Shyamalie Jayawardena, PhD 1, and David Kellstein, PhD 1. Background. Article

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1 678818CPJXXX / Clinical PediatricsJayawardena and Kellstein research-article2016 Article Antipyretic Efficacy and Safety of Ibuprofen Versus Suspension in Febrile Children: Results of 2 Randomized, Double-Blind, Single-Dose Studies Clinical Pediatrics 1 8 The Author(s) 2016 Reprints and permissions: sagepub.com/journalspermissions.nav DOI: / cpj.sagepub.com Shyamalie Jayawardena, PhD 1, and David Kellstein, PhD 1 Abstract Two blinded single-dose studies randomized children 6 months to 11 years old with fever to receive ibuprofen (IBU) pediatric suspension 7.5 mg/kg or acetaminophen (APAP) suspension 10 to 15 mg/kg. The primary efficacy parameter was time-weighted sum of temperature differences (TWSTD) from baseline through 8 hours for each study. Secondary end points included TWSTD from baseline through 6 hours, time to onset and duration of temperature control, and proportion with temperature control. Studies were pooled for post hoc analyses of efficacy and adverse event end points. The primary efficacy parameter significantly favored IBU over APAP in study 1 and the pooled analysis (both P <.001), but was not significant in study 2. Onset of temperature control significantly favored IBU in study 2 (P =.007). Individual and pooled secondary efficacy outcomes supported significant advantages (P <.05) of IBU over APAP. IBU pediatric suspension provided greater temperature reduction versus acetaminophen in febrile children, with a comparable safety profile. Keywords ibuprofen, acetaminophen, pediatrics, fever, randomized controlled trial Background Fever is an important part of the body s immune response to infection and is a common symptom occurring in childhood. 1-3 Current guidelines recommend that antipyretics be administered to febrile children who otherwise appear healthy in an effort to improve comfort, rather than in an attempt to normalize temperature. 1,2,4 Although several antipyretic medications are available, ibuprofen (IBU) and acetaminophen (APAP) represent the most widely used drugs in this class, 5 and both drugs are recommended by the American Academy of Pediatrics and the UK National Institute for Health and Clinical Excellence for the treatment of fever. 2,4 Despite their long history of use, the differential antipyretic efficacy of IBU versus APAP has been the subject of some debate. APAP has been used since the 1950s, when it replaced aspirin as the preferred antipyretic because of an association between aspirin and Reye s syndrome. The current labeled dose of APAP is 10 to 15 mg/kg every 4 hours in children older than 3 months. 2 IBU was approved by the US Food and Drug Administration in 1989 for prescription use in children with fever; in 1995, it was approved for over-the-counter use, with recommended dosages of 5 to 10 mg/kg every 6 to 8 hours in children older than 6 months. 6 Two early studies comparing the antipyretic effects of IBU 7.5 or 10 mg/kg with APAP 10 mg/kg in children with fever found significant benefits of IBU over APAP, 7,8 including earlier temperature reduction 7,8 as well as greater and longer-lasting antipyresis. 7 Here, we provide the details of 2 studies that compared the antipyretic efficacy and safety of the currently labeled nonprescription doses of IBU (7.5 mg/kg) and APAP suspension (10-15 mg/kg) in children with fever. Both individual study results and a pooled analysis are presented. 1 Pfizer Consumer Healthcare, Madison, NJ, USA Corresponding Author: David Kellstein, Global Medical Affairs, Pfizer Consumer Healthcare, 1 Giralda Farms, Madison, NJ 07940, USA. david.kellstein@pfizer.com

2 2 Clinical Pediatrics Methods Both trials were double-blind, randomized, parallelgroup studies that stratified enrollment by baseline temperature ( F vs >102.5 F) and had a similar design. Prior to study initiation, the protocol for study 1 (single center) was approved by the Arkansas Institutional Review Board (Little Rock, AR; protocol AF-95-05); study 2 (multicenter) was approved by the Western Institutional Review Board (Olympia, WA; protocol WIRB 96126). Parents or guardians of all participants provided written consent for their child to participate in the study. In addition, children who were at least 7 years of age provided written consent, and those younger than 7 years of age provided verbal consent. Participants Participants were boys and girls aged 6 months through 11 years who weighed 13 to 95 lb ( kg) and reported initial onset of fever at least 2 hours prior to entering the study. Fever was defined as a rectal temperature of F to F in children 