Acetaminophen and ibuprofen in the treatment of pediatric fever: a narrative review

Abstract

Objective

A narrative review of randomized, blinded, controlled studies assessing the antipyretic effect of ibuprofen versus acetaminophen or combined or alternating treatment in children was conducted.

Methods

Searches of the PubMed and Embase literature databases were conducted to identify relevant articles. Selected articles were limited to studies published in English that investigated OTC oral tablet and syrup formulations of acetaminophen and ibuprofen; there were no publication date limits. Open-label studies, nonrandomized studies, and those evaluating intravenous or suppository formulations of acetaminophen or ibuprofen were excluded. Variations in designs, endpoints, methods, and patient populations precluded our ability to conduct a formal systematic review.

Results

At physician-directed dosing (acetaminophen 15 mg/kg vs ibuprofen 10 mg/kg), no significant differences in antipyretic effects from 0‒6 h and between 0‒6, ‒12, ‒24, or ‒48 h, with single or multiple-doses, respectively, were observed. Tolerability profiles at physician dosing were similar. In 14 over-the-counter dose comparisons (acetaminophen, 10–15 mg/kg; ibuprofen, 2.5–10 mg/kg), antipyresis favored ibuprofen in 6, was similar between groups in 7, and favored acetaminophen (15 mg/kg vs ibuprofen 5 mg/kg) in 1 comparison. Both medications were well tolerated. Efficacy favored combination over individual components in 3 of 4 studies; alternating use results were mixed. All combination or alternating treatments were well tolerated.

Conclusions

Antipyretic effects of ibuprofen and acetaminophen are similar at physician-directed doses; ibuprofen may be modestly superior at over-the-counter doses.

Keywords:

• Acetaminophen
• ibuprofen
• combination therapy
• alternating therapy
• paracetamol
• pediatric fever
• antipyresis

Introduction

Fever in children is generally a benign process that, in and of itself, does not require treatment in the absence of underlying disease that may reduce tolerance to fever¹. However, when fever causes discomfort and distress, it can lead to parental concern¹. In this setting, acetaminophen (paracetamol) and ibuprofen are over-the-counter (OTC) antipyretics that are commonly used for relief of fever and associated discomfort².

Ibuprofen impacts a variety of inflammatory pathways and cellular systems via nonselective and reversible inhibition of cyclooxygenase (COX) isoenzymes³. COX-1 is a constitutive enzyme that catalyzes the production of prostanoids and thromboxane A2 from arachidonic acid, compounds involved in a range of physiological functions that regulate vascular, gastric, and renal function. COX-2 is an inducible isoenzyme whose activity is increased in painful and inflammatory conditions, leading to increased production of prostaglandin E2, the key mediator of fever in humans³. In contrast, the mechanism of action of acetaminophen is still unknown although preclinical studies have provided evidence of COX inhibition centrally⁴, and other data have shown that the antinociceptive effects of acetaminophen involve activation of descending spinal serotonergic pathways⁵.

The American Academy of Pediatrics clinical report on antipyretic use in children summarizes the individual antipyretic effects of acetaminophen and ibuprofen and makes recommendations for pediatric dosing². Both drugs are more effective than placebo in reducing fever at physician-directed doses (acetaminophen, 15 mg/kg every 4 h; ibuprofen, 10 mg/kg every 6 h), and there is no evidence suggesting a significant difference in safety at these doses². In addition, both medications are available OTC for use at 10–15 mg/kg doses for acetaminophen and 5–10 mg/kg doses for ibuprofen.

Ibuprofen has a favorable overall safety profile in a range of acute and chronic pain and inflammatory conditions^3,6. However, ibuprofen has also been associated with renal and hepatic adverse events, depending on the dose, concomitant use of other medications, comorbidities, and patient population^3,6,7. In children, the most common ibuprofen-related adverse events were gastrointestinal (nausea, vomiting, abdominal pain, diarrhea, constipation, dyspepsia, and flatulence)⁸. Rarer (<0.01%), potentially life-threatening gastrointestinal adverse events were peptic ulcers, gastric hemorrhage, and gastric perforation⁸. Renal adverse events associated with ibuprofen are rare (<0.01%) and include acute kidney failure, interstitial nephritis, and, with long-term use, papillary necrosis⁸. Acetaminophen has an established record of safety when taken according to the recommended therapeutic dose range⁹. However, the use of acetaminophen at levels exceeding the maximum daily dose is a well-document leading cause of hepatotoxicity and acute liver failure^7,10.

While acetaminophen and ibuprofen are effective as antipyretics individually, they have also been used in combined or alternating regimens, with some authors suggesting that the combination is more effective than either agent alone¹¹. Indeed, combination use of acetaminophen and ibuprofen has gained traction with pediatricians; caregivers commonly coadminister acetaminophen and ibuprofen^12,13. Their combined use can be well tolerated when both are taken as directed¹³. Unfortunately, concerns exist regarding potential dosing errors that lead to unintentional overdose with these more complicated regimens. A recent systematic literature review and meta-analysis of 199 cases of repeated supratherapeutic acetaminophen ingestion found that liver failure occurred in 127/199 (64%), and of these, 49 (39%) died, despite the fact that the reported dose taken was below the 24-h total daily allowance in 28% of the cases¹⁴. In contrast, ibuprofen overdose is associated with few significant clinical sequelae, although severe side effects, including rare cases of death, have been reported^15–17.

While both acetaminophen and ibuprofen have been extensively studied and have well-established efficacy and safety profiles, there have been few studies comparing the antipyretic efficacy of the 2 drugs for the management of childhood fever. Here we review studies comparing acetaminophen versus ibuprofen at physician-directed doses (acetaminophen, 15 mg/kg; ibuprofen, 10 mg/kg), as well as comparative studies assessing approved OTC doses (acetaminophen, 10–15 mg/kg; ibuprofen, 5–10 mg/kg). Additionally, the current state of evidence for both combined and alternating use of acetaminophen and ibuprofen in the treatment of pediatric fever is reviewed.

