1. European Congenital Heart Disease Organisation (ECHDO) Berlin 23 – 24 March 2007 H. W. Seyberth Chairman of the Commission on Drug Safety of German Society of Pediatrics (DGKJ) Member of the Paediatric Working Party (PEG) at the EMEA Save Drugs for Children with CHD: New European Regulation

2. The labelled percentage of 41 “standard drugs” used in a neonatal and pediatric intensive care unit (Heidelberg, 1981). – – newborns infants children 100% 50% 0% 5 13 23 32% 57% 11% H.W. Seyberth, Kinderarzt 1984

3. Consequences of unlicenced and off label drug perscriptions:  No adequate pediatric formulations  No dosing regimen  No warning of possible adverse drug reactions  No information about possible drug interactions  No product liability for the drug by the sponsor  No long term surveillance

4. When we choose a drug for a child ... We rely on: - Personal experience (trial/error)? - Advice from colleagues/mentors? - Anecdotal reports in the literatur? - Extrapolation from adult data? - Small „trending“/inclusive trials?

5. - - 10 5 0 3.9 6.0 1.4 3.4 ADR % In label and licensed Of label and unlicensed On the wards (UK) In the outpatient clinics (FR) (Turner et al, Acta Paed. 1999) (Horen et al, Brit J Clin Pharm 2002) Adverse Drug Reactions (ADR) of unlicensed and of label drug prescription in paediatrics

6. What has happened in the past ? Some examples !

7. fluid restriction furosemide digoxin NSAID´s ACE- inhibitor Adverse effects of geriatric heart failure therapy applied to the preterm infant with sPDA: arrhythmias with cerebral bleeding marked volume depletion renal hypoperfusion PG-stimulation nephrocalcinosis intestinal perforation renal failure

8. Congenital salt losing tubulopathies (SLTs) Different age at manifestation and ontogeny of targets (Jeck et al., AJ P 2005) Thiazid - SLT : NCCT Furosemid -SLT : NKCC2 Postnatal leading symptoms polyuria hyponatremia hypotension (shock) hypercalciuria nephrocalcinosis hypokalemia carpopedal spasms hypomagnesemia hypocalciuria growth retardation Age at first presentation antenatal: 12/12 <1 year: 1/13 1-5 years: 4/13 6-13 years: 8/13 Polyhydramnios 12/12 0/13 thick ascending limb distal convolute Affected nephron segment

9. Medium analgesic dosage of morphine in children with an age between 0 and 6 years (Olkkola et al., CPT 1988) 0 10 20 30 40 0 - ½ year n = 5 6 year n = 4 2 - 4 year n = 5 Morphine plasma concentration [µg/l] at time point of pain recovery p < 0.01 dosis: 0.05 mg/kg/min infusion rate until painlessness

10. Legislative Incentives in Europe?

13. Key measures for patented medicines Rewards for studies conduced in children : - 6-months extension of the supplementory protection certificate (in-effect, a patent extension ) - For orphan medicines , 2-years additional market exclusivity (10+2 years)

18. Some Examples from the EMEA Priority-List of Off-Patent Medicinal Products for Paediatric Studies ( http:// www . emea . eu . int / pdfs /human/ peg /49677706en. pdf ) All age groups All age groups incl. neonates < 6 months All age groups All age groups < 1 year Efficacy, safety for procedures Efficacy, safety Efficacy, safety Longterm safety Longterm safety, efficacy, safety Chloralhydrate Propofol AC-inhibitors Diuretics Catecholamines Morphine NSAID´s Steroids (inhaled, oral) Sedation Heart failure Pain Obstr.lung dis. Age Group Needs Products Conditions

20. Members of the European Network Drug Investigation in Children (ENDIC1997 in the ESDP) Elisabeth Autret-Leca, Tours Jean-Paul Langhendries, Liege Maurizio Bonati, Milano Gérard Pons, Paris Imti Choonara, Derby Anders Rane, Stockholm Rafaël Gorodischer, Beer-Sheva Hannsjörg W. Seyberth, Marburg Kalle Hoppu, Helsiniki John N. van den Anker, Rotterdam Evelyne Jacqz-Aigrain, Paris Bart van Overmeire, Antwerp

21. Thank you for your attention !