6 months to 3 years old or oral temperature of 101 F to F in those 4 to 11 years old. Oral or rectal temperatures were measured using a B-D Digital Fever Thermometer (Becton Dickinson Consumer Products, Franklin Lakes, NJ) at baseline (time 0) and then at 15, 30, and 45 minutes and 1, 2, 3, 4, 5, 6, 7, and 8 hours after treatment. At each time point, the recorded temperature was the average of 2 temperature readings taken within 5-minute intervals (for values at 15, 30, and 45 minutes) or within 15-minute intervals (for values at baseline [ie, time 0], and 1, 2, 3, 4, 5, 6, 7, and 8 hours after dosing). If paired temperature readings differed by more than 0.5 F, a third temperature was taken, and the 2 readings within 0.5 F of each other were used to determine the average. Children were excluded from the studies if they showed signs of dehydration, malnourishment, or severe debilitation, or if they were below the 5th percentile or above the 95th percentile in weight. Those who had received antipyretic medication within 8 hours or systemic antibiotics/steroids within 72 hours of enrollment or had received any investigational drug within 30 days of enrollment were not eligible to participate. Other exclusion criteria included a known hypersensitivity to APAP, aspirin, IBU, or any other nonsteroidal anti-inflammatory drug; history of febrile seizures; asthma or any bronchospastic condition; recurrent hives or urticaria; diagnosis of chronic renal disorder; blood coagulation defect; metabolic disease; hepatic disease; or anemia secondary to blood loss. Treatments and Evaluations Each study randomized febrile children to receive a single dose of either IBU suspension (Children s Advil Suspension 100 mg/5 ml; 7.5 mg/kg; Pfizer Consumer Healthcare, Madison, NJ) or APAP suspension (Children s Tylenol Suspension 160 mg/5 ml; mg/kg; McNeil Consumer Products, Fort Washington, PA), followed by an 8-hour evaluation period. In study 1, all post-baseline temperature assessments occurred at the study center. In study 2, post-baseline measurements through hour 1 were taken at the study center; subsequent measurements were either taken at the study center or at the participant s home by an assigned health care professional. End Points The primary efficacy end point in each study was the time-weighted sum of temperature differences (TWSTDs) from baseline through 8 hours. Secondary end points in each study included the TWSTDs from baseline through 2, 4, and 6 hours; maximum temperature difference from baseline; temperature difference from baseline at each postdose assessment; proportion of participants who were treatment failures (defined as temperature 1 F over baseline, above F orally or F rectally at any time, or at or above baseline 2 hours postdose); and time to treatment failure. Other secondary end points were time to onset of temperature control (ie, <100 F orally or <101 F rectally), duration of temperature control (the difference between time of onset and time of offset, where time of offset was defined as the midpoint between the time at which the temperature was no longer controlled and the prior scheduled time point), and the proportion of individuals with temperature control at each time point. Adverse events (AEs) were recorded; pulse and respiration rates were measured at hours 2, 4, 6, and 8 hours to monitor treatment safety and tolerability. Study data were also pooled for analyses assessing the primary efficacy end point (TWSTDs from baseline through 8 hours), secondary outcomes pertaining to onset and duration of temperature control, and AEs. Statistics Within each study, efficacy analyses were performed on the evaluable population, which comprised all participants with a postdose measurement and no significant protocol violation. Two-way analysis of variance (ANOVA) with treatment and baseline temperature stratum in the model was used to analyze the TWSTDs from baseline, temperature differences from baseline at each time point, and maximum temperature difference from

