prescribing information and patient information for paediatric medicines kalle hoppu md, phd...

Prescribing Prescribing information and information and Patient information for Patient information for paediatric medicinespaediatric medicines

Prescribing Prescribing information and information and Patient information for Patient information for paediatric medicinespaediatric medicines

Kalle Hoppu MD, PhDKalle Hoppu MD, PhDDirector, Poison Information Centre, Helsinki University Director, Poison Information Centre, Helsinki University Central HospitalCentral Hospital

Docent (Ass. professor) Dept.s of Paediatrics and Clinical Docent (Ass. professor) Dept.s of Paediatrics and Clinical Pharmacology, University of Helsinki, Helsinki, FinlandPharmacology, University of Helsinki, Helsinki, Finland

Chairman, Sub-Committee for Paediatric Clinical Chairman, Sub-Committee for Paediatric Clinical Pharmacology, Pharmacology, IUPHAR, Division of Clinical PharmacologyIUPHAR, Division of Clinical Pharmacology

Kalle Hoppu MD, PhDKalle Hoppu MD, PhDDirector, Poison Information Centre, Helsinki University Director, Poison Information Centre, Helsinki University Central HospitalCentral Hospital

Docent (Ass. professor) Dept.s of Paediatrics and Clinical Docent (Ass. professor) Dept.s of Paediatrics and Clinical Pharmacology, University of Helsinki, Helsinki, FinlandPharmacology, University of Helsinki, Helsinki, Finland

Chairman, Sub-Committee for Paediatric Clinical Chairman, Sub-Committee for Paediatric Clinical Pharmacology, Pharmacology, IUPHAR, Division of Clinical PharmacologyIUPHAR, Division of Clinical Pharmacology

2©K. Hoppu 18.9.2007

Topics to be coveredTopics to be coveredTopics to be coveredTopics to be covered

•General aspects

•Therapeutic indications

•Dosing considerations

•Contraindications and precautions

•Interactions

•Adverse effects

•Overdose

3©K. Hoppu 18.9.2007

Requirements for approval of Requirements for approval of medicines:medicines:Requirements for approval of Requirements for approval of medicines:medicines:

•Quality•Safety•Efficacy

RiskBenefit

4©K. Hoppu 18.9.2007

Requirements for approval of Requirements for approval of medicines:medicines:Requirements for approval of Requirements for approval of medicines:medicines:

•Quality•Safety•Efficacy

Risk

Benefit

5©K. Hoppu 18.9.2007

International agreements on International agreements on human rightshuman rightsInternational agreements on International agreements on human rightshuman 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©K. Hoppu 18.9.2007

Drugs approved for adults but not Drugs approved for adults but not containing dosage recommendations* containing dosage recommendations* for childrenfor children

Drugs approved for adults but not Drugs approved for adults but not containing dosage recommendations* containing dosage recommendations* for childrenfor children

Country Year Listing% of

drugs Reference

US 1973 PDR 78 Wilson J 1977

US 1991 PDR 81Gilman JT, Gal P 1992

Finland 1995Pharmaca Fennica

72Hoppu K, Jaakkola R 1996

* Disclaimed use in children, did not contain paediatric dosage recommendations or excluded children below a specific age

7©K. Hoppu 18.9.2007

Unlicensed and off-label use of medicines in Unlicensed and off-label use of medicines in children in Europechildren in EuropeUnlicensed and off-label use of medicines in Unlicensed and off-label use of medicines in children in Europechildren in Europe

Country

Setting/population

Unlicensed and off-label

Reference

of prescripti

ons

of childre

n

UK Children’s hospital 25 % 36 % Turner et al

1998

UK, S,

D, I, NL

Children’s hospitals 46 % 67 % Conroy et al

2000

UK General practice 11 % 65 % McIntyre et al

2000

F Office based paediatr. 33 % 56 % Chalumeau et

al 2000

NL Children’s hospital 66 % 90 % ‘t Jong et al

2001

IR District hospital ward 23 % 43 % Craig et al

2001

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)

Preclinical development


Clinical developmentClinical development

Regulatory submission of MAA


Regulatory approval of MA


Marketing of

the new drug

Marketing of

the new drug

Development of line extensions including paediatric labelling


Postmarketing surveillance

studies


studies

Regulatory approval of

paediatric MA

Regulatory approval of

paediatric MA

Drug used in adults

Drug used in adults

Marketing of the new drug for

children

Marketing of the new drug for

childrenDrug used in

childrenDrug used in

children








Drug not used in adults

Drug not used in adults

Drug not used in children









Marketing of the new drugMarketing of the new drug


studies


studies

Drug used in adults

Drug used in adults

Drug used in children off-label




Drug not developed for children

Drug not developed for children








Marketing of

the new drug

Marketing of

the new drug




studies


studies

No regulatory approval of

paediatric MA

No regulatory approval of

paediatric MA

Drug used in adults

Drug used in adults



12©K. Hoppu 18.9.2007

When specific data in the When specific data in the paediatric population is not paediatric population is not available?available?

