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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. Don‘t worry, potentially a new Ritalin ® customer. What do these gentlemen have in common ?. ICD-10 versus DSM IV.
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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
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
School Delinquency ADHD Occupational status Social/financial status Drug abuse Peer relationships Traffic accidents Marital status
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 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
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AD/HD Diagnosis
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 Mescaline Methylphenidate Dopamine MDMA „Extasy“
Mode of action Krause et al.
AD/HD Because of time one example of efficacy only
Substance Abuse relative risk
Ritalin® LA Product backgrounder and competitors
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 Ritalin® LA 20 mg (n=19) Markowitz J, et al. Clin Pharmacokinet. In press.
Concerta® - OROS™ Concerta® is a trademark of Janssen Cilag, / J&J
Ritalin® LA vs. Concerta® Concerta® 18 mg (n=19) MPH concentration (ng/mL) Time (h) Ritalin® LA 20 mg (n=19) Markowitz J, et al. Clin Pharmacokinet (2003) 42(4) 1-9
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 Important differences 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 !
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
Worsening Improvement Ritalin® LA vs. Concerta®SKAMP Attention over first 4 hours Change from Baseline (Predose) 0-4 Hours N=36 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.
Ritalin® LA vs. Concerta®SKAMP Attention over schoolday Worsening Improvement Change from Baseline (Predose) 0-8 HoursN=36 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.
Placebo Ritalin® LA 20 mg Ritalin® LA vs. Concerta®SKAMP Combined Concerta® 36 mg N=36 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) *P<0.05 for Ritalin® LA 20 mg vs Concerta® 36 mg. †P<0.05 for Ritalin® LA 20 mg vs Concerta® 18 mg.
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™