Methods

Searches of the PubMed and Embase literature databases were conducted to identify relevant articles to include in this narrative review. The following search terms were employed individually and in combination: acetaminophen (including APAP, paracetamol), alternating dosing, antipyretic, antipyretic agents, antipyretic/analgesic agents, combined dosing, comparative studies, efficacy, fever, ibuprofen, ibuprofen/acetaminophen combination product, multiple/multi-dose, over-the-counter, pediatric, randomized studies, safety, and single dose. Selected articles were limited to studies published in English that investigated OTC oral tablet and syrup formulations of acetaminophen and ibuprofen; there were no publication date limits. Open-label studies, nonrandomized studies, and those evaluating intravenous or suppository formulations of acetaminophen or ibuprofen were excluded. Variations in designs, endpoints, methods, and patient populations precluded our ability to conduct a formal systematic review.

Results

Single-dose studies

A total of 9 publications detailing 10 single-dose pediatric studies, including treatment at both physician-directed dosing and OTC doses, were identified and are summarized in Table 1^18–26. These included 1 single-dose pediatric study at physician-directed doses and 9 studies comparing single-dose treatment with acetaminophen and ibuprofen at OTC doses (acetaminophen range of 9.8–15 mg/kg; ibuprofen range of 5‒10.3 mg/kg). These studies had variable designs, endpoints, methods of temperature measurement, doses, medication formulations, and patient populations. The specific doses and formulations of ibuprofen and acetaminophen employed in these studies are summarized in Table 1.

Table 1. Summary of single-dose studies comparing acetaminophen versus ibuprofen at physician-directed and over-the-counter dosing strengths.

