Download Prescribing information for paediatric medicines

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
Topics to be covered
• General aspects
• Therapeutic indications
• Dosing considerations
• Contraindications and precautions
• Interactions
• Adverse effects
• Overdose
©K. Hoppu 18.9.2007
2
Requirements for approval of
medicines:
• Quality
• Safety
• Efficacy
Benefit
©K. Hoppu 18.9.2007
Risk
3
Requirements for approval of
medicines:
• Quality
• Safety
• Efficacy
Risk
Benefit
©K. Hoppu 18.9.2007
4
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
©K. Hoppu 18.9.2007
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Drugs approved for adults but not containing
dosage recommendations* for children
Country
Year Listing
US
1973 PDR
% of
drugs
78
US
1991 PDR
81
Finland
Pharmaca
1995
Fennica
72
Reference
Wilson J 1977
Gilman JT, Gal P
1992
Hoppu K,
Jaakkola R 1996
* Disclaimed use in children, did not contain paediatric dosage
recommendations or excluded children below a specific age
©K. Hoppu 18.9.2007
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Unlicensed and off-label use of medicines in children in Europe
Unlicensed and off-label
of
of
Country Setting/population prescriptions children
Reference
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)
©K. Hoppu 18.9.2007
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Preclinical development
Clinical development
Regulatory submission of MAA
Regulatory approval of MA
Marketing of
the new drug
Drug used
in adults
Postmarketing
surveillance
studies
Development of line
extensions including
paediatric labelling
Regulatory approval
of paediatric MA
Marketing of the new
drug for children
Drug used in children
Preclinical development
Clinical development
Regulatory submission of MAA
Regulatory approval of MA
Drug not used
in adults
Drug not used
in children
Preclinical development
Clinical development
Regulatory submission of MAA
Regulatory approval of MA
Drug not developed for
children
Marketing of
the new drug
Postmarketing
surveillance
studies
Drug not used in
children
Drug used
in adults
Drug used in children off-label
Preclinical development
Clinical development
Regulatory submission of MAA
Regulatory approval of MA
Marketing of
the new drug
Drug used
in adults
Postmarketing
surveillance
studies
Development of line
extensions including
paediatric labelling
No regulatory approval
of paediatric MA
Drug used in children off-label
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.
©K. Hoppu 18.9.2007
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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
©K. Hoppu 18.9.2007
MA = Market Authorisation
13
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 >‘.
©K. Hoppu 18.9.2007
A guideline on Summary of product characteristic; The Rules Governing Medicinal Products in
the European Union Volume 2C Notice to Applicants
15
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
©K. Hoppu 18.9.2007
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Posology and method of administration
Paediatric 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
©K. Hoppu 18.9.2007 European Union Volume 2C Notice to Applicants
17
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
©K. Hoppu 18.9.2007
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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
©K. Hoppu 18.9.2007
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Posology and method of administration
Paediatric 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
©K. Hoppu 18.9.2007
20
Posology and method of administration
Paediatric 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
©K. Hoppu 18.9.2007
21
Posology and method of administration
Paediatric 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
©K. Hoppu 18.9.2007 European Union Volume 2C Notice to Applicants
22
Paediatric dosing
• Should account for
• Size
• mg/kg
• mg/m2
• Development
• Age groups
• Developmental groups
• Single active substance vs.
combination
• Constrained by available formulations
©K. Hoppu 18.9.2007
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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.
©K. Hoppu 18.9.2007
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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.
©K. Hoppu 18.9.2007
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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
©K. Hoppu 18.9.2007
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30-59 kg
10 kg
7-18 mo
©K. Hoppu 18.9.2007
12 yrs
27
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
©K. Hoppu 18.9.2007
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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
©K. Hoppu 18.9.2007
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Strength (mg/ml)
Avoiding dosing errors/inaccuracy
Risk for
dosing errors
Ease of
administration
Volume of dose (ml)
©K. Hoppu 18.9.2007
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How to get the child to take the
medicine?
• Mixing with drink, food?
• Cultural differences
• Administration technique
Elina Vanninen – Lääkeopas 1997
©K. Hoppu 18.9.2007
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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
©K. Hoppu 18.9.2007
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Posology and method of administration
Paediatric 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
©K. Hoppu 18.9.2007 European Union Volume 2C Notice to Applicants
33
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
©K. Hoppu 18.9.2007 European Union Volume 2C Notice to Applicants
34
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
©K. Hoppu 18.9.2007 European Union Volume 2C Notice to Applicants
35
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
©K. Hoppu 18.9.2007
36
Interactions
Paediatric 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
©K. Hoppu 18.9.2007 European Union Volume 2C Notice to Applicants
37
Undesirable effects
Paediatric 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
©K. Hoppu 18.9.2007
38
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...
©K. Hoppu 18.9.2007
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Overdose
Paediatric 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
©K. Hoppu 18.9.2007 European Union Volume 2C Notice to Applicants
40
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
©K. Hoppu 18.9.2007
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