Download Review of application by Expert Committee Member

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Application for paediatric ibuprofen formulations to be added to the
WHO Model List of Essential Medicines
Review of application by Expert Committee Member
The Boots Healthcare International (BHI) application is based mainly on the belief
that evidence are sufficient to include the paediatric ibuprofen in the next WHO
Essential Medicines list. The application makes reference to variety of evidence
showing antipyretic effect of the ibuprofen and suggests the introduction of the drug
in children younger than twelve as suspension and suppository.
Ibuprofen is used in the management of mild to moderate pain and inflammation.
Nevertheless, this latter property is weaker than the analgesic effect. The diseases
such as dysmenorrhoea, headache including migraine, postoperative pain, dental pain
and musculoskeletal, joint and rheumatoid disorders are the main indications. It is also
pointed out as an agent reducing fever in children and the relief of this symptom is the
matter in the BHI application.
Studies about the use of ibuprofen as an antipyretic agent
In one randomised open study including 39 patients aged 2 – 12 years, the comparison
of ibuprofen and paracetamol with regard to the rate of the reduction in temperature,
degree and the duration of the reduction, indicated that both the drugs have
comparable antipyretic activity. The acceptability and tolerability for both medicines
are similar1.
In a randomised double blind study accounting 36 children with age range 11 months
to 11 ½ years showed that 6 mg/kg ibuprofen is effective in reducing childhood fever
and the reduction lasts longer than 11.6 ± 0.7 mg/kg paracetamol 2.
A randomised double blind cross over trial enrolling 70 patients aged 10 months to 4
years conclude that the antipyretic efficacy of ibuprofen and paracetamol is similar in
children with or without a history of febrile seizures 3.
A randomised double blind multidose trial in 90 patients aged 5 months to 13 years,
comparing ibuprofen 7 mg/kg, 10 mg/kg and paracetamol 10 mg/kg concluded that
the all three treatment groups showed a significant reduction in temperature from
baseline to three hours and the temperature remained lower over the 24 hours of the
study 4.
In a randomised double blind parallel study comparing the efficacy and tolerability of
7.5 mg/kg ibuprofen syrup and 10 mg/kg paracetamol syrup in 154 children (6 months
– 5 years) with fever ≥ 38°C with infections and treated with antibiotic therapy, the
efficacy of ibuprofen was not shown to be different from that of paracetamol and 7.5
mg/kg ibuprofen appears to have at least comparable antipyretic activity to 10 mg/kg
paracetamol 5.
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A further randomised double blind study comparing the efficacy of ibuprofen 7.5
mg/kg and 10 mg/kg, paracetamol 10 mg/kg, placebo in 37 children aged 2 – 12
years. Ibuprofen and paracetamol produced significant antipyresis when both are
compared to placebo, no adverse effect were observed in any treated group 6. The
authors concluded that ibuprofen is a potent antipyretic agent for a selected febrile
child who can neither take nor achieve satisfactory antipyresis with paracetamol6 .
In a double blind parallel group with 127 children aged 2 – 11 years, the authors
concluded in cases with temperature ≥ 38.3°C : 10 mg/kg ibuprofen > 5 mg/kg
ibuprofen > 10 mg/kg paracetamol > placebo but all agents were more effective than
placebo 7.
In an open comparative study involving 22 patients (2 – 8 years) with fever due to
upper respiratory infections or other causes and receiving both single doses of
ibuprofen 400 mg and paracetamol 300 mg (optimal single doses in adults), both
drugs produced significant reduction in temperature decrease 8.
An another study evaluating the relative efficacy of ibuprofen in a single oral dose of
either 5 mg/kg or 10 mg/kg versus paracetamol in a single dose of 12.5 mg/kg as
antipyretic agents and identifying potential confounding variables, the study found out
that the age of the patients appear to have an influence on the antipyretic response and
they point out that ibuprofen group received more antibiotics before the study 9.
A randomised double blind parallel trial in 64 febrile children aged 6 months to 11
years 7 months, receiving ibuprofen 2.5, 5 or 10 mg/kg or paracetamol 15 mg/kg
every 6 hours for 24 – 48 hours, the study shows that the rate of temperature reduction
and the maximal reduction of fever were equal for patients receiving 10 mg/kg
ibuprofen and 15 mg/kg paracetamol therapy 10.
Conclusion
The present report does not constitute a systematic review about the subject. Further
review on this topic seems indispensable. Nevertheless, the confounding variables
such as different ages of the patients, preexisting bacterial infection and positive
culture blunting the drop in temperature during the study period or antibiotherapy
intake before the drug administration, these previous factors changing the antipyretic
efficacy were not always taken into account in the studies. Moreover, the evidence
suggests that the effect on pyrexia is equal for both ibupropfen and paracetamol, if 15
mg/kg of paracetamol and 10 mg/kg of ibuprofen were regularly used in the studies.
There is also some evidence that ibuprofen work more quickly and the effect may be
longer, but it is not clear if this has a clinical significance 11. According to these
arguments, ibuprofen does not provide better response than paracetamol in fever, I
recommend that ibuprofen pediatric formulations are not added to the WHO Essential
Medicines list.
Abdelkader Helali
Member of the Expert Committee
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References
1. Y.K. Amdekar, R.Z. Desai: Antipyretic activity of ibuprofen and paracetamol in
children with pyrexia. Br. J. Clin. Pract. 1985; 41: 140 – 143.
2. M.T. Kelley, P.D. Walson, J.H. Edge & al : Pharmacokinetics and
pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children. Clin.
Pharmacol. Ther. 1992; 52 :181 – 189.
3. A. Van Esch, H.A Van Steensel-Moll & al : Antipyretic efficacy of ibuprofen and
acetaminophen in children with febrile seizures. Arch. Pediatr. Adolesc Med 1995,
149 : 632 – 637.
4. J. Sidler, B. frey, K. Baerlocher : A double-blind comparison of ibuprofen and
paracetamol in juvenile pyrexia. Br.J..Clin.Pract. 1990 ; 44 (suppl. 70) : 22 – 25.
5. E.Autret, G. Breart, A.P. Jonville & al : Comparative efficacy and tolerance of
ibuprofen syrup in children with pyrexia associated with infections disease and
treated with antibiotics. Eur.J. Clin. Pharmacol. 1994, 46 : 197 – 201.
6. R.E. Kauffman, L.A. Sawyer, M.L. Scheinbaum : Antipyretic efficacy of ibuprofen
vs acetaminophen. AJDC 1992 ; 146 : 622 – 625.
7. P.D. Walson, G. Galletta & al : Ibuprofen, acetaminophen, and placebo treatment of
febrile children. Clin. Pharmacol. Ther. 1989; 46 : 9 – 17.
8. U. K. Sheth, K. Gupta, T. Paul & al : Measurement of antipyretic activity of
ibuprofen and paracetamol in children. J. Clin. Pharm. 1980; Nov/Dec : 672 – 675.
9. J.T. Wilson, R.D. Brown, G.L. Kearns : Single-dose, placebo-controlled comparative
study of ibuprofen and acetaminophen antipyresis in children. J. Pediatr. 1991; 119 :
803 – 811.
10. P. D. Walson, G. Galletta, F. Chomilo & al : Comparison of multidose ibuprofen and
acetaminophen therapy in febrile children. AJDC 1992; 146 : 626 – 632.
11. Philip J Wiffen : Ibuprofen Liquid formulations for treating fever in children. Report;
Tuesday, December 31, 2002.