Simple review for articles carried on the subject, with main principles of off-label prescription of antibiotics

1. OFF - Label Used Antibiotics in Pediatrics
By: Alaa F. Hassan (Pharmacy/Pharmacology)

2. Entrance, Paediatric Population
• Paediatric populations are defined as individuals of 0-
18 yr. of age (Kimland E. and Odlind V., 2012).
• They are categorized into: neonates (0-27 days),
children (2-11 yr.), and adolescents (12-17 yr.)
according to The European Medicines Agency (Porta A.
et al., 2010).
• Jong G.T., (2002) stated that: formulas that
extrapolated paediatric doses from adults would
overestimate the dose required in neonates or may
underestimate the drequired dose in children, since
children shoudn’t be treated as small adults (Mir A. and
Geer M. 2016) .

3. Off-label use of Drugs, definition
• It is the use of drug which has a marketing
authorization, but in situation not covered by the
product license or the summary of product
characteristics (SPC) or at a dose or frequency, via
a route, or for an age (Porta A. et al., 2010; Tefera Y.G. et
al., 2016; Man S. et al., 2017).
• Off-label is generally legal unless it violates the
ethical guidelines or safety regulations, but it dose
carry health risks & differences in legal liabilities
(Jong G.T., 2002; Mir A. and Geer M. 2016).

4. Off-label use of Drugs
• It account for 11% in England, 33.3% in Taiwan,
54% in France, 29% in Netherland with
paediatrics & 80% in Australia with neonates
(Huang K-H. et al., 2012; Man S. et al., 2017).
• Also account to be between 16 & 60% in
infants & 90% in neonates (Tefera Y.G. et al., 2016).
• In Finland 2011, its account to be 79% in
pediatric wards & 100% in neonatal care unit
(Man S. et al., 2017).

5. Development of Paediatrics medical authorities
• At 1979, Food & Drug Administration (FDA) determined that specific pediatric indication with
appropriate dosage must be mentioned in drug label. While at 1997, Modernization Act (FDAMA)
section III was designed to stimulate paediatric labelling by FDA & at 1998, the Pediatric Rule was
published. Then A new Committee for Proprietary Medicinal products (CPMP) note for Guidance on
Clinical Investigation of Medicinal Products in Pediatric population was established at 2001 (Jong G.T.,
2002).
• The 2 complementary federal laws established at 2003: Best Pharmaceuticals for Children Act (BPCA)
and Pediatric Research Equity Act (PREA) have substantially resulted in improvement in rational
prescribing for children (the American Academy of Pediatrics 2014; Mir A. and Geer M. 2016).
• World Health Organization (WHO) adopted “Better Medicines for children” to improve medicines
safety in paediatrics & highlighted its concern on off-label use, also estimated the Better Medicines
for children programme with UNICF (Tefera Y.G. et al., 2016; Mir A. and Geer M. 2016).
• The European Medicines Agency (EMA) laid down specific rules for marketing authorizations of
drugs for paediatric use, also aid in establishing the European network of paediatric research while
the European Union (EU) Paediatric Regulation granted responsibilities that stimulate drug use in
children researches which leads to their authorization in all age groups (Porta A. et al., 2010; Mir A. and
Geer M. 2016).

6. Off-label use of Drugs, Reasons
• Differences in the list of approved drugs between countries so
drugs that are approved in 1 country may not be approved in
another (Kimland E. and Odlind V., 2012).
• The prohibitive cost of obtaining FDA approval since it consumes
very much time (Mir A. and Geer M. 2016).
• Drugs are not studied in paediatrics due to ethical, scientific &
technical issues (Jong G.T., 2002; Mir A. and Geer M. 2016).
• The absence of appropriate information to guide therapy &
availability for use in children (Jong G.T. 2002; the American Academy of
Pediatrics 2014; Tefera Y.G. et al., 2016).
• Lack of the registered alternative treatment for specific age group
(Mir A. and Geer M. 2016; Man S. et al., 2017).
• The prescribing physician confirms the efficacy and safety of
unapproved use of medications (Man S. et al., 2017).

7. Off-label use of Drugs, associated risks
• Toxic effect from excessive dose or Ineffective
therapy from underdosing (Jong G.T., 2002).
• Can cause significant damage in developing fetus
or child (Porta A. et al., 2010).
• Predispose children to medication error & give rise
to many minor adverse event requiring
hospitalization, extension of hospital stay or add
to medical care utilization and expense (Porta A. et
al., 2010; Huang K-H. et al., 2012; Tefera Y.G. et al., 2016).
• Results in antibiotics consumption and increased
bacterial resistance (Man S. et al., 2017).

