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