Ritalin Workshop Dublin

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Ritalin AD/HD just calming the troublemaker
???

• Dr.med.Sven Schellberg
• Global Communications Brand Manager Psychiatry
• NOVARTIS Pharma AG, Basel, Switzerland

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Dont worry, potentially a new Ritalin customer
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What do these gentlemen have in common ?
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ICD-10 versus DSM IV
inattentive Type 314.00
Inattentiveness Impulsivity Disturbed
activity (Hyperactivity)
hyperkinetic Syndrome F90
combined Type 314.01
hyperactive impulsive Type 314.01
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School
Delinquency
ADHD
Occupational status Social/financial status
Drug abuse
Peer relationships
Traffic accidents
Marital status
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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

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AD/HD in adolescence / adulthood
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AD/HD

• Etiology

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Etiology
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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

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Etiology
Krause et al.
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Etiology
Bush et al.
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Etiology
Family and Interactions
Education
Environmental Effects
Food
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Stroop
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AD/HD

• Diagnosis

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There is no single diagnostic test for AD/HD
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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

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AD/HD

• Treatment

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

• The use of stimulants started in the 1930s 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 1960s
• Detailed descriptions in the 1980s by Wender et
  al.

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Methylphenidate (Ritalin)
Dr.Leando Panizzon Marguerite (Rita) Panizzon
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Stimulants - Chemistry
Amphetamine
Mescaline
Methylphenidate
Dopamine
MDMA Extasy
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Mode of action

• First a paradox way of action was assumed when
  Methylphenidate, a stimulant, improved attention
  and hyperactivity of the children
• AD/HD was explained as a dopamine deficit
  syndrome, which is treated by stimulants by an
  increase in neurotransmitter release
• This theory was not able to explain the missing
  tolerance effect of the drug and its efficacy in
  non hyperactive only inattentive patients

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Mode of action
Krause et al.
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AD/HD

• Because of time one example of efficacy only

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Substance Abuse
relative risk
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Ritalin LA

• Product backgrounder and competitors

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Methylphenidat IR vs. SR
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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

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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

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Ritalin LA - SODAS
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Ritalin LA
Ritalin LA 20 mg (n19)
Markowitz J, et al. Clin Pharmacokinet. In press.
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Concerta - OROS
Concerta is a trademark of Janssen Cilag, / JJ
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Ritalin LA vs. Concerta
Ritalin LA 20 mg (n19)
Markowitz J, et al. Clin Pharmacokinet (2003)
42(4) 1-9
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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, / JJ
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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 !

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Pharmacodynamics

• Or what does this mean in daily practice ?

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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

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Ritalin LA vs. ConcertaSKAMP Attention over
first 4 hours
Change from Baseline (Predose) 0-4 Hours N36
Ritalin LA 20 mg
-2.481

Concerta 18 mg
-1.362
Concerta 36 mg
-1.55
1.24
Placebo

P0.015 for Ritalin LA 20 mg vs Concerta 18
mg. P0.043 for Ritalin LA 20 mg vs Concerta
36 mg. Plt0.001 vs all active treatment groups.
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Ritalin LA vs. ConcertaSKAMP Attention over
schoolday
Change from Baseline (Predose) 0-8 HoursN36
Ritalin LA 20 mg

-4.481
Concerta 18 mg
-2.719
Concerta 36 mg
-3.244
3.786
Placebo

P0.074 for Ritalin LA 20 mg vs Concerta 18
mg. P0.208 for Ritalin LA 20 mg vs Concerta
36 mg. Plt0.001 vs all active treatment groups.
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Ritalin LA vs. ConcertaSKAMP Combined
Concerta 36 mg
N36
Concerta 18 mg




Mean change from predose in SKAMP-combined
0.5
1.0
2.0
3.0
4.0
6.0
8.0
0
Time (h)
Plt0.05 for Ritalin LA 20 mg vs Concerta 36
mg. Plt0.05 for Ritalin LA 20 mg vs Concerta 18
mg.
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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)

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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

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What about the critics ?

• Scientology

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Scientologys view
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Questions