11 December 2002
Comments by the Department of Child and Adolescent Health and Development on the application by Boots Healthcare International to include paediatric ibuprofen formulation on the WHO model list of essential medicines.
1. Appropriateness of application. In general, inclusions on WHO's model list of essential drugs should be driven by the intended users (clinicians, experts, regulatory authorities, etc.).
2. Applicant. Various manufacturers of ibuprofen exist. It is not clear whether the quality of Boots Healthcare International (BHI) ibuprofen is superior to other manufacturers.
3. Age. The application is not specific as to for which age group ibuprofen would be suitable. Evidence on the safety of ibuprofen use in children under one month of age is not available.
4. Administration route. The application implies (in the second paragraph of the "Introduction" section) the inclusion request of ibuprofen to be for suspension AND suppository. However, in the application information provided, no clear distinction is made between efficacy, safety and tolerance of oral versus rectal administration. In fact, evidence on the safety of rectal ibuprofen administration is not available in the literature.
5. Indications.
Use as analgesic. Acute conditions - postoperative pain. The effectiveness of paracetamol with or without codeine in postoperative pain in children is well established. Its adequate use is associated with less postoperative nausea and vomiting, and has a morphine sparing effect1. The use of ibuprofen as post -operative analgesic however is controversial. Ibuprofen use was considered less safe (due to postoperative hemorrage and bleeding time differences) and efficacious (due to longer duration of medication) than paracetamol in the management of posttonsillectomy/adenotonsillectomy, a common childhood surgical procedure. Another prospective randomized controlled trial found no postoperative bleeding differences and equal pain control3. For bilateral myringotomy with tympanostomy tube placement, another frequent pediatric surgical procedure, efficacy of ibuprofen compared to acetominaphen was not superior . For dental surgery, ibuprofen was found to be a superior analgesic compared to paracetamol and placebo5. Chronic conditions - migraine. The benefits of ibuprofen as analgesic agent in children with acute recurrent migraines is not proven to be superior to paracetamol6.
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' Korpela R, Korvenoja P, Meretoja OA. Morphine-sparing effect of paracetamol in pediatric day-case surgery. Anesthesiology, 1999; 91(2):442-7.
2 Harley EH, Dattolo RA. Ibuprofen for tonsillectomy pain in children: efficacy and complications.
Otolaryngology-Head & Neck Surgery, 1998; 119(5):492-6.
3 St Charles CS, Matt BH, Hamilton MM, Katz BP. A comparison of ibuprofen versus acetominaphen
with codeine in the young tonsillectomy patient. Otolaryngology-Head & Neck Surgery, 1997;
117(l):76-82.
4 Derkay CS, Wadsworth JT, Darrow DH, Strasnick B, Thompson GK, O'Master J. Tube placement: a
prospective, randomized double-blind study. Laryngoscope, 1998; 108(lPtl):97-101.
5 McGaw T, Raborn W, Grace M. Analgesics in pediatric dental surgery: relative efficacy of
aluminium ibuprofen suspension and acetamonophen elixir. ASDC Journal of Dentistry for Children,
1987;54(2):106-9.
6 Anonymous. Ibuprofen and paracetamol reduced pain in children with migraine headache. Evidence
Based Medicine. 1997; 2: 111
Use as antipyretic. In general, controversy exists on the use of antipyretics in children. Although the efficacy of ibuprofen in pediatric patients with fever has been demonstrated7, the efficacy and tolerance of ibuprofen as antipyretic is similar to that of paracetamol in children8. Cough is the most frequent reason for health service attendance. The improvement of cough in children with upper respiratory tract infections and given paracetamol is superior to those given ibuprofen9. Therefore, use of ibuprofen as antipyretic should be discouraged. Use as anti-inflammatory. Ibuprofen is an effective anti-inflammatory drug for the management of juvenile rheumatoid arthitis, and associated with less discontinuation of medication due to side effects than acetylsalicylic acid10.
6. Contraindications. Although the frequency of acetylsalicylic acid and nonsteroidal anti-inflammatory drug induced asthma, is rarer in children than adults, the use of ibuprofen is contraindicated in patients who have previously shown hypersensitivity reactions, including asthma, to aspirin or other NSAIDs according to leading publications11,12 .
7. Interactions.
Malnutrition. In some of the countries mentioned in appendix 1 of the application, ibuprofen is not recommended for children under 7 kg11,12. In developing countries, malnutrition is a substantial problem. Under these circumstances dosage by age rather than weight (a common practice) risks inappropriate administration or overdosage.
8. Formulation. In general, pharmaceuticals for pediatric use should be sugar free. No reference to the sugar content is made in the application.
9. Cost. While no comparable international data exist on ibuprofen and paracetamol pediatric formulation (suspension), it should be noted that the average tender price per adult dosage paracetamol tablet (500 mg) is $0.0047 and that for ibuprofen (400 mg) $ 0.0089, almost twice as much13.
Conclusions:
· Without evidence of user support for the application, the application by a pharmaceutical company alone is not considered to be sufficient.
· For consideration of inclusion on the WHO model list of essential medicines, age limitations should be stated for the pediatric use of ibuprofen.
· As evidence on safety of rectal administration of ibuprofen is lacking, only oral formulations should be considered for inclusion in the WHO model list of essential medicines.
7 Nahata MC, Powell DA, Durrell DE, Miller MA, Gupta N. Efficacy of ibuprofen in pediatric patients
with fever. International Journal of Clinical Pharmacology, Therapy, & Toxicology, 1992; 30(3):94-6.
8 Mclntyre J, Hull D. Comparing efficacy and tolerability of ibuprofen and paracetamol in fever.
Archives of Disease in Childhood, 1996; 74(2): 164-7.
9 Ulukol B, Koksal Y, Cin S. Assessment of the efficacy and safety of paracetamol, ibuprofen and
nimesulide in children with upper respiratory tract infections. European Journal of Clinical
Pharmacology, 1999;55(9):615-8.
10 Giannini EH, Brewer EJ, Miller ML, Gibbas D, Passo MH, Hoyeraal HM, Bernstein B, Person DA,
Fink CW, Sawyer LA. Ibuprofen suspension in the treatment of juvenile rheumatoid arthritis. Pediatric
Rheumatology Collaborative Study Group. Journal of Pediatrics, 1990;117(4):645-52.
11 British Medical Association and the Royal Pharmaceutical Society of Great Britain. British National
Formulary. London, 2001
12 Royal College of Paediatrics and Child Health. Medicines for children. London , 1999
13 Management Sciences for Health. International Drug Price Indicator Guide. 2001 Edition. Boston,
2001.
· Given the efficacy and uncontroversial safety of paracetamol (with or without codeine), the use of ibuprofen should be discouraged as analgesic and antipyretic, in children, also for common post operative care. Inscription as an analgesic on WHO’s model essential medicines list may only be warranted for very selected (and relatively rare) conditions, such as dental surgery.
· The efficacy and safety of ibuprofen as analgesic for chronic conditions may need to be studied better before pediatric use can be recommended
· Inscription on WHO’s model essential medicines list is warranted as an anti-inflammatory agent for the indication of juvenile rheumatoid arthritis.
· More evidence needs to be provided on the safety in children with asthma.
· In populations with a high prevalence of malnutrition, the probability of faulty administration and overdosage is increased.
· Only sugar free formulations should be considered for pediatric use and inscription on WHO’s model essential medicines list.
· With equal effectiveness, generally higher safety, and probably lower costs of pediatric formulations, paracetamol is to be recommended over ibuprofen for developing country use.