Author, year	Study design; temperature measurement technique; study duration	Dose; n		Primary outcome result	Key secondary outcome result	Adverse events
		Acetaminophen; N	Ibuprofen; N
Single-dose comparison of acetaminophen vs ibuprofen at physician-directed dosing
Autret-Leca et al. 2007^18	Randomized, double-blind, parallel-group; Tympanic; 8 h	15 mg/kg; n = 150	10 mg/kg; n = 151	Area under the temperature reduction curve from 0–6 h: Acetaminophen = ibuprofen	For (1) area under the temperature reduction curve from 0‒4 and 0‒8 h; (2) individual temperature readings at each time point from 30 min to 8 h; (3) time to recurrence of a temperature > 38.5 °C; (4) time to reach a temperature of  ≤ 38 °C; (5) time to maximal temperature reduction and time to reach apyrexia (≤37.4 °C): Acetaminophen = ibuprofen For parental global assessment: Ibuprofen > acetaminophen (p < .001 after double-blind period and p < .01 after the open-label period)	Ibuprofen: 11.2% of patients Acetaminophen: 10.6% of patients
Single-dose comparisons of acetaminophen vs ibuprofen at over-the-counter dosing
Jayawardena and Kellstein^19	Randomized, double-blind, parallel-group; Oral, rectal; 8 h for each study	10–15 mg/kg: Study 1, n = 82; Study 2, n = 74	7.5 mg/kg: Study 1, n = 78; Study 2, n = 85	TWSTD0–8 : Study 1: Ibuprofen >  acetaminophen (p<.001) Study 2: Acetaminophen  = ibuprofen Studies 1 and 2 pooled: Ibuprofen > acetaminophen (p<.001)	TWSTD0–2, 0–4, 0–6: Ibuprofen > acetaminophen (Study 1, p = .015 at 2 h; p<.001 at 4 and at 6 h) Maximum temperature difference from baseline: Ibuprofen > acetaminophen, (Study 1, p < .001) Greater temperature reductions 1–8 h: Ibuprofen >  acetaminophen (Study 1, p < .05 for each) Faster onset of temperature control: Ibuprofen >  acetaminophen (Study 1, p=.003; Study 2, p=.007) Longer duration of temperature control: Ibuprofen > acetaminophen (Study 1, p < .001) Treatment failures: Ibuprofen > acetaminophen (Study 1, p = .018 at 8 h) Longer time to treatment failure: Ibuprofen > acetaminophen (Study 1, p = .015) Faster onset temperature control: Ibuprofen > acetaminophen (pooled, p < .001) Longer duration of temperature control: Ibuprofen > acetaminophen (pooled, p = .042)	Pooled AE rates: Ibuprofen, 7.5% of patients Acetaminophen, 7.5% of patients; Most common AE was vomiting: 6.3% with acetaminophen; 4.6% with ibuprofen; NS
Figueras Nadal et al.^20	Double-blind, double-dummy; Tympanic; 8 h	10.7 mg/kg , n = 87	6.7 mg/kg, n = 88	Mean temperature change at 4 h: Acetaminophen = ibuprofen	For (1) percentage of patients with temperature reduction at 4 h; (2) maximum temperature decrease; (3) mean time to apyrexia; (4) patients with temperature reduction of ≥ 1.5 °C; and (5) percentage of patients reaching normal temperature: Acetaminophen  = ibuprofen For temperature reduction of ≥ 2 °C: Ibuprofen >  acetaminophen (p = .043)	AEs occurred in 10.0% of patients taking ibuprofen and 9.1% of patients taking acetaminophen. Twelve patients vomited within 30 min of receiving medication (acetaminophen, 5; ibuprofen, 7)
Wong et al.^21	Randomized, double-blind, parallel-group; Tympanic; 6 h	12 mg/kg, n = 210	5 mg/kg for temperature < 39.2 °C; 10 mg/kg for temperature ≥ 39.2 °C; n = 209 total	Percentage achieving ≥ 1.5 °C reduction from baseline in tympanic membrane temperature: Acetaminophen = ibuprofen	For 1) time to achieve 1.5 °C reduction or 2) time to normalization of temperature: Acetaminophen = ibuprofen For percentage achieving ≤ 37.5 °C (i.e. temperature normalization): Ibuprofen > acetaminophen (p=.004)	Ibuprofen, n = 22; Acetaminophen, n = 19; NS
Vauzelle-Kervroëdan et al.^22	Randomized, double-blind; Rectal; 6 h	9.8 ± 1.9 mg/kg, n = 56	10.3 ± 1.9 mg/kg, n = 60	Time to the lowest observed temperature between 0–6 h: Acetaminophen = ibuprofen	For (1) extent of temperature decrease; (2) rate of temperature decrease; (3) duration of temperature < 38.5 °C; 4) percentage of children whose temperature fell < 38.5 °C: Acetaminophen = ibuprofen	Vomiting: Ibuprofen, 0% acetaminophen, 3.6%
Kauffman et al.^23	Randomized, double-blind, placebo-controlled (placebo, n = 9), double-dummy; Oral; 8 h	10 mg/kg, n = 8	7.5 mg/kg, n = 12; 10 mg/kg, n = 8	Antipyresis vs placebo: Significant for acetaminophen at hours 3‒5 (p ≤ .05); significant for both ibuprofen doses at hours 1‒6 (p ≤ .05): Ibuprofen 7.5 mg/kg > acetaminophen 10 mg/kg at hours 3‒5 (p≤ .05)	For (1) faster onset; (2) greater maximum temperature reduction; (3) longer duration of action: Ibuprofen >  acetaminophen (p≤.05)	No AEs or laboratory abnormalities were attributed to either of the 2 treatments
Wilson et al.^24	Randomized, double-blind, placebo-controlled (placebo, n = 22); Rectal; up to 12 h	12.5 mg/kg, n = 52	5 mg/kg, n = 43; 10 mg/kg, n = 47	Temperature reduction at 4 h: Ibuprofen 10 mg/kg > ibuprofen 5 mg/kg and > acetaminophen (p≤ .05)	Ibuprofen 10 mg/kg had longest duration of action than any other group (p ≤ .05); For area under the curve measures for (1) temperature; (2) change in temperature; and (3) Percentage achieving antipyresis: Ibuprofen 10 mg/kg > ibuprofen 5 mg/kg and acetaminophen 12.5 mg/kg (p ≤ .05)	Ibuprofen 10 mg/kg, n = 1 event (transient hypothermia without sequelae in the context of profuse night sweats from pulmonary tuberculosis); Ibuprofen 5 mg/kg, n = 1 event (transient hypothermia (< 97 °F) that occurred 12 h after dosing; Acetaminophen, n = 0 events; Placebo, n = 0 events.
Sidler et al.^25	Randomized, double-blind, parallel-group; Rectal; up to 24 h	10 mg/kg, n = 30	7 mg/kg, n = 30; 10 mg/kg, n = 29	Temperature reduction at 3 h: Ibuprofen 10 mg/kg > acetaminophen (p ≤ 0.01); Ibuprofen 7 mg/kg > acetaminophen (p≤.05)	Percentage achieving ≥ 1 °C reduction: Acetaminophen  = ibuprofen	Ibuprofen 7 mg/kg, n = 3 (10%) patients (vomiting, abdominal pain, rash) Ibuprofen 10 mg/kg, n = 1 (3.4%) patients (hypothermia) Acetaminophen, 10 mg/kg, n = 2 (6.7%) patients (vomiting in both)
Walson et al.^26	Randomized, double-blind, placebo-controlled (placebo, n = 34), parallel-group; Oral, rectal; 8 h	10 mg/kg, n = 33	5 mg/kg, n = 32; 10 mg/kg, n = 28	Area under the percentage reduction time curve at 4, 6, and 8 h: Ibuprofen 10 mg/kg > acetaminophen 10 mg/kg (p<.05 for each time point); acetaminophen 10 mg/kg = ibuprofen 5 mg/kg	For oral temperature > 102.5 °F, antipyretic efficacy ranking was ibuprofen 10 mg/kg > ibuprofen 5 mg/kg > acetaminophen 10 mg/kg > placebo	Mild drug-related GI AEs in 31% treated with ibuprofen 5 mg/kg, 21% of those treated with ibuprofen 10 mg/kg, 18% of those treated with acetaminophen 10 mg/kg, and 6% of those treated with placebo; NS

Abbreviations. AE, adverse event; GI, gastrointestinal; NR, not reported; NS, not significant; q6h, every 6 h; TWSTD 0–2/4/6/8, time-weighted sum of temperature differences from baseline through 2/4/6/8 h.

Physician-directed dosing

One study, by Autret-Leca and colleagues, compared single-dose treatment with acetaminophen and ibuprofen when administered according to physician-directed dosing¹⁸. This randomized, double-blinded study was conducted in children aged 3 months to 12 years with fever of non-serious origin who were followed over 8 h after treatment administration. Subsequent doses given over 3 additional days (acetaminophen up to 4 times daily or ibuprofen up to 3 times daily) were administered by parents in an open-label manner. No significant difference between the acetaminophen and ibuprofen groups was observed for the area under the temperature reduction curve from 0 − 6 h (AUC_0–6h; primary endpoint), expressed as an absolute difference in tympanic temperature from baseline; mean AUC_0–6h was −7.77 ± 3.54 °C minutes with ibuprofen and −7.66 ± 3.76 °C minutes with acetaminophen (p = .82). At the end of the double-blind phase, open-label first-dose efficacy was rated as “very efficacious” by 59.2% of parents of children given ibuprofen compared with 37.2% of the parents of children given acetaminophen (p < .001 for the treatment difference).

