Ritalin ® & AD/HD just calming the troublemaker ??? Dr.med.Sven Schellberg Global Communications & Brand Manager Psychiatry NOVARTIS Pharma AG, Basel,

Ritalin® & AD/HD just calming the troublemaker ???

Dr.med.Sven Schellberg

Global Communications & Brand Manager Psychiatry

NOVARTIS Pharma AG, Basel, Switzerland

Don‘t worry, potentially a new Ritalin® customer

What do these gentlemen have in common ?

ICD-10 versus DSM IV

Inattentiveness

Impulsivity

Disturbed activity(Hyperactivity)

hyperactiveimpulsive Type314.01

inattentive Type314.00

hyperkineticSyndromeF90

combinedType314.01

ADHD

School

Occupational statusSocial/financial status

Peer relationships

Marital status

Traffic accidents

Drug abuse

Delinquency

Statistics

• 2 - 6 % of pupils (age 6 – 16) show symptoms of AD/HD

• Hyperactivity is more common in boys

• in 70 % of the patients, symtomatology calms in adolescence

• 30 % keep symptoms which need therapy in adulthood

AD/HD in adolescence / adulthood

30

40

15

15

30

no symptomsmildmoderate to severepharmacological treatment required

AD/HD

Etiology

Etiology

Etiology

• Attention, evaluation of situations, learning and activity are functions which are located in dopaminergic areas of the brain

• In animal experiments a depression of dopaminergic function leds to hyperactivity, aggression and worsening of learning procedures

Etiology

Krause et al.

Etiology

Bush et al.

Etiology

Family and Interactions

Education

Environmental Effects

Food

Stroop

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AD/HD

Diagnosis

There is no single diagnostic test for AD/HD

Diagnosis

• History and anamnesis including interviews with patient, parents, teachers

• Symptomatology (differing criterias between DSM IV (AAP) and ICD-10)

• Rating Scales (CRS, CBCL etc.)

• Exclusion of other medical disorders (e.g. epilepsy, brain damage, schizophrenia, hyperthyreosis)

• physical examination including EEG, lab, intelligence testing

AD/HD

Treatment

Treatment of AD/HD always has to combine educational, psychotherapeutical and

psychopharmacological methods

Stimulants

• The use of stimulants started in the 1930‘s when their stimulative effects on the dopamingergic system and their psychotropic effects were discovered

• First Amphetamine and Metamphetamine were used

• First descriptions of an use of Methylphenidate in „MCD“ in the 1960‘s

• Detailed descriptions in the 1980‘s by Wender et al.

Methylphenidate (Ritalin®)

Dr.Leando Panizzon & Marguerite („Rita“) Panizzon

Stimulants - Chemistry

Amphetamine

MDMA „Extasy“

Mescaline

Dopamine

Methylphenidate

Mode of action

Krause et al.

AD/HD

Because of time one example of efficacy only

Substance Abuse

0

1

2

3

4

5

6

7

8

"Any"Alcohol

Marihuana

Hallucinogens

Cocain/StimulantsTabac

AD/HD w/o therapy vs. controlAD/HD w therapy vs AD/HD w/o therapy

relative risk

Product backgrounder and competitors

Ritalin® LA

Methylphenidat IR vs. SR

Facts and Problems

• Onset of action after 20 – 40 minutes• Duration of action 2-4 hours• Repeated dosing – often over school-time - mandatory• Acute tolerance requires peaked doses with raising

plasma levels over the day and drug free interval at night• Stable plasma levels show poor clinical efficacy, sharp

increase in plasma levels in the morning required

Ritalin® LA - Objectives

• Fast onset of action in the morning, with a high morning dose

• Double peak pharmacokinetic with raising plasma levels over the day

• Duration of action about 8 – 10 h to cover schoolday, but not to interfer with sleep at night

• Easy to swallow, no food interaction• Easy switch from standard medication• Individualized dosing

Ritalin® LA - SODAS™

0

2

4

6

8

10

0 4 8 12 16 20 24

Ritalin® LA 20 mg (n=19)

Markowitz J, et al. Clin Pharmacokinet. In press.