3 Jayawardena and Kellstein 3 Figure 1. Study flow. a One participant <6 months of age was classified as discontinued after completing the 8-hour study; this infant was deemed eligible for primary efficacy analysis. baseline. The proportions of participants who achieved temperature control or who were classified as treatment failures were analyzed using the Cochran-Mantel- Haenszel test. The Cox proportional hazards regression model was used to analyze time to treatment failure, time to temperature control, and duration of temperature control. Kaplan-Meier estimates were used to estimate time to treatment failure, time to onset of temperature control, and duration of control. For the pooled post hoc analysis, subject-level data from the 2 studies were pooled and analyzed using similar models, except that the effect of study was also incorporated into each analysis. Treatment by study interaction was also evaluated. In all analyses, statistical significance was defined as P.05, 2 sided. All participants who took study medication (safety population) were included in safety analyses. Adverse events were summarized using descriptive statistics, and Fisher s exact test was used to compare AEs between treatment groups. Pulse and respiration rates were analyzed using 2-way ANOVA. Results Patient Population A summary of patient flow through each individual study is presented in Figure 1. The pooled efficacy analyses included 163 patients randomized to IBU suspension and 156 randomized to APAP suspension. The pooled safety analysis population comprised 173 patients randomized to IBU and 160 randomized to APAP. Patient demographics and baseline characteristics for both studies are presented in Table 1. Patients randomized to receive IBU pediatric suspension in study 1 were significantly younger, weighed less, and had a higher pulse rate at screening than patients randomized to APAP, but these differences were not considered clinically meaningful. Efficacy Outcomes Primary Efficacy. The mean (SD) TWSTDs from baseline to 8 hours was significantly better (P <.001) for the IBU group than for the APAP group: 10.5 (7.3) versus 5.7 (7.3) in study 1. In study 2, a numerical advantage favoring IBU over APAP was observed for the primary efficacy parameter: 11.7 (9.6) versus 9.7 (8.2), respectively, but the difference was not statistically significant (Figure 2, Table 2). Secondary Efficacy. The secondary efficacy outcomes of TWSTDs from baseline to hours 2, 4, and 6 significantly favored IBU pediatric suspension over APAP in study 1 (P =.015 at hour 2, P <.001 at hours 4 and 6). In study 2,

4 4 Clinical Pediatrics Table 1. Demographics and Baseline Characteristics for All Evaluable Individuals. a Study 1 (n = 160) Study 2 (n = 159) Characteristic Ibuprofen 7.5 mg/kg (n = 78) mg/kg (n = 82) Ibuprofen 7.5 mg/kg (n = 85) mg/kg (n = 74) Age, years 4.1 (2.7) b 4.9 (3.2) 4.6 (3.1) 4.8 (3.2) Sex Male 34 (43.6) 38 (46.3) 39 (45.9) 33 (44.6) Female 44 (56.4) 44 (53.7) 46 (54.1) 41 (55.4) Race White 71 (91.0) 75 (91.5) 81 (95.3) 72 (97.3) Black 7 (9.0) 6 (7.3) 1 (1.2) 1 (1.4) Other 0 1 (1.2) 3 (3.6) 1 (1.4) Weight, lb c 37.1 (15.3) b 42.3 (17.9) 39.4 (17.9) 41.1 (17.6) Height, inches c 40.5 (8.2) 42.8 (9.2) 40.9 (8.9) 41.7 (8.9) Body temperature, F c (0.9) (0.9) (0.9) (0.8) Respiration rate, breaths/ 26.8 (6.7) 25.5 (5.5) 29.1 (10.2) 30.8 (13.2) min c Pulse rate, beats/min c (19.3) b (19.7) (20.3) (22.3) Length of fever, hours c 28.8 (22.9) 25.7 (21.9) 36.1 (28.9) 32.8 (26.2) a Data are mean (SD) or number (%). b P.05. c Measurement taken at screening. Figure 2. Time-weighted sum of temperature differences from baseline (evaluable patients). Data are mean ± standard error of the mean. a P <.05. b P <.001. the TWSTDs through hours 2, 4, and 6 favored IBU over APAP at each time point but did not reach statistical significance (Figure 2, Table 2). IBU was associated with a significantly greater maximum temperature difference from baseline in study 1 compared with APAP (P <.001; Table 2), with significantly greater temperature reductions starting at hour 1 and continuing throughout the 8-hour study duration (P <.05 for each; Figure 3). In study 2, temperature differences noted throughout the study and the maximum temperature difference associated with IBU treatment

5 Jayawardena and Kellstein 5 Table 2. Summary of Efficacy Outcomes. Study 1 Study 2 Pooled End Point Ibuprofen 7.5 mg/kg (n = 78) mg/kg (n = 82) Ibuprofen 7.5 mg/kg (n = 85) mg/kg (n = 74) Ibuprofen 7.5 mg/kg (n = 163) mg/kg (n = 156) Time-weighted sum of temperature difference ( F): mean (SD) Hour (1.1) a 2.4 (1.1) 3.3 (1.5) 3.0 (1.4) b Hour (2.7) c 5.6 (3.1) 8.2 (3.8) 7.5 (3.5) Hour (5.1) c 6.4 (5.4) 11.0 (6.7) 9.6 (6.1) Hour 8 d 10.5 (7.3) c 5.7 (7.3) 11.7 (9.6) 9.7 (8.2) 11.1 (8.5) c 7.6 (8.0) Maximum temperature 2.9 (0.9) c 2.2 (0.9) 3.1 (1.2) 2.8 (1.0) difference ( F) Treatment failures, n (%) Hour 4 1 (1.3) e 10 (12.2) 3 (3.5) 3 (4.1) Hour 6 13 (16.7) e 31 (37.8) 20 (23.5) 19 (25.7) Hour 8 31 (39.7) a 48 (58.5) 31 (36.5) 33 (44.6) Time to treatment failure, hours (95% CI) >8 (>8, >8) a 7.7 (7.0, 8.0) >8 (8, >8) >8 (7.1, >8) Temperature control (median [95% CI]) Time to onset of control, 110 (110, 180) e 154 (120, >480) 88 (60, >480) e 100 (60, >480) 95 (94, >480) c 112 (120, 180) minutes (min, max) Duration of control, minutes (min, max) 