OTC dosing

A total of 8 publications detailing 9 single-dose treatment studies of acetaminophen versus ibuprofen at OTC doses (acetaminophen range of 9.8–15 mg/kg; ibuprofen range of 5‒10.3 mg/kg) were identified (Table 1) ^19–26.

In 5 of the 9 studies identified, ibuprofen provided significantly greater temperature reductions than acetaminophen^19,23–26. In the first of 2 randomized, double-blind studies reported by Jayawardena and Kellstein¹⁹ that compared ibuprofen 7.5 mg/kg with acetaminophen 10−15 mg/kg in patients aged 6 months to 11 years with fever, ibuprofen 7.5 mg/kg provided a significantly better mean (standard deviation [SD]) time-weighted sum of temperature differences from baseline to 8 h of −10.5 (7.3) versus −5.7 (7.3) with acetaminophen. Kauffman et al.²³ conducted a randomized, double-blind, placebo-controlled study comparing the efficacy of suspensions of acetaminophen and ibuprofen in febrile children aged 2–12 years of age. Temperature reductions versus placebo were significant for acetaminophen 10 mg/kg at hours 3–5 and for ibuprofen at hours 1–6 (p ≤ .05), with ibuprofen 7.5 mg/kg treatment producing a significantly (p ≤ .05) greater oral temperature reduction than acetaminophen at hours 3–5. Ibuprofen 10 mg/kg resulted in a temperature reduction that was achieved significantly earlier, was of greater magnitude, and lasted longer than with acetaminophen (all p ≤ .05). A double-blind, parallel-group study conducted by Sidler and colleagues²⁵ compared the efficacy of acetaminophen syrup with ibuprofen syrup over 12–24 h in febrile (rectal temperature ≥38.5 °C) hospitalized children aged 5 months to 13 years. The mean temperature reduction observed from baseline to 3 h (the primary efficacy endpoint) was significant for all groups but was significantly lower with ibuprofen (either dose) compared with acetaminophen (p ≤ .05 for ibuprofen 7 mg/kg and p ≤ .01 for ibuprofen 10 mg/kg, vs acetaminophen 10 mg/kg). There were no apparent differences in the clinical condition of the patients at 3 h or over time between the 2 treatments. However, more patients receiving acetaminophen than ibuprofen 7 mg/kg or 10 mg/kg required a second dose of antipyretic treatment (59% vs 38% vs 44%, respectively²⁵. Wilson et al.²⁴ evaluated the single-dose efficacy of ibuprofen and acetaminophen in febrile children aged 3 months to 12 years in a placebo-controlled, modified double-blind study. Although both acetaminophen 12.5 mg/kg and ibuprofen 5 mg/kg were significantly better than placebo in terms of fever reduction, there was no difference between the 2 treatment arms. However, ibuprofen 10 mg/kg was associated with a significantly greater reduction in temperature versus both acetaminophen 12.5 mg/kg and ibuprofen 5 mg/kg at 4 h (p ≤ .05). Similarly, Walson et al.²⁶ compared the efficacy, tolerability, and dose-response of acetaminophen and ibuprofen in febrile children aged 2–11 years in a double-blind, placebo-controlled study. Following single-dose administration, ibuprofen 10 mg/kg lowered temperatures significantly more than acetaminophen 10 mg/kg for the group as a whole (p < .05), as well as in a subgroup of patients with higher temperatures (> 102.5 °F) at baseline. No significant differences between treatments were observed in fever reduction after single-dose acetaminophen 10 mg/kg compared with single-dose ibuprofen 5 mg/kg.

No difference in antipyretic efficacy was observed in 4 of 9 studies comparing acetaminophen and ibuprofen^19–22. In a double-blind study by Figueras Nadal and colleagues²⁰, which compared single oral doses of acetaminophen and ibuprofen in hospitalized children aged 6 months to 12 years, there was no significant difference between groups for the primary efficacy endpoint of mean (SD) change in tympanic temperature at 4 h (acetaminophen, 1.2 °C [0.96]; ibuprofen, 1.3 °C [1.1]) or at any other time up to 8 h. More patients taking ibuprofen had a ≥ 2 °C reduction in temperature compared with the number achieving this outcome with acetaminophen (p = .043). No differences in irritability, somnolence, or food rejection were noted between treatment groups, with all of these symptoms improving over the first 4 h in both groups²⁰. In the prospective, randomized, double-blind study by Wong et al.²¹ in febrile children aged 6 months to 6 years, the primary endpoint of a tympanic temperature reduction of ≥ 1.5 °C from baseline was achieved by similar percentages of patients across treatment groups (acetaminophen, 77%; ibuprofen, 83%). However, more patients taking ibuprofen reached a temperature <37.5 °C (ibuprofen, 78%, acetaminophen, 68%; p = 004)²¹. Vauzelle-Kervroëdan et al.²² conducted a randomized, double-blind study comparing the efficacy of acetaminophen granules 9.8 ± 1.9 mg/kg versus ibuprofen granules 10.3 ± 1.9 mg/kg in children (N = 116) aged 8 months to 12 years (average, 4.1 ± 2.6 years) with fever due to viral or bacterial infection. Study medications were administered in a spoonful of yogurt, cream cheese, or stewed fruit. The time required to achieve the lowest observed rectal temperature between 0 and 6 h (primary efficacy endpoint) was not different between groups (acetaminophen, 3.65 ± 1.47 h; ibuprofen, 3.61 ± 1.34 h); in addition there were no significant differences observed between treatments in the extent or rate of temperature decrease, duration of time with temperature < 38.5 °C, or the number of children with temperatures < 38.5 °C.