Ritalin® LA

Concerta® - OROS™

Concerta® is a trademark of Janssen Cilag, / J&J

0

2

4

6

8

10

0 4 8 12 16 20 24

Ritalin® LA 20 mg (n=19)

Time (h)

Concerta® 18 mg (n=19)

MP

H c

on

cen

trat

ion

(n

g/m

L)

Markowitz J, et al. Clin Pharmacokinet (2003) 42(4) 1-9

Ritalin® LA vs. Concerta®

Important differences

Concerta®

• Dose strenghts 18, (27), 36, (54) mg

• Initial dose 22 %• Sustained dose 78 %• Duration of action up to

12 h• Capsule must not be

opened

Ritalin® LA

• Dose strenghts 20, 30, 40 mg

• Initial dose 50 %• Sustained dose 50 %• Duration of action up to

8 h• Capsule may be opened

and sprinkled on soft food

Concerta® is a trademark of Janssen Cilag, / J&J

How to switch ?

• Switching can be done from day to day

• Switching sometimes needs new dose adjustment

• Always remind initial 50 % of dose (10 mg, 15 mg, 20 mg)

• Starting with too high doses may lead to initial side effects and bad compliance !

Previous methylphenidate dose Recommended Ritalin Uno dose

10 mg methylphenidate b.i.dor 20 mg methylphenidate SR

20 mg qd

15 mg methylphenidate b.i.d 30 mg qd

20 mg methylphenidate b.i.dor 40 mg of methylphenidate SR

40 mg qd

Pharmacodynamics

Or what does this mean in daily practice ?

School Day Efficacy of Ritalin® LA vs. Concerta®

• Randomized, rater blind, placebo controlled clinical trial• 36 children, 6-12 years, 29 boys, 7 girls• All stabilized on 20 mg MPH/die ahead of trial• 4 way crossover design• Study medication on days 7, 14, 21, 28, standard

medication in-between• Swanson, Kotkin, Alger M-Flynn, Pelham (SKAMP)

Attention/Deportment Scale • Age/intelligence-appropriate, 400-question, 10-minute

written math test

*P=0.015 for Ritalin® LA 20 mg vs Concerta® 18 mg.†P=0.043 for Ritalin® LA 20 mg vs Concerta® 36 mg.‡P<0.001 vs all active treatment groups.

Change from Baseline (Predose) 0-4 Hours N=36

Worsening Improvement

Ritalin® LA 20 mg

Concerta®

18 mg

Concerta®

36 mg

‡ 1.24

-1.55

-1.362

-2.481 *†

Placebo

Ritalin® LA vs. Concerta®

SKAMP Attention over first 4 hours

Change from Baseline (Predose) 0-8 HoursN=36

*†

Worsening Improvement

3.786

-3.244

-2.719

-4.481Ritalin® LA

20 mg

Concerta®

18 mg

Concerta®

36 mg

Placebo

*P=0.074 for Ritalin® LA 20 mg vs Concerta® 18 mg.†P=0.208 for Ritalin® LA 20 mg vs Concerta® 36 mg.‡P<0.001 vs all active treatment groups.

‡

Ritalin® LA vs. Concerta®

SKAMP Attention over schoolday

-80

-60

-40

-20

0

20

40

60

80

0.5 1.0 2.0 3.0 4.0 6.0 8.0

Time (h)

Mea

n c

han

ge

fro

m p

red

ose

in

SK

AM

P-c

om

bin

ed

N=36Placebo

Concerta® 36 mg

Concerta® 18 mg

Ritalin® LA 20 mg

*P<0.05 for Ritalin® LA 20 mg vs Concerta® 36 mg.†P<0.05 for Ritalin® LA 20 mg vs Concerta® 18 mg.

*† *†

*†

*

0

Ritalin® LA vs. Concerta®

SKAMP Combined

Strattera® (Atomoxetine, Eli Lilly)

• Atomoxetine is a norepinephrine-reuptake inhibitor, orginally developed as antidepressant (Pharmacia)

• Atomoxetine has no dopaminergic activity• Atomoxetine is the first non-stimulant approved for

treatment of AD/HD• Atomoxetine is the first pharmacologic treatment,

approved for the use of adult AD/HD• Onset of action as with other antidepressants is delayed

(4 – 6 weeks at minimum)

Strattera® (Atomoxetine, Eli Lilly)

• Efficacy of Atomoxetine seems to be lower than that of stimulants

• Common side effects are nervousness, sleeplesness, loss of appetite, decreased body weight, sexual dysfunction, especially in boys

• In US Atomoxetine gained 15 % market share in AD/HD market within 6 months after launch

• Approval and launch in EU has been delayed several times – expected currently for H2/2004

What about the critics ?

Scientology™

Scientology‘s view…

Questions