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

4. Don‘t worry, potentially a new Ritalin® customer

6. What do these gentlemen have in common ?

7. ICD-10 versus DSM IV Inattentiveness Impulsivity inattentive Type
314.00
Inattentiveness
Impulsivity
Disturbed activity
(Hyperactivity)
hyperkinetic
Syndrome
F90
combined
Type
314.01
hyperactive
impulsive Type
314.01

8. Social/financial status
School
Delinquency
ADHD
Occupational status
Social/financial status
Drug abuse
Peer relationships
Traffic accidents
Marital status

9. 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

10. AD/HD in adolescence / adulthood

11. AD/HD
Etiology

12. Etiology

13. 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

15. Etiology
Krause et al.

16. Etiology
Bush et al.

17. Etiology
Family and Interactions
Education
Environmental Effects
Food

18. Stroop blackredgreenyellowblueredblackgreenyellow

19. AD/HD
Diagnosis

20. There is no single diagnostic test for AD/HD

21. 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

22. AD/HD
Treatment

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

24. 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.

25. Methylphenidate (Ritalin®)
Dr.Leando Panizzon &
Marguerite („Rita“) Panizzon

26. Stimulants - Chemistry
Amphetamine
Mescaline
Methylphenidate
Dopamine
MDMA „Extasy“

27. 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

28. Mode of action Krause et al.
Diese SPECT (Single Photon Emission Computed Tomography) Abbildung zeigt die Dichte des Dopamintransporters im sog. Striatum (Gehirnregion) an.
Ganz rechts ein gesunder Proband. Ganz links ein unbehandelter Patient mit ADHD, in der Mitte ein Patient mit ADHD nach Methylphenidat-Therapie. Man sieht eine deutliche Reduktion der erhöhten Transporterdichte unter Ritalin®
Krause et al.

29. Because of time one example of efficacy only
AD/HD
Because of time one example of efficacy only

30. Substance Abuse
relative risk

31. Product backgrounder and competitors
Ritalin® LA
Product backgrounder and competitors

32. Methylphenidat IR vs. SR

33. 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

34. 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

35. Ritalin® LA - SODAS™

36. Ritalin® LA Ritalin® LA 20 mg (n=19)
Bimodal Release of Ritalin® LA Achieved Greater Exposure
Ritalin® LA 20 mg provided a more rapid rise (Tmax) and achieved greater plasma concentrations (Cmax) over the first 8 hours compared with Concerta® 18 mg
Markowitz J, et al. Clin Pharmacokinet. In press.

37. Concerta® - OROS™
Concerta® is a trademark of Janssen Cilag, / J&J

38. Ritalin® LA vs. Concerta®
Time (h)
Concerta® 18 mg (n=19)
MPH concentration (ng/mL)
Ritalin® LA 20 mg (n=19)
Bimodal Release of Ritalin® LA Achieved Greater Exposure
Ritalin® LA 20 mg provided a more rapid rise (Tmax) and achieved greater plasma concentrations (Cmax) over the first 8 hours compared with Concerta® 18 mg
Markowitz J, et al. Clin Pharmacokinet (2003) 42(4) 1-9

39. 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

40. How to switch ? Switching can be done from day to day
Previous methylphenidate dose
Recommended Ritalin Uno dose
10 mg methylphenidate b.i.d
or 20 mg methylphenidate SR
20 mg qd
15 mg methylphenidate b.i.d
30 mg qd
20 mg methylphenidate b.i.d
or 40 mg of methylphenidate SR
40 mg qd
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 !

41. Or what does this mean in daily practice ?
Pharmacodynamics
Or what does this mean in daily practice ?

42. 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

43. Ritalin® LA vs. Concerta® SKAMP Attention over first 4 hours
Change from Baseline (Predose) 0-4 Hours N=36
Worsening
Improvement
Ritalin® LA 20 mg
-2.481 *†
Concerta® 18 mg
-1.362
Concerta® 36 mg
-1.55 ‡
1.24
Placebo
*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.

44. Ritalin® LA vs. Concerta® SKAMP Attention over schoolday
Change from Baseline (Predose) 0-8 Hours N=36
Worsening
Improvement
Ritalin® LA 20 mg
-4.481 *†
Concerta® 18 mg
-2.719
Concerta® 36 mg
-3.244 ‡
3.786
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.

45. Ritalin® LA vs. Concerta® SKAMP Combined
Ritalin® LA 20 mg
Concerta® 36 mg
N=36
Concerta® 18 mg
Placebo *† *† *† *
Mean change from predose in SKAMP-combined
0.5
1.0
2.0
3.0
4.0
6.0
8.0
Time (h)
*P<0.05 for Ritalin® LA 20 mg vs Concerta® 36 mg.
†P<0.05 for Ritalin® LA 20 mg vs Concerta® 18 mg.

46. 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)

47. 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

48. What about the critics ?
Scientology™

49. Scientology‘s view…

50. Questions