151 (91, 211) c 20 (0, 31) 198 (150, 270) 140 (150, 210) 191 (150, 210) a 123 (122, >465) Abbreviations: min, minimum; max, maximum. a P.05. b Indicates that data were not evaluated. c P <.001. d The time-weighted sum of the temperature differences from baseline over 8 hours was the primary efficacy variable. e P <.01. Figure 3. Mean temperature changes from baseline for study 1 (A) and study 2 (B). Data are mean ± standard error of the mean. a P <.05. b P <.01. c P <.001. were greater than those observed with APAP treatment but were not statistically significant. In study 1, IBU was associated with significant advantages over APAP in terms of a faster onset of temperature control (P =.003; Figure 4), longer duration of temperature control (P <.001), fewer treatment failures (P =.018 at 8 hours), and a longer time to treatment failure (P =.015). Onset of temperature control was significantly faster with IBU versus APAP in study 2 (P =.007). Although IBU was associated with a longer duration of temperature control and time to treatment failure as well as a lower percentage of treatment failures in comparison to APAP, the differences observed were not statistically significant (Table 2).

6 6 Clinical Pediatrics Figure 4. Time to onset of temperature control for study 1 (A) and study 2 (B). a P <.01. Subgroup Analyses. Antipyretic efficacy in study 1, as measured by the primary efficacy parameter (i.e., TWSTDs from baseline to 8 hours), significantly favored IBU over APAP regardless of patient age (<4 years of age [P <.001] or 4 years of age [P =.036]), baseline temperature ( F [P =.008] or >102.5 F [P =.002]), or medical diagnosis (i.e., otitis media [P <.001], upper-respiratory infection [URI; P =.011], or other condition [P =.019]). In study 2, the TWSTDs from baseline to 8 hours (P =.036), maximum temperature reduction (P =.016), and onset of temperature control (P <.001) in children 4 years of age significantly favored IBU over APAP. In children <4 years of age, no significant treatment differences were noted between IBU and APAP for any efficacy parameters. Evaluation of the primary efficacy parameter by baseline temperature ( F or >102.5 F) and baseline diagnosis failed to show any treatment differences between IBU and APAP. Pooled Analysis. The Treatment Study interaction was not statistically significant for any parameter. In the pooled analysis, mean (SD) TWSTDs from baseline to 8 hours significantly favored IBU over APAP: 11.1 (8.5) versus 7.6 (8.0), respectively; P <.001 (Figure 2, Table 2). In addition, IBU provided a significantly faster onset of temperature control (95 vs 112 minutes; P <.001) and significantly longer duration of temperature control (191 vs 123 minutes; P =.042) versus APAP (Table 2). Safety and Tolerability Across the 2 individual studies, AEs occurred at similar rates for both treatments, and all were mild to moderate in severity. In study 1, AEs were reported in 6 children (n = 3 per group); only vomiting occurred in more than Table 3. Pooled Adverse Events. a Ibuprofen 7.5 mg/kg (n = 173) mg/kg (n = 160) Patients b 13 (7.5) 12 (7.5) Adverse events Vomiting 8 (4.6) 10 (6.3) Chills 2 (1.2) 2 (1.3) Headache 1 (0.6) 1 (0.6) Abdominal pain 1 (0.6) 0 Diarrhea 0 1 (0.6) Pharyngitis 1 (0.6) 0 Rash 1 (0.6) 0 Urticaria 0 1 (0.6) Eye pain 1 (0.6) 0 a Data are reported as number (%). b Patients reporting any adverse event. 2% of the population (IBU, n = 2 [2.5%]; APAP, n = 3 [3.6%]). In study 2, AEs were reported in 19 children (IBU, n = 10; APAP, n = 9), and only vomiting and chills occurred in more than 2% of the study population (vomiting: IBU, n = 6 [6.5%], APAP, n = 7 [9.1%]; chills: IBU, n = 2 [2.2%], APAP, n = 2 [2.6%]). Pooled AE results are summarized in Table 3. In total, 7.5% of patients in each treatment group had AEs. In the IBU group, 1 incidence each of headache, vomiting, and rash were considered related to the study drug. In the APAP group, 3 incidences of vomiting were considered related to the study drug. Discussion Study 1 showed a clear advantage and statistical superiority of IBU suspension (7.5 mg/kg) over APAP

