Prescribing information and Patient information for paediatric medicines

1. Prescribing information and Patient information for paediatric medicines Kalle Hoppu MD, PhD Director, Poison Information Centre, Helsinki University Central Hospital Docent (Ass. professor) Dept.s of Paediatrics and Clinical Pharmacology, University of Helsinki, Helsinki, Finland Chairman, Sub-Committee for Paediatric Clinical Pharmacology, IUPHAR, Division of Clinical Pharmacology

2. Topics to be covered • General aspects • Therapeutic indications • Dosing considerations • Contraindications and precautions • Interactions • Adverse effects • Overdose

3. Benefit Risk Requirements for approval of medicines: • Quality • Safety • Efficacy

4. Risk Benefit Requirements for approval of medicines: • Quality • Safety • Efficacy

5. International agreements on human rights • Give children the right to the same level of health, health care and rehabilitation enjoyed by others • Children have the right • To medicines fulfilling the same criteria of Quality, Safety and Efficacy as adult medicines • To enjoy the benefits of modern drug development

6. Drugs approved for adults but not containing dosage recommendations* for children * Disclaimed use in children, did not contain paediatric dosage recommendations or excluded children below a specific age

7. Unlicensed and off-label use of medicines in children in Europe Unlicensed = Not licensed for children at all. Off-label = Prescribed outside the terms of the product license (not licensed for the age group, not licensed formulation, not licensed route of administration)

8. Preclinical development Clinical development Regulatory submission of MAA Regulatory approval of MA Marketing of the new drug Postmarketing surveillance studies Development of line extensions including paediatric labelling Drug used in adults Regulatory approval of paediatric MA Marketing of the new drug for children Drug used in children

9. Preclinical development Clinical development Regulatory submission of MAA Regulatory approval of MA Drug not used in adults Drug notused in children

10. Preclinical development Clinical development Regulatory submission of MAA Regulatory approval of MA Drug notdeveloped for children Marketing of the new drug Postmarketing surveillance studies Drug notused in children Drug used in adults Drug used in children off-label

11. Preclinical development Clinical development Regulatory submission of MAA Regulatory approval of MA Marketing of the new drug Postmarketing surveillance studies Development of line extensions including paediatric labelling Drug used in adults No regulatory approval of paediatric MA Drug used in children off-label

12. When specific data in the paediatric population is not available? • Risk for adverse effects • Unknown adverse effects • Use of (older) drugs with data available, but more adverse effects • Risk for suboptimal efficacy • Use of (older) drugs with data available, but lesser effect • Underdosing, if data for correct dosing n.a.

13. Prescribing medicines for children • Favourable risk/benefit ratio • Assessed by regulatory authorities for MA • To be determined by prescriber if medicine not approved for children • Age appropriate dose • Age appropriate formulation • Off-label and unlicensed use if drug available but not approved for children • Off-label vs. off-knowledge prescribing • Product information the most easily available information for prescribing MA = Market Authorisation

15. Therapeutic indications • The indication(s) should be stated clearly and concisely and should define the target disease or condition distinguishing between treatment (symptomatic, curative or modifying the evolution or progression of the disease), prevention (primary or secondary) and diagnostic indication. When appropriate it should define the target population especially when restrictions to the patient populations apply • When the product is indicated in a specific age group such as children/adolescents, the indication should state the age limit e.g. ‘X is indicated in <children> <adolescents> from the age of X <months><years >‘. A guideline on Summary of product characteristic; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

16. Posology and method of administration • Additional information on special populations • Available relevant information on special populations such as paediatric patients should be presented • When the medicinal product is to be used in children, a specific sub-section ‘paediatric patients’ should be identified A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

17. Posology and method of administrationPaediatric population • Information should be given for the different sub-populations of children • The age limits should reflect the assessment of the available documentation and relate to age intervals where a different dosing is recommended • The information given should relate to ages for which satisfactory efficacy and safety have been shown. If necessary in preterm and term newborns, information should be written taking into account the gestational age or the post-conception age. A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

18. ICH 11 Age categories Preterm newborn infants Term newborn infants (0 to 27 d) Infants and toddlers (28 d to 23 mo) Children (2 to 11 yrs) Adolescents (12 to 16-18*yrs) * Dependent on region ICH Topic E 11 Clinical Investigation of Medicinal Products in the Paediatric Population; note for guidance on clinical investigation of medicinal products in the paediatric population (CPMP/ICH/2711/99). Http://www.emea.eu.int/pdfs/human/ich/271199EN.pdf

19. Age classification of paediatric patients Any age classification of the paediatric population into age categories is to some extent arbitrary.... ... Decisions on how to stratify studies and data by age need to take into consideration developmental biology and pharmacology... ICH Topic E 11 Clinical Investigation of Medicinal Products in the Paediatric Population; note for guidance on clinical investigation of medicinal products in the paediatric population (CPMP/ICH/2711/99). Http://www.emea.eu.int/pdfs/human/ich/271199EN.pdf

20. Posology and method of administrationPaediatric population... If a paediatric indication has not been approved, the following text is suggested under a subheading ‘paediatric patients’: a. X is not recommended for use in children <above> <below> age Y due to <a lack of > <insufficient> data on safety and/or efficacy (the age should be specified)’ b. The experience in children is limited. There is no experience in children. c. ‘Use in children – there is no relevant indication for use of <Invented name> in children’ (when the indication is not relevant to this population). d. ’X is contraindicated in children’ A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