When specific data in the When specific data in the paediatric population is not paediatric population is not available?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©K. Hoppu 18.9.2007

Prescribing medicines for Prescribing medicines for childrenchildrenPrescribing medicines for Prescribing medicines for childrenchildren

•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 prescribingMA = Market Authorisation

15©K. Hoppu 18.9.2007

Therapeutic indicationsTherapeutic indicationsTherapeutic indicationsTherapeutic 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©K. Hoppu 18.9.2007

Posology and method of Posology and method of administrationadministrationPosology and method of Posology and method of administrationadministration

•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©K. Hoppu 18.9.2007

Posology and method of Posology and method of administrationadministrationPaediatric populationPaediatric population

Posology and method of Posology and method of administrationadministrationPaediatric populationPaediatric 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.


18©K. Hoppu 18.9.2007

ICH 11 Age categoriesICH 11 Age categoriesICH 11 Age categoriesICH 11 Age categories

Preterm newborn infantsTerm 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) 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

* Dependent on region

19©K. Hoppu 18.9.2007

Age classification of paediatric Age classification of paediatric patientspatientsAge classification of paediatric Age classification of paediatric patientspatients

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©K. Hoppu 18.9.2007

Posology and method of Posology and method of administrationadministrationPaediatric population...Paediatric population...


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’

If a paediatric indication has not been approved, the following text is suggested under a subheading ‘paediatric patients’:


21©K. Hoppu 18.9.2007




• 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

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•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).


23©K. Hoppu 18.9.2007

Paediatric dosingPaediatric dosingPaediatric dosingPaediatric dosing

•Should account for•Size

•mg/kg•mg/m2

•Development•Age groups•Developmental groups•Single active substance vs. combination

•Constrained by available formulations

24©K. Hoppu 18.9.2007

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©K. Hoppu 18.9.2007

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©K. Hoppu 18.9.2007

Age as a surrogate marker for Age as a surrogate marker for body size/growthbody size/growthAge as a surrogate marker for Age as a surrogate marker for body size/growthbody 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©K. Hoppu 18.9.2007

7-18 mo

10 kg

30

-59

kg

12 yrs

28©K. Hoppu 18.9.2007

Age as a surrogate marker for Age as a surrogate marker for developmentdevelopmentAge as a surrogate marker for Age as a surrogate marker for developmentdevelopment

•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©K. Hoppu 18.9.2007

Dosing constrained by available Dosing constrained by available formulationsformulationsDosing constrained by available Dosing constrained by available formulationsformulations

•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©K. Hoppu 18.9.2007

Avoiding dosing Avoiding dosing errors/inaccuracyerrors/inaccuracyAvoiding dosing Avoiding dosing errors/inaccuracyerrors/inaccuracy

Str

en

gth

(m

g/m

l)

Volume of dose (ml)

Risk for dosing errors

Ease of administrati

on

31©K. Hoppu 18.9.2007

How to get the child to take the How to get the child to take the medicine?medicine?How to get the child to take the How to get the child to take the medicine?medicine?

•Mixing with drink, food?

•Cultural differences

•Administration technique

Elina Vanninen – Lääkeopas 1997

32©K. Hoppu 18.9.2007

Administration to newbornsAdministration to newbornsAdministration to newbornsAdministration 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©K. Hoppu 18.9.2007



• 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.


34©K. Hoppu 18.9.2007

ContraindicationsContraindicationsContraindicationsContraindications

• 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 sectionA guideline on Summary of product characteristics; The Rules Governing Medicinal

Products in the European Union Volume 2C Notice to Applicants

35©K. Hoppu 18.9.2007

Special warnings and precautions Special warnings and precautions for usefor useSpecial warnings and precautions Special warnings and precautions for usefor 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...


36©K. Hoppu 18.9.2007

Contraindications and Contraindications and precautionsprecautionsContraindications and Contraindications and precautionsprecautions

•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©K. Hoppu 18.9.2007


InteractionsInteractionsPaediatric populationPaediatric populationInteractionsInteractionsPaediatric populationPaediatric 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

38©K. Hoppu 18.9.2007

Undesirable effectsUndesirable effectsPaediatric populationPaediatric populationUndesirable effectsUndesirable effectsPaediatric populationPaediatric 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.


39©K. Hoppu 18.9.2007

Adverse effectsAdverse effectsAdverse effectsAdverse 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©K. Hoppu 18.9.2007

OverdoseOverdosePaediatric populationPaediatric populationOverdoseOverdosePaediatric populationPaediatric 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.


41©K. Hoppu 18.9.2007

OverdoseOverdoseOverdoseOverdose

•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

prescribing information and patient information for paediatric medicines kalle hoppu md, phd...

Documents

children drug

approval of medicines

excluded children

children countryyearlisting

adults drug

university of helsinki

specific age slide

label use of medicines