7 Jayawardena and Kellstein 7 suspension (10-15 mg/kg) in reducing fever in children, with a faster onset of temperature control, greater maximum and overall temperature reduction, and longer duration of effect. In study 2, IBU was associated with non-significant numerical advantages versus APAP for most efficacy parameters, with the exception of a significantly faster onset of temperature control noted with IBU treatment. Despite the lack of statistical separation between IBU and APAP on most efficacy parameters in study 2, the consistent numerical advantages favoring IBU support findings from study 1. The 2 studies described herein were very similar in design, but 2 differences may have contributed to the statistical separation of active treatments (i.e., greater sensitivity) that was observed in study 1 but not in study 2. First, study 1 was conducted at a single site, whereas study 2 was conducted at multiple sites (1 primary site and 12 satellite sites) to increase the rate of participant enrollment. Second, all temperature measurements in study 1 were conducted at the study site by trained site personnel, whereas study 2 allowed assessments performed after hour 1 to be conducted by a health care professional at the patient s home. The greater number of study sites in study 2 as well as the off-site pain assessments in that same study may have contributed to greater variability in results because of differences in post-treatment care, temperature-measuring techniques, and timing of study measurements and may have played a role in the lack of statistical separation between IBU and APAP in study 2. Combining the 2 studies in a pooled analysis provided additional power to detect treatment differences between the 2 medications and suggests superiority of IBU over APAP in the treatment of pediatric fever. The results observed in these studies are consistent with those observed in previous comparisons of IBU and APAP, in which IBU was associated with faster onset, greater magnitude, and/or a longer duration of temperature reduction compared with APAP In addition, it should be noted that the doses evaluated in the current studies are identical to the labeled doses in the United States and Canada for both products. The results of the current studies are consistent with literature reviews and meta-analyses. A 2004 meta-analysis of 10 randomized, blinded trials that compared single doses of IBU (5-10 mg/kg) and APAP (10-15 mg/kg) in those younger than 18 years of age with pain or fever reported a significantly greater effect of IBU on temperature reduction over 6 hours compared with APAP. 5 In a more recent meta-analysis and qualitative review of 30 pediatric studies comparing IBU versus APAP in pediatric fever, Pierce and Voss 11 found that IBU provided superior antipyretic efficacy to APAP in 15 of the studies reviewed, whereas no significant treatment differences in fever reduction were noted in the remaining 15 studies. In the randomized controlled studies for which a standardized mean difference was able to be calculated (i.e., in 7 of 30 studies), results indicated significantly better control of fever at 4 hours after dosing with IBU in comparison with APAP. The safety and tolerability of short-term treatment with IBU pediatric suspension in generally healthy children with fever is well established, 2,3,5,7,9,12,13 and results from our studies are supportive of these findings. Importantly, the antipyretic efficacy advantages of IBU, exemplified by a faster, stronger, and longer duration of temperature reduction, are not negated by a compromised safety and tolerability profile. This fact is evidenced by 3 meta-analyses comparing the 2 products in the pediatric population. 5,11,14 Perrott et al 5 analyzed data from 17 pediatric trials and found no difference in the risk of minor or major harm with IBU versus APAP. In their analysis of systemic AEs from 18 pediatric studies, Southey et al 14 found no increase in the risk ratio for experiencing an AE with IBU versus APAP or for IBU versus placebo. A large, randomized trial in 84,192 children found no difference in terms of all-cause hospitalization, nor was there any evidence of increased rates of acute gastrointestinal bleeding with IBU versus APAP. 15 Furthermore, in a review of safety data from 31 pediatric studies comparing IBU with APAP, Pierce and Voss 11 found no statistically significant safety/tolerability differences between the 2 products in 30 of 31 studies, whereas 1 reported an advantage for APAP. In a meta-analysis of 19 of these 31 studies, there were no significant differences in the proportion of children reporting AEs with IBU versus APAP. 11 Conclusions The results of our studies indicate that IBU suspension (7.5 mg/kg) provides greater antipyretic efficacy than APAP suspension (10-15 mg/kg) in the treatment of pediatric fever. Pooled analysis of both studies showed that IBU provides faster, greater, and longer temperature reduction than APAP. In addition, IBU had a safety profile comparable with APAP. Acknowledgments Medical writing support was provided by Autumn Kelly, MA, and John H. Simmons, MD, of Peloton Advantage, LLC, and was funded by Pfizer. Authors Note These studies predated trial registration requirements.