21. Posology and method of administrationPaediatric population... • If the product has not been studied in the paediatric population or if there are insufficient data on which to base an approval for paediatric use, it should be stated that the medicinal product is not recommended in the paediatric age group until further data become available. If available, additional information on the reason for the advice, and on the use in the paediatric age groups, can be included, as appropriate. • Any such statement(s) regarding paediatric age groups should be transparent and reflect the available data A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

22. Posology and method of administrationPaediatric population... • The dose schedule studied and found satisfactory should be given • Taking account of available paediatric formulations, the dose may be related to weight or body surface area depending on what has been found optimal, e.g. children age 2-4 years, 1 mg/bodyweight b.i.d. for 1 week (up to the adult dose). A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

23. Paediatric dosing • Should account for • Size • mg/kg • mg/m2 • Development • Age groups • Developmental groups • Single active substance vs. combination • Constrained by available formulations

24. From: Bleyer W. Antineoplastic agents. In: Yaffe SJ, editor. Pediatric pharmacology. Theraupeutic principles in practice. 1 ed. New York: Grune & Stratton; 1980. p. 349-77.

25. From: Bleyer W. Antineoplastic agents. In: Yaffe SJ, editor. Pediatric pharmacology. Theraupeutic principles in practice. 1 ed. New York: Grune & Stratton; 1980. p. 349-77.

26. Age as a surrogate marker for body size/growth • Body size reflecting growth can be determined • Body size used as basis for dosing of prescription medicines • Age groups used as basis for OTC medicines • Dosing at extremes of body size problematic

27. 10 kg 30-59 kg 7-18 mo 12 yrs

28. Age as a surrogate marker for development • Age not good surrogate for development • Important development thresholds • Premature - full term newborns • Begin of puberty • End of growth • Development seldom used to determine individual doses

29. Dosing constrained by available formulations • Continuously variable dosing • Liquid formulations • Using accurate dosing devices (syringe) • Dosing variable in intervals • Liquid formulations • Using inaccurate dosing devices (spoon) • Tablets, capsules • Suppositories • Inhalations

30. Avoiding dosing errors/inaccuracy Risk for dosing errors Strength (mg/ml) Ease of administration Volume of dose (ml)

31. How to get the child to take the medicine? • Mixing with drink, food? • Cultural differences • Administration technique

32. Administration to newborns • Oral • Unreliable in sick newborns due to slow gastric emptying/regurgitation • I.m. • Low muscular mass • I.v. • Risk for 10 fold dosing errors • Volume overload • Low infusion flow rate

33. Posology and method of administrationPaediatric population... • In exceptional cases where the “adult formulation” of a medicinal product includes an indication and a posology for use in children.... ....and where no adequate paediatric formulation can be developed based on duly justified scientific grounds (i.e. where the extemporaneous preparation of a formulation for paediatric use from the adult one is necessary) • relevant instructions for the extemporaneous preparation shall be included in section ‘Special precautions for handling of the product’. • Such information shall be provided by the Marketing Authorisation Holder with a view to improve the quality, safety and efficacy of such extemporaneous preparations for use in children. A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

34. Contraindications • In general, patient populations not studied in the clinical trial programme should be mentioned in section ‘Special warnings and precautions for use’ and not in this section unless a safety issue can be predicted (e.g. use of renally cleared substances with narrow therapeutic margin in renal failure patients) • If, however, patients have been excluded from studies as being contraindicated on serious grounds of safety, they should be mentioned in this section A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

35. Special warnings and precautions for use • Special patient groups, such as children, that are likely to experience product or class related adverse reactions (ADRs) occurring under normal conditions of use e.g. specified age groups, patients with renal, hepatic impairment (including the degree of impairment, such as mild, moderate or severe)... • Any warnings necessary for excipients... A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

36. Contraindications and precautions • Based on data or lack of data? • Off-label vs. Off-knowledge use • Specific paediatric contraindications and precautions • Effects on growth and development • Toxic excipients • Aspiration/chocking risk when administering tablets to young children

37. InteractionsPaediatric population • If interactions specific to children exist this information could be given under a subheading ‘paediatric patients’ • If the interaction studies have been performed in adults, the statement ‘Interaction studies have only been performed in adults’ should be included if considered relevant to the prescriber • If there is an interaction with food leading to a recommendation on co-administration with a meal or specific food, it should, if possible, be noted whether this information is relevant for children (especially newborns and infants) whose diet may be totally different (100 % milk in newborns versus maybe 0 % in adults) compared to the study setting leading to the recommendation A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

38. Undesirable effectsPaediatric population • If some undesirable effects are specifically observed in children or if altered frequencies of undesirable effects are observed, this information should be given in a subsection entitled ‘paediatric patients’. If possible, the information could be divided into ICH E11 age groups. If a similar safety profile is expected in children as in adults this could be stated. A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

39. Adverse effects • Specific paediatric adverse effects • Effects on growth and development • Long-term effects • Relevance of adult adverse effects • Children may not be able to express symptoms in the same way as adults • Headache, dizziness, tremor, hearburns...

40. OverdosePaediatric population • If there are specific paediatric considerations, there should be a sub-section entitled ‘paediatric patients’ • It might be useful to have a special mentioning for those medicinal products which can cause a fatal poisoning in the special risk group of young children (for instance a bodyweight of 10 kg could be used as the limit) if just a single tablet is ingested. This is a limited special group of medicines, which should be kept with extra care. A guideline on Summary of product characteristics; The Rules Governing Medicinal Products in the European Union Volume 2C Notice to Applicants

41. Overdose • Childhood poisoning accidents • Related to normal development • All medicines should be kept safe from children • Severe poisonings • Rare with paediatric medicines • Usually caused by adult medicines • Information on acute treatment of overdose valuable only, if it is reliable