8. Off-label used Antibiotics, study carried out in
England, Italy & Greece (Porta A. et al., 2010)
Antibiotic indication Why used off- label
Meropenem
Imipenem
Proven or suspected sepsis
Lower RTI
Outside registered age
<3 mnth
Quinolone ciprofloxacin
levofloxacin
Severe infection /
underlying chr. dis.
Outside registered age
<18 yr
Linzolid Severe infection /
underlying chr. dis.
Outside registered age
< 18 yr
Aminoglycosides
Amikacin
Gentamicin
Sepsis / lower RTI or
surgical prophylaxis
Unregistered dose
Amoxicillin – clavulanate &
Ampicillin – sulbactam
Sepsis / lower RTI /UTI or
surgical prophylaxis
Unregistered dose & off
label indication
flucloxacillin
Cefaclor
Sepsis or medical
prophylaxis
Off-label indication
Cefuroxime
Trimethoprim
Metronidazole
Vancomycin
Sepsis / lower RTI /UTI or
surgical prophylaxis
Unregistered dose

9. Off-label used Antibiotics, examples
• Off-label indicated antibiotics in study carried in
Taiwan were prescribed for upper RTI & special
viral respiratory infections (Huang K-H. et al., 2012).
• In study performed in India, mostly prescribed
antibiotics were ceftriaxone, amikacin,
amoxicillin and vancomycin in higher doses than
recommended (Saiyed M. et al., 2014).
• Commonly off-label prescribed antibiotics in
study performed in Ethiopia were ceftriaxone
20.7%, cloxacillin 10.6%, gentamicin 9.52% and
ampicillin (Tefera Y.G. et al., 2016).

10. Off label used Antibiotics, examples
• In a study performed in Romania,
azithromycin, ceftriaxone, clarithromycin
and meropenem were used in off-label
prescription dose while erythromycin was
used as prokinetic i.e. off-label indication,
and antibiotics + corticosteroid ophthalmic
combination registered as eye drops
prescribed for rhinosinositis (off-label route
of administration) (Man S. et al., 2017).

11. References
• Huang K-H., Hsieh Y-C., Huang C-T. and Hsiao F-Y. (2012) Off-Label Antibiotic Use in the Pediatric Population:
A Population-based Study in Taiwan. Journal of Food and Drug Analysis, Vol. 20, No. 3, 2012, Pages 597-602.
• Jong G.T., (2002) Unlicensed and off -label drug use in children. Thesis, Erasmus University Rotterdam. ISBN
90-77-017-550.
• Kimland E. and Odlind V. (2012) Off-Label Drug Use in Pediatric Patients. Clinical pharmacology &
Therapeutics, VOLUME 91 NUMBER 5, may 2012.
• MAN S.C., PRIMEJDIE D.P., SÁRKŐZI I.-K. and POPA A. (2017) OFF-LABEL AND UNLICENSED PRESCRIBING IN
HOSPITALIZED CHILDREN: PREVALENCE AND REASONS. FARMACIA, 2017, Vol. 65, 3.
• Mir A.N. and Geer M.I. (2016) OFF-LABEL USE OF MEDICINES IN CHILDREN. International Journal of
Pharmaceutical Sciences and Research, 2016; Vol. 7(5): 1820-1828.
• Porta A., Esposito S., Menson E., Spyridis N., Tsolia M., Sharland M. and Principi N. (2010) Off-label
antibiotic use in children in three European countries. European Journal of Clinical Pharmacology (2010)
66:919–927.
• Saiyed M.M., Lalwani T., and Rana D. (2014) Off-Label Medicine Use in Pediatric Inpatients: A Prospective
Observational Study at a Tertiary Care Hospital in India. International Journal of Pediatrics Volume 2014,
Article ID 415815, 6 pages.
• Tefera Y.G., Gebresillassie B.M., Mekuria A.B., Abebe T.B., Erku D.A., Seid N. and Beshir H.B. (2016) Off-label
drug use in hospitalized children: a prospective observational study at Gondar University Referral Hospital,
Northwestern Ethiopia. Pharmacology Research and Perspectives, 5(2), 2017, e00304.
• the American Academy of Pediatrics, COMMITTEE ON DRUGS (2014) POLICY STATEMENT Off-Label Use of
Drugs in Children. PEDIATRICS Volume 133, Number 3, March 2014.

12. THANK YOU