8 8 Clinical Pediatrics Author Contributions Data analysis/interpretation: SJ, DK Statistical analyses: SJ Manuscript preparation: DK Critical revision and review of the manuscript: SJ, DK Approval of final draft for submission: SJ, DK Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: DK is an employee and SJ is a former employee of Pfizer Consumer Healthcare. Funding The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: These studies were sponsored by Whitehall-Robins Healthcare, currently Pfizer Consumer Healthcare. Medical writing support was provided by Autumn Kelly, MA, and John H. Simmons, MD, of Peloton Advantage, LLC, and was funded by Pfizer. References 1. Consolini DM. Fever in infants and children. Merck Manuals pediatrics/symptoms-in-infants-and-children/fever-ininfants-and-children. Accessed July 27, Sullivan JE, Farrar HC. Fever and antipyretic use in children. Pediatrics. 2011;127: Sarrell EM, Wielunsky E, Cohen HA. Antipyretic treatment in young children with fever: acetaminophen, ibuprofen, or both alternating in a randomized, double-blind study. Arch Pediatr Adolesc Med. 2006;160: Richardson M, Lakhanpaul M. Assessment and initial management of feverish illness in children younger than 5 years: summary of NICE guidance. BMJ. 2007;334: Perrott DA, Piira T, Goodenough B, Champion GD. Efficacy and safety of acetaminophen vs ibuprofen for treating children s pain or fever: a meta-analysis. Arch Pediatr Adolesc Med. 2004;158: Medscape. Ibuprofen (Rx, OTC). medscape.com/drug/advil-motrin-ibuprofen Accessed July 27, Kauffman RE, Sawyer LA, Scheinbaum ML. Antipyretic efficacy of ibuprofen vs acetaminophen. Am J Dis Child. 1992;146: Autret E, Breart G, Jonville AP, Courcier S, Lassale C, Goehrs JM. Comparative efficacy and tolerance of ibuprofen syrup and acetaminophen syrup in children with pyrexia associated with infectious diseases and treated with antibiotics. Eur J Clin Pharmacol. 1994;46: Hay AD, Redmond NM, Costelloe C, et al. Paracetamol and ibuprofen for the treatment of fever in children: the PITCH randomised controlled trial. Health Technol Assess. 2009;13(27):iii-x, Wilson JT, Brown RD, Kearns GL, et al. Single-dose, placebo-controlled comparative study of ibuprofen and acetaminophen antipyresis in children. J Pediatr. 1991;119: Pierce CA, Voss B. Efficacy and safety of ibuprofen and acetaminophen in children and adults: a metaanalysis and qualitative review. Ann Pharmacother. 2010;44: Lesko SM, Mitchell AA. The safety of acetaminophen and ibuprofen among children younger than two years old. Pediatrics. 1999;104:e Walson PD, Galletta G, Chomilo F, Braden NJ, Sawyer LA, Scheinbaum ML. Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. Am J Dis Child. 1992;146: Southey ER, Soares-Weiser K, Kleijnen J. Systematic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever. Curr Med Res Opin. 2009;25: Lesko SM, Mitchell AA. An assessment of the safety of pediatric ibuprofen: a practitioner-based randomized clinical trial. JAMA. 1995;273: