REVIEW ON APPLICATION OF IBUPROFEN PEDIATRIC SUSPENSION FOR INCLUSION IN WHO MODEL LIST 2005

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1 1 REVIEW ON APPLICATION OF IBUPROFEN PEDIATRIC SUSPENSION FOR INCLUSION IN WHO MODEL LIST 2005 An application has been submitted by the International Ibuprofen Foundation. The application is based on the belief that the evidence is sufficient to include ibuprofen paediatric suspension in the WHO Model Essential Medicines List. The application is based on the fact that ibuprofen is previously included in the model list and formulary as tablets for the treatment of pain, but paediatric ibuprofen suspension for the treatment of pyrexia still lacking. Electronic databases are furnished in support to this application (see annex). Essential medicines are selected with the regard to disease prevalence, evidence on efficacy and safety, and comparative cost-effectiveness. Otherwise, we examine whether ibuprofen is more effective, safer and less costly than paracetamol. Is paracetamol less effective than ibuprofen? According to the table summarising comparative evidence on efficacy, when we take into account only the controlled studies comparing ibuprofen to paracetamol : 14 studies found that the both medicine produced equal temperature decrease in children, ibuprofen seems more effective than paracetamol in 7 studies. Furthermore, in recent systematic review of 22 controlled trials, Wahba H. describe ibuprofen as providing a longer duration of antipyretic effect than paracetamol at 4 hours after intervention, but paracetamol produced a greater body temperature reduction 0.5 hour after the intervention when compared to ibuprofen. As pointed out in the application, symptomatic treatment of fever with rapid onset is often required to avoid any distress or discomfort of dehydration or seizures in child, according to this statement, paracetamol is more effective than ibuprofen because it acts more quickly than ibuprofen and prevent the complications. Is ibuprofen safer than paracetamol? An analysis of the outcome at the large scale follow up programme ( children) the author found that the risk of hospitalisation for gastro-intestinal bleeding, renal failure or anaphylaxis was no greater in children given ibuprofen than in those receiving paracetamol (Lesko S.M. JAMA 1995; 273: , see also Martindale 2002 ; 33 th edition : 43). Is paracetamol more expensive than ibuprofen? On the basis of price indicator WHO/AFRO/EDP/30.2 published by WHO Regional Office for Africa in December 2003, the mean costs treatment calculated on the basis of Defined Daily Dose in tablets of each drug for the three main providers of the African market (International Dispensary Association IDA, ORBI-PHARMA, TRI-MED Limited ) are US $ for ibuprofen, US $ for paracetamol, treatment with paracetamol seems more expensive than ibuprofen at least for tablets. Furthermore, comparing paracetamol in tablets to the syrup formulation, the syrup is (twelve) times more expensive than tablets, that s the reason why the suspension formulation is rarity in African pharmaceutical market, the mothers of babies often crush the tablets. Does ibuprofen present any public health relevance in comparison to paracetamol? In developing countries fever in children is the widespread health problem particularly at the primary health care system. Many consulting room in primary health care in Africa are managed by nurses, female or male, without any medical doctor at ten kilometres around. A Health authorities provide the nurses with standard therapeutic diagram (STD) for advising

2 2 them in symptomatic treatment of the diseases. All the STD are recommending paracetamol, I am afraid the introduction of ibuprofen become a conflicting issue and will complicate the management of fever at the primary health care in Africa. In view of the above, and also regarding the difficulties of managing paediatric formulations in developing countries and specially in African area where stocking and handling of materials are difficult, I recommend that ibuprofen paediatric formulation is not added to the essential medicine list and that paracetamol remain the medicine of choice for treating fever at this time. References: The references for ibuprofen are based mainly on the table summarising comparative evidence on efficacy provided by international ibuprofen foundation (see Annex). Some articles draw special attention: E. Autret, G. Breart, A.P Jonville : Comparative efficacy and tolerance of ibuprofen syrup in children with pyrexia associated with infectious disease and treated with antibiotics. Eur.J.Clin.Pharmacol. 1994, 46 : 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) : A. Van Esch, H.A Van Steensel-Moll : Antipyretic efficacy of ibuprofen and acetaminophen in children with febrile seizures. Arch. Pediatr. Adolesc. Med 1995; 149 : P.D Walson, G. Galleta, F. Chomilo : Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. AJDC 1992 ; 146: WHO Regional Office for Africa : Afro Essential Medecines, Price Indicator; December 2003 : A11 & A16. J.T Wilson, R.D Brown, G. L Kearns :, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J. Pediatr. 1991; 119 : Algiers 19 December 2004 A. Helali Member of the Expert Committee

3 3 Annex : Table summarising comparative evidence on efficacy of ibuprofen in fever. Amdekar, et al years IBU 7mg /kg APAP 8mg/kg Single Dose Both IBU and APAP produced a significant reduction in temperature and were comparable for rate, degree, and duration of reduction in temperature. Autret, et al France mos.- 5years IBU 7.5 mg/kg q6h for 12hrs. APAP 10 mg /kg q6h for 12 hrs. IBU> APAP in percent temperature reduction at 4h for all subjects IBU = APAP < 39 C, n=74 IBU = APAP > 39 C, n=77 Over 12hrs., IBU = APAP Autret, et al France mos.- 2 years IBU 7.5 mg/kg APAP 10mg/kg ASA 10 mg /kg IBU> APAP, ASA for AUC, mean reduction in temperature IBU > APAP for number on subjects with normal rectal temperature at 4hrs. Child s Comfort : IBU> ASA, APAP at 6hrs. Goldman et al 2004 Literature review Narrative review Ibuprofen was significantly more effective than acetaminophen in reducing fever after a single dose. Ibuprofen was found to be more effective after 6 hours but not after a longer period of time. Studies with multiple doses have also failed to show that one drug is better than the other.

4 4 Heremans, et al. Belgium years IBU 6mg/kg ASA 10mg/kg Single Dose IBU = ASA rate, degree, duration of temperature reduction Joshi, et al mos.- 12 years IBU 7mg/kg APAP 8mg /kg IBU = APAP rate and degree of temperature reduction APAP > IBU at 0.5 hrs. Kandoth, et al Mean age- 4.3 years IBU 7mg/kg ASA 15 mg/kg IBU = ASA Kauffman, et al years IBU 7.5 or 10 mg/kg APAP 10 mg /kg PBO IBU> APAP temperature reduction, duration; IBU 7.5 mg/kg = IBU 10mg / kg Keinänen- Kiukaanniemi, et al Finland 64 3 mos.- 14 years IBU 6mg/kg KETO 0.5 mg/kg KETO 1.0 mg/kg FEN 10 mg/kg NAP 2mg/kg IBU = KETO 1.0 = FEN = NAP > KETO 0.5 maximum decrease in temperature at 4 hrs. Kelley, et al mos.- 11 years IBU 6mg/kg APAP 10 or 15 mg/kg IBU > APAP 4-8 hrs. maximum temperature decrease: IBU = 183 min., APAP = 133 min.

5 5 Khubchandani, et al years IBU 7mg /kg Mefanamic acid 10mg/kg APAP 10 mg/kg Mefanamic acid > APAP, IBU AUC temp-time curve McIntyre and Hull 1996 England Nahata, et al years 56 6mos.- 12 years IBU 20 mg/kg/d APAP 50mg/kg/d in 4 divided doses q6h for up to 3 days IBU 5 mg/kg or 10 mg /kg PBO IBU =APAP mean temperature change, irritability, clinical condition, overall efficacy, palatability IBU 10mg/kg>IBU 5mg/kg>PBO mean temperature, duration of action, maximum temperature reduction, maximum reduction: IBU10=4hrs IBU 5 = 3hrs PBO = 7hrs Pelen, et al France NA 6mos.- 15 years IBU 10 mg/kg Significant reduction in temperature from 15 mins. through 12 hrs.87-88% acceptable, palatable Perrott et al Systematic review Meta-analysis 10 randomised clinical trials IBU (5-10 mg/kg) > PARA (10-15 mg/kg): ibuprofen was a more effective antipyretic at 2,4 and 6hrs post dose Phadke, et al Purssell E 2002 Literature review years SYSTEMATIC REVIEW IBU 20 mg/kg/day in 3 divided doses APAP mg based on age 8 randomised controlled trials IBU = APAP in reducing temperature and overall therapeutic efficacy IBU = PARA post 1hr IBU > PARA at 6 hrs

6 6 Schactel years IBU 10 mg/kg PARA 15 mg/kg IBU = PARA at significantly reducing oral temperature Sidler, et al Switzerland 89 5mos.- 13 years IBU 7 mg /kg or 10mg/kg APAP 10 mg/kg IBU> APAP lower mean temperature and rate of temperature reduction Similä, et al Finland 79 3mos.- 13 years IBU 0.5 mg/kg IBU 6.0 mg/kg INDO 0.5 mg /kg ASA 10 mg /kg APHZ 5mg/kg IBU 6.0 mg/kg = INDO = ASA= APHZ >IBU0.5mg/kg Thoden et al mos.- 11years IBU7.5mg /kg APAP 12.5mg/kg Temperature control attained significantly earlier (110 mins (p<0.003) ) with IBU compared to APAP (154 mins) &lasted significantly longer (p< 0.001) Van Esch, et al Netherlands mos.- 4years IBU 5mg/kg APAP 10mg/kg IBU> APAP temperature reduction in children with a history of febrile seizures Vauzelle Kervrëdan 1997 France mos.- 12 years IBU 10mg/kg APAP 10 mg/kg IBU= APAP time to peak reduction and rate, extent and duration of temperature reduction Vinh HA et al years IBU 10 mg/kg PARA 12.5mg/kg Multi dose The median (range) fever clearance time (hours) was shorter in the ibuprofen group than the paracetamol group (68,4 to 260vs.104, 12 to 404; P= 0.055) as was the area under the temperature time curve above 37 degree C(74,0 to 237 vs.127,0 to 573; P= 0.013) in typhoid fever

7 7 Wahba H 2004 Literature Review Systematic Review 22 papers Ibuprofen provides a longer duration of antipyretic effect than acetaminophen 4 hours after intervention, and the initial temperature decrement lasts longer. Acetaminophen produced a greater body temperature reduction at 0.5 hour after intervention compared with ibuprofen. Walson, et al years IBU 5mg/kg or 10mg/kg APAP 10mg/kg PBO IBU > 10mg/kg> APAP > PBO IBU 10mg/kg>IBU 5mg/kg>APAP> PBO for temp >102.5 F Walson, et al years IBU>PARA and Dipyrone>PARA temperature normalization rates (82 %, & 78 % respectively) acetaminophen group (68 %) P= Walson, et al mos.- 12 years IBU 2.5, 5, 10mg/kg APAP 15 mg/kg q6h IBU 10mg/kg = APAP 15mg/kg>IBU 2.5mg/kg and IBU 5mg/kg mean percent decrease for first dose but were comparable thereafter Wilson, et al Portugal 35 2 mos.- 10 years IBU50-200mgby age APAP 125mg-500mg by age Q8h IBU>APAP extent and duration of reduction in temperature Wilson, et al mos.- 12 years IBU 5mg/kg 10mg/kg APAP 12.5mg/kg PBO IBU10mg/kg > 5mg/kg, APAP >PBO overall antipyretic effect IBU 10mg/kg = IBU 5mg/kg = APAP for onset and maximum antipyresis IBU 10mg/kg > IBU 5mg/kg in children with high temperatures

8 8 Wong et al mos-6years Dipyrone 15mg/kg IBU5mg/kg/10mg/kg APAP 12mg/kg IBU = Dipyrone > APAP for temperature normalisation frequencies (p< 0.04) ie. percentage of febrile children in the test population whose temp was reduced to 37.5 degrees C. APAP = acetaminophen APHZ = aminophenazone ASA = aspirin FEN = fenoprofen IBU= ibubrophen INDO= indomethacin KETO = ketoprofen NAP = naproxen PARA = paracetamol PBO = placebo