Multiple-dose studies

One multi-dose study compared physician-directed doses and OTC doses of acetaminophen and ibuprofen²⁷, and 4 others^28–31 compared multiple doses of the 2 medications at OTC doses (Table 2). As was the case in the single-dose studies, these studies utilized variable designs, endpoints, methods of temperature measurement, medication formulations, and patient populations. OTC doses studied were 10–15 mg/kg/dose for acetaminophen and 2.5–10 mg/kg/dose for ibuprofen. The exact doses and formulations used in these trials are summarized in Table 2. All 6 multiple-dose studies utilized an every-6-h dosing interval.

Table 2. Summary of multiple-dose studies comparing acetaminophen versus ibuprofen at physician-directed and over-the-counter dosing strengths.

Author, year	Study design; temperature measurement technique; study duration	Dose; n		Primary outcome result	Key secondary outcome result	Adverse events
		Acetaminophen; N	Ibuprofen; N
Multiple-dose comparisons of acetaminophen vs ibuprofen at physician-directed dosing
Walson et al.^27	Randomized, double-blind, parallel-group Oral, rectal; up to 48 h	15 mg/kg q6h, n = 16	10 mg/kg q6h, n = 15	Temperature reduction 0–6 h: Ibuprofen 10 mg/kg = acetaminophen 15 mg/kg	Temperature reduction at 0‒12, 0‒24, and 0‒48 h: Ibuprofen 10 mg/kg = acetaminophen 15 mg/kg	Ibuprofen groups combined, most common AEs were sweating (n = 8); GI (n = 7); Acetaminophen, most common AEs were hypothermia (n = 3); abdominal pain (n = 3); agitation and/or nervousness (n = 3)
Multiple-dose comparisons of acetaminophen vs ibuprofen at over-the-counter dosing
Vinh et al.^28	Randomized, double-blind; Axillary; until 36 h after defervescence	12 mg/kg q6h, n = 40	10 mg/kg q6h, n = 40	Fever “clearance”: Acetaminophen = ibuprofen	Temperature duration and severity: Ibuprofen > acetaminophen (p = .013)	Ibuprofen, n = 13 (32.5%); Acetaminophen, n = 7 (17.5%; p = .12; NS)
McIntyre and Hull,^29	Double-blind, parallel-group; Axillary; maximum of 3 days	50 mg/kg/24 h (i.e. 12.5 mg/kg q6h), n = 74	20 mg/kg/24 h (i.e. 5 mg/kg q6h); n = 76	Change in temperature at 4 h: Acetaminophen = ibuprofen	Distribution of times until temperature fell below 37.5 °C and distribution of times to second dose: Acetaminophen = ibuprofen	Ibuprofen AE rate, 13% (when administered at the minimal dosing level of 5 mg/kg); Acetaminophen AE rate, 19% (when administered at full over-the-counter dosing level; p = .34, NS) 8 acetaminophen- and 7 ibuprofen-treated patients withdrew from the study due to AEs or lack of efficacy
Van Esch et al.^30	Randomized, double-blind, crossover; Rectal; 24 h	10 mg/kg q6h, n = 36	5 mg/kg q6h, n = 34	Temperature at 4 h after first dose: Ibuprofen > acetaminophen (p = .05; p = .04 after adjusting for covariates)	Mean and highest temperature during treatment: Acetaminophen = ibuprofen	14 AEs recorded in 9 patients overall; 8 occurred with acetaminophen and 6 with ibuprofen
Autret et al.^31	Randomized, double-blind, parallel-group Rectal; 72 h	10 mg/kg q6h, n = 74	7.5 mg/kg q6h, n = 77	Area under the percentage reduction in temperature curve from 1–12 h: Acetaminophen = ibuprofen	Percentage temperature reduction from 0–4 h: Ibuprofen > acetaminophen (p<.04) Mean temperature reduction from 0‒4 h and time to maximum antipyresis: Acetaminophen = ibuprofen	Ibuprofen, 9 patients (11.7%): 5 with GI symptoms 3 skin reactions, 1 epistaxis Acetaminophen, 5 (6.5%): 2 with GI symptoms, 2 skin reactions, 1 epistaxis
Walson et al.^27	Randomized, double-blind, parallel-group Oral, rectal; up to 48 h	15 mg/kg q6h, n = 16	2.5 mg/kg q6h, n = 15; 5 mg/kg q6h, n = 15	Temperature reduction 0–6 h: Ibuprofen 10 mg/kg > ibuprofen 2.5 mg/kg and 5 mg/kg; acetaminophen 15 mg/kg > ibuprofen 2.5 mg/kg (p<.05)	Temperature reduction at 0‒12, 0‒24, and 0‒48 h: Acetaminophen 15 mg/kg > ibuprofen 5 mg/kg at 0‒12 and 0‒24 h (p < .05 for each), but not at 0‒48 h	Ibuprofen groups combined, most common AEs were sweating (n = 8); GI (n = 7); Acetaminophen, most common AEs were hypothermia (n = 3); abdominal pain (n = 3); agitation and/or nervousness (n = 3)

Abbreviations. AE, adverse event; GI, gastrointestinal; NR, not reported; NS, not significant; q6h, every 6 h.

Physician-directed dosing

Walson et al.²⁷ reported the results of a block-randomized, double-blind study comparing the efficacy and safety of acetaminophen 15 mg/kg and ibuprofen 2.5 mg/kg, 5 mg/kg, or 10 mg/kg administered every 6 h for 24–48 h in febrile children aged 6 months to 11 years, 7 months. In the comparison of acetaminophen 15 mg/kg with ibuprofen 10 mg/kg, there were no differences in mean oral or rectal temperature reduction at any time interval (0‒6, 0‒12, 0‒24, or 0‒48 h after treatment) tested²⁷.

OTC dosing

Five multiple-dose comparisons of acetaminophen versus ibuprofen in pediatric fever at OTC doses were found. In 3 of the studies^28,29,31, acetaminophen and ibuprofen showed similar efficacy as antipyretics. Vinh et al.²⁸ conducted a double-blind comparison of acetaminophen syrup 12 mg/kg and ibuprofen syrup 10 mg/kg administered every 6 h for up to 36 h after defervescence in children (N = 80) aged 2–14 years hospitalized with uncomplicated typhoid fever. On the primary efficacy measure, median axillary fever clearance time was reduced by 35% with ibuprofen (68 h) versus with acetaminophen (104 h), but the difference did not reach statistical significance (p = .055). The duration/severity of fever as measured by the area under the temperature-time curve was reduced with ibuprofen by 42% compared with acetaminophen (74 h vs 127 h, respectively; p = .013). Similarly, McIntyre and Hull²⁹ found no difference between ibuprofen and acetaminophen in the change from baseline temperature at 4 h in hospitalized febrile children aged 2 months to 12 years. Likewise, there were no significant differences in time to axillary temperature below 37.5 °C or time until second dose. Significantly more patients who received acetaminophen experienced improvements in irritability scores than those who received ibuprofen (38% vs 18%, respectively; p = .047). A study by Autret et al.³¹ in children aged 6 months to 5 years hospitalized with fever associated with infectious diseases and treated with antibiotics found no significant difference between acetaminophen and ibuprofen in the area under the temperature reduction curve during the first 12 h after treatment (95% CI: −21.3, 115.7).

In the remaining 2 studies, results were mixed. In a randomized, double-blind, crossover study in children aged 10 months to 4 years with febrile seizures, Van Esch et al.³⁰ found that ibuprofen reduced rectal temperatures more than acetaminophen at the primary endpoint of 4 h (p = .05; p = .04 after adjusting for covariates). Finally, in the study by Walson and colleagues²⁷ detailed above, OTC dose comparisons were also studied. Ibuprofen 10 mg/kg was associated with a significantly greater percent temperature reduction at 0–6 h (p < .05) versus ibuprofen 2.5 mg/kg and ibuprofen 5 mg/kg. Acetaminophen 15 mg/kg was associated with significantly greater fever reduction versus ibuprofen 2.5 mg from hours 0‒6 and versus ibuprofen 5 mg/kg during the 0- to 12- and 0- to 24-h intervals (p < .05 for each) but not over the interval of 0‒48 h versus ibuprofen 5 mg/kg.

Combination studies

The possibility of drug-drug interactions between acetaminophen and ibuprofen has raised concerns regarding patient safety. However, the likelihood of drug-drug interactions when co-administered is low. Acetaminophen and ibuprofen have different mechanisms of action^3,5,32 and follow different metabolic pathways^33,34. Furthermore, pharmacokinetic studies have revealed no alterations in individual plasma drug concentrations when the 2 agents were administered together^35–39. Given the potential for drug-drug interactions involving acetaminophen or ibuprofen with other agents (e.g. aspartame or diuretics), it is important that the healthcare provider consider the patient's medical history and that caregivers communicate with the healthcare provider and pharmacist regarding the patient's past or current medical treatments, dietary restrictions, and conditions. Four studies were identified in which the combined use of acetaminophen and ibuprofen in pediatric fever was reported; the dosing and formulations of ibuprofen and acetaminophen used in these studies are summarized in Table 3^11,40–42.

Table 3. Studies of combination acetaminophen and ibuprofen administration.

Author, year	Study design; temperature measurement technique; study duration	Dose; n			Primary outcome result	Key secondary outcome result	Adverse events
		Acetaminophen; N	Ibuprofen; N	Acetaminophen + ibuprofen combined or alternating; N
Vyas et al.^40	Randomized, investigator-blind, parallel-group Tympanic; 4 h	15 mg/kg, n = 33	10 mg/kg, n = 33	Acetaminophen 15 mg/kg + Ibuprofen 10 mg/kg, n = 33	Temperature reduction over 4 h: Combination > ibuprofen or acetaminophen alone (p = .013)	Post hoc multiple comparison test at 4 h: Combination  > acetaminophen (p=.03); acetaminophen = ibuprofen; ibuprofen = combination	Ibuprofen, 3 (9.3%), abdominal pain, nausea, and maculopapular skin rash; Acetaminophen, 2 (6.7%), abdominal pain and vomiting; Combination, 4 (12.9%), abdominal pain^2, vomiting and skin rash; No serious or severe AEs were reported in any group
Paul et al.^11	Randomized, controlled Temporal artery; 6 h	NA	Single dose of 10 mg/kg, n = 20 febrile episodes	Single-dose ibuprofen 10 mg/kg followed 3 h later by single-dose acetaminophen 15 mg/kg; n = 20 febrile episodes	Antipyresis at 4–6 h: Combination > ibuprofen alone (4 h, p = .002; 5 h and 6 h, p < .001 for each)	NR	Not collected
Hay et al.^41	Randomized, blinded Axillary; 48 h	15 mg/kg q4–6h (maximum 4 doses/24 h) for 48 h, n = 52	10 mg/kg q6–8h (maximum 3 doses/24 h) for 48 h, n = 52	Ibuprofen 10 mg/kg + acetaminophen 15 mg/kg for 48 h, n = 52	Time without fever 0–4 h: Combination and ibuprofen > acetaminophen (p<.001 for both)	Temperature reduction at 24 h: Combination > ibuprofen (p = .008) and acetaminophen (p = .001)	Most common AEs:Diarrhea: ibuprofen, 9 (17.3%); acetaminophen, 10 (19.2%); combination, 12 (23.1%); Vomiting: ibuprofen, 3 (5.8%); acetaminophen, 6 (11.5%); combination, 2 (3.8%); Rash: ibuprofen, 2 (3.8%); acetaminophen, 2 (3.8%); combination, 1 (1.9%) Cough: ibuprofen, 0; acetaminophen, 2 (3.8%); combination, 1 (1.9%) Cold to the touch: ibuprofen, 3 (5.8%); acetaminophen, 0; combination, 2 (3.8%); AEs were equally distributed between groups.
Lal et al.^42	Randomized, double-blind, parallel-group Axillary; 5 days	10 mg/kg thrice-daily for 5 days, n = 33	NA	Acetaminophen 10 mg/kg + ibuprofen 10 mg/kg thrice daily for 5 days, n = 18	Temperature reduction: Acetaminophen = combination	NR	“Only a few adverse effects namely, epigastric pain, vomiting were encountered”; there were no differences between groups

Abbreviations. AE, adverse event; NA, not applicable; NR, not reported; q4–6h, every 4–6 h; q6h, every 6 h; q6–8h, every 6–8 h.

