adderall administered 4

hours apart

• Private plansAdderall XR® Product Monograph, March, 2009

4 hrs later

Patients Who Fail One Stimulant Should be Tried on Another

28%

16%

41%

83%

0%

20%

40%

60%

80%

100%

Response to

AMPH only

Response to MPH

only

Equal response to

AMPH and MPH

Response to at

least one

Arnold LE. J Attention Dis 2000;3(4):200-11.

Meta-analysis of 6 within-subject comparative trials (n=174) evaluating response to stimulant medications

AMPH, amphetamine; MPH, methylphenidate.

% P

ati

en

t re

sp

on

se

Some patients respond

preferentially to one

stimulant

Most Common Stimulant AEs

• Decreased appetite

• Sleep difficulties

• Headache

• Irritability

• Tics

• Growth effects

Specific Norepinephrine Reuptake Inhibitor

Atomoxetine (Strattera®)

STRATTERA® (atomoxetine)

• Effective when administered once daily in the morning• Can be discontinued without being tapered• Capsules not intended to be open, should be taken whole • Not associated with pattern of response that suggested

stimulant or euphoriant properties• 3 step titration • Paxil, Prozac increase steady state blood levels of Strattera

in extensive metabolizers• No precautions for co-morbid disorders (Bipolar, tics or anxiety)• Private Plans

Strattera ® Product Monograph, October 30, 2007

Side Effects of Strattera® :

• Common:• Nausea & vomiting (take with meal)

• Sedation • Appetite decreased

• Rare:• Hepatitis

• Suicidal thoughts: greater in 7-12 yr old boys on Strattera than controls 5/1357 (0.37%) vs 0/851 (0%) p<.016

Strattera ® Product Monograph, October 30, 2007

Atomoxetine and Methylphenidate:Effects on Extracellular Dopamine in Rat Prefrontal Cortex, Nucleus Accumbens, and Striatum

1. Bymaster FP et al., Neuropsychopharmacology 2002;27: 699–711.

Prefrontal cortex (3 mg/kg)

Nucleus accumbens (3 mg/kg)Striatal dopamine (10 mg/kg)

Time (Hours)

-1 0 1 2 3 4%

Do

pam

ine B

aselin

e0

50

100

150

200

250

300

350

Time (Hours)

-1 0 1 2 3 4

% D

op

am

ine B

ase

lin

e

0

50

100

150

200

250

300

350 *p <.05 vs. baseline

Prefrontal cortex

Nucleus accumbensStriatum

***

AtomoxetineMethylphenidate

Methylphenidate 3 mg/kg ip Atomoxetine 1 mg/kg ip

**p <.05 curve vs. baseline

***

Have you heard of Vyvanse® yet?

A. Yes

B. No

A New Long-Acting ADHD Medication:

Lisdexamfetamine Dimesylate

Chemical Structure of Vyvanse

Therapeutically inactive until it is

converted to active d-amphetamine in the body

Lisdexamfetamine

(Prodrug)

H N2

O

NH

NH 2

CH 3

l-lysine

H N2

O

OH

NH 2

+

d-amphetamine

(active)

H N2

CH 3

Site of cleavage

Release of the active ingredient in Vyvanse does not rely on gastrointestinal factors such as GI transit time or gastric pH

Vyvanse Dosing

Dosages available in Canada: 30 mg and 50 mg

Designed as a once-daily capsule

Indicated for children ages 6 to 12

Starting treatment or switching from another agent

recommended dose 30 mg given in the morning

Therapeutically inactive until it is converted to active

d-amphetamine in the body

May be taken with or without food

The capsule may be opened and the entire contents

dissolved in a glass of water

Vyvanse ® Product Monograph, SHIRE LLC, May 29, 2009

Stability of Pharmacokinetics with Prodrug

* Data are individual subject Tmax and Cmax for the largest cohort

Ermer JC, et al. Presented at the 160th Annual Meeting of the American Psychiatric Association;

May 19-24; San Diego, CA.

0

50

100

150

200

250

0 1 2 3 4 5 6 7 8 9 10 11 12

Max

imu

m C

on

cen

tra

tio

n

d-A

mp

heta

min

e (

ng

/mL

) C

ma

x

Time (h) to Maximum Concentration (Tmax)

MAS XR 30 mg (n=9)

LDX 70 mg (n=8)

**

**

*

*

**

**

**

*

LDX MAS XR Placebo

Time Post-Dose (h)

* p<0.05 vs. placebo; N=50; † Average of all doses tested

Biederman J, Boeliner SW, Childress A, et al. Biol Psychiatry 2007.

LS

Mea

n S

KA

MP

-A S

co

re†

(Ch

an

ge F

rom

1s

tT

ime

Po

int

Me

as

ure

d)

8:00 a.m.

First

Assessment

7:00 p.m.

Last

Assessment

7:00 a.m.

Dose

Significant Improvements in Attention for Up to 12 Hours (SKAMP-A)

-0,8

-0,6

-0,4

-0,2

0,0

0,2

0,4

0,6

1 2 3 4.5 6 8 10 12

Vyvanse® -Incidence of Most

Commonly Reported AEs

26.1

11.9

2.2 2.8

17.4

2

5.43.9

8.7

2.50.5

2.22.8 3.5 3.82.2

0

5

10

15

20

25

30

1

(n=218)

2

(n=202)

3

(n=186)

4

(n=178)

Decreased appetite Insomnia

Abdominal pain Irritability

Pati

en

ts (

%)

WeekData on file, LDX 004. Shire US Inc.

1st Occurrence or Recurrence

15 min Break W

Pharmacists are often a patient’s 1st contact with the health care system.

They are considered unbiased experts on medication

They can play an important role in management of ADHD

Role of the Pharmacist

In Conclusion :1. ADHD is a clinical diagnosis with genetic

& neuroimaging findings.

2. Parents reluctant to treat ADHD must

understand the significant dangers of

non-treatment.

3. Parents who are interested should be

informed why a specific medication has

been prescribed and how it works.

4. Pharmacists have an important role in

educating & supporting patients with

ADHD and their families.

Questions…