Three of the 4 studies showed that the acetaminophen/ibuprofen combination was superior to either agent alone. Vyas et al.⁴⁰ compared single-dose acetaminophen, ibuprofen, and their combination in febrile children aged 6 months to 12 years. In a multivariate analysis, there was a significant difference between groups in tympanic temperature reduction 4 h postdose (p = .013), with the maximum reduction being observed in the combination group. In a post hoc multiple comparisons test, the combination was statistically superior to acetaminophen alone (p = .03), but not to ibuprofen alone (p = .17); there was no difference between acetaminophen alone and ibuprofen alone (p = .10).

Paul and colleagues¹¹ conducted a 3-arm, randomized, controlled study comparing the effectiveness of a single dose of ibuprofen with the combined administration of ibuprofen and acetaminophen, as well as an alternating regimen of ibuprofen and acetaminophen (see below for results from the alternating arm) in febrile children aged 6–84 months. The combined use of ibuprofen and acetaminophen produced greater decreases in temporal artery temperature compared with ibuprofen alone over the 6-h observation period, with significant differences favoring the combination treatment at hours 4 (p = .002), 5 (p < .001), and 6 (p < .001).

Hay et al.⁴¹ reported results of a randomized, blinded comparison of either acetaminophen every 4–6 h, ibuprofen suspension every 6–8 h, or a combination of the two in febrile children aged 6 months to 6 years managed at home. After 4 h, the combined treatment group and the ibuprofen group had achieved 55 min and 39 min without fever (axillary), respectively, which was significantly more than the 16 min observed with acetaminophen alone (p < .001 for both comparisons). Children given both drugs spent less time with fever over the first 24 h. Although the combined treatment resulted in greater control of objective measures of fever, there was some suggestion that more fever-associated symptoms were normalized in children given ibuprofen alone than in those receiving acetaminophen alone or combination treatment after 24 and 48 h.

Lal et al.⁴² conducted a randomized, double-blind comparison of acetaminophen, nimesulide, and ibuprofen plus acetaminophen combination administered 3 times daily for 5 days in hospitalized children with acute respiratory tract infections. In contrast to the other studies, no significant differences in axillary temperature reduction were observed between any of the treatment groups.

Alternating studies

Six studies evaluated the antipyretic efficacy of alternating doses of acetaminophen (10−15 mg/kg) and ibuprofen (5−10 mg/kg) in children^11,43–47; dosing schedule and drug formulation details from these studies are summarized in Table 4.

Table 4. Studies of alternating acetaminophen and ibuprofen administration.

Author, year	Study design/temperature measurement technique; treatment duration	Dose; n			Primary outcome result	Key secondary outcome result	Adverse events
		Acetaminophen; N	Ibuprofen; N	Acetaminophen + ibuprofen combined or alternating; N
Luo et al.^43	Randomized, controlled Axillary; 24 h	10 mg/kg q4h, for 24 h; n = 158	10 mg/kg q6h, for 24 h; n = 158	Acetaminophen Acetaminophen 10 mg/kg ≥ q4h alternating with ibuprofen 10 mg/kg ≥ q6h, for 24 h; n = 158; shortest interval between acetaminophen and ibuprofen was ≥ 2 h	Temperature or Non-Communicating Children’s Pain Checklist: Acetaminophen and ibuprofen = alternating treatment	Percentage with persistent fever at 4 and 6 h: Alternating treatment > ibuprofen and acetaminophen (4 h, p = .003; 6 h, p<.001)	No significant differences in rates of AEs between groups For the combination, acetaminophen, and ibuprofen groups, respectively, rates of AEs were as follows: low body temperature, 1.92%, 2.53%, and 1.91%; rash, 8.33%, 8.86%, and 8.28%; asthma, 0%, 0%, and 1.27%; and GI AEs, 84.62%, 84.18%, and 85.35%
Paul et al.^11	Randomized, controlled Temporal artery; 6 h	NA	Single dose of 10 mg/kg, n = 20 febrile episodes	Single dose of ibuprofen 10 mg/kg followed by single dose of acetaminophen 15 mg/kg 3 h later, n = 20 febrile episodes	Antipyresis at 4–6 h: Ibuprofen alternating with acetaminophen > ibuprofen alone (4 h, p = .003; 5 h and 6 h, p < .001 for each)	NR	Not collected
Pashapour et al.^44	Randomized, controlled Rectal; 8 h	15 mg/kg q4h for 2 doses, n = 35	NA	Acetaminophen 15 mg/kg alternating with ibuprofen 10 mg/kg 4 h later; patients received 1 dose of each medication in the study; n = 35	Antipyresis at 2 h: Acetaminophen = alternating treatment Antipyresis at 4, 5, 7, and 8 h: Alternating treatment > acetaminophen (4 h, p = .048; 5 h, p = .04; 7 h, p = .04; 8 h, p = .02)	NR	No “major complications” of treatment were observed in any group
Kramer et al.^45	Randomized, double-blind, placebo-controlled, prospective; Oral; 6 h	15 mg/kg alternating with placebo, n = 19; Acetaminophen at hour 0, placebo at hour 3, then acetaminophen at hour 4	NA	Acetaminophen 15 mg/kg alternating with ibuprofen 10 mg/kg, n = 19; Acetaminophen at hour 0, ibuprofen at hour 3, and placebo at hour 4	Temperature reduction between groups: Alternating treatment > acetaminophen/placebo at 4 h (p = .05) and 5 h (p = .003) Alternating treatment = acetaminophen/placebo at 0, 3, and 6 h	NR	21% of patients had AEs including diarrhea, flatulence, emesis, decreased appetite, epigastric pain, nausea, headache, and insomnia; there were no difference in the rates of any of these AEs between groups
Nabulsi et al.^46	Randomized, double-blind, placebo-controlled; Rectal; 8 h	NA	Single dose of 10 mg/kg initial dose, with a single dose of placebo 4 h later, n = 33	Single dose of ibuprofen 10 mg/kg initially, then acetaminophen 15 mg/kg 4 h later, n = 37	Percentage afebrile at 6 (primary efficacy time point), 7, 8 h: Ibuprofen alternating with acetaminophen > ibuprofen (6 h, p = .018	Percentage afebrile at 7 or 8 h: Ibuprofen alternating with acetaminophen > ibuprofen at 7 h, p < .001; 8 h, p < .001); Duration of antipyresis: Ibuprofen alternating with acetaminophen > ibuprofen at 8 h (p < .001)	Low body temperature (i.e. < 36.5 °C rectally): ibuprofen alternating with acetaminophen, 5 (13.9%); ibuprofen, 6 (18.2%); (p = .6, NS). No serious AEs were observed. No symptoms suggestive of GI, hepatic, or renal toxicity
Sarrell et al.^47	Randomized, double-blind, parallel-group; Each treatment group received a loading dose of either ibuprofen 10 mg/kg (half of each treatment group) or acetaminophen 25 mg/kg (half of each treatment group); 3 days	12.5 mg/kg q6h for 3 days, n = 154	5 mg/kg q8h for 3 days, n = 155	Study medication was administered every 4 h; Administration began with acetaminophen 12.5 mg/kg and was followed with ibuprofen 5 mg/kg 4 h later; the drugs were given in this alternating fashion for 3 days, n = 155	Temperature reduction, less antipyretic medication use, less stress, (regardless of initial loading dose): Ibuprofen alternating with acetaminophen > ibuprofen or acetaminophen alone (p < .001 for all measures)	Fever recurrence at day 5: Ibuprofen alternating with acetaminophen > ibuprofen or acetaminophen alone (p = .02) Less absenteeism from day care: Ibuprofen alternating with acetaminophen > ibuprofen alone or acetaminophen alone (p < .001)	No drug-related AEs or serious illnesses were reported

Abbreviations. AE, adverse event; GI, gastrointestinal; NA, not applicable; NR, not reported; q4h, every 4 h; q6h, every 6 h; q8h, every 8 h.

Luo et al.⁴³ compared the 24-h efficacy of alternating acetaminophen and ibuprofen (shortest dosing intervals were 4 h for acetaminophen and 6 h for ibuprofen; it was stipulated that at least 2 h were to pass between doses of acetaminophen and ibuprofen) versus monotherapy with either ibuprofen or acetaminophen alone every 4 h in 474 febrile children aged 6 months to 5 years. The alternating regimen began with acetaminophen. No significant clinical or statistical differences were found in axillary temperatures over 24 h across the 3 treatment groups. There was, however, a significantly lower percentage of children with persistent fever for a duration of 4 or 6 h in the alternating group versus in either monotherapy group (p ≤ .003 for both).

In the study by Paul et al.¹¹, the alternating regimen using single-dose ibuprofen followed 3 h later by single-dose acetaminophen oral solution had a greater antipyretic effect than single-dose ibuprofen alone at hours 4, 5, and 6 (p ≤ .003 for all). All patients in the alternating group were afebrile (< 38.0 °C) at hours 4, 5, and 6 versus only 30%, 40%, and 50%, respectively, in the ibuprofen-alone group (p ≤ .002 for each hour vs alternating treatment). There was no significant difference between the combined and alternating regimens.

Pashapour et al.⁴⁴ compared the clinical effectiveness of acetaminophen every 4 h with a regimen of acetaminophen alternating with ibuprofen every 4 h in hospitalized infants aged 9–24 months with fever of nonbacterial origin. There was no significant difference in rectal temperature after 2 h. However, temperatures were significantly lower with the alternating regimen versus acetaminophen monotherapy at hours 4, 5, 7, and 8 (p < .05 for all).

Kramer et al.⁴⁵ conducted a randomized, prospective, double-blinded, placebo-controlled study comparing the antipyretic effects of acetaminophen alternating with either ibuprofen or placebo in febrile, but otherwise healthy, children aged 6 months to 6 years who presented at a pediatric clinic. Alternating acetaminophen with ibuprofen significantly decreased fever compared with alternating acetaminophen with placebo at hour 4 (37.4 °C vs 38.0 °C; p = .05) and hour 5 (37.1 °C vs 37.9 °C; p = .003); however, there were no differences in oral temperature between the groups at hours 0, 3, and 6. There were no differences between treatment groups regarding parental perception of the need for additional fever medication at hours 3 or 4 (p = .14 and p = .20), respectively, suggesting that the small differences in oral temperature were not clinically important.

Nabulsi et al.⁴⁶ performed a randomized, double-blind, placebo-controlled comparison of the “efficacy and safety” of a single dose of ibuprofen followed 4 h later by either acetaminophen or placebo in febrile children aged 6 months to 14 years. Alternating ibuprofen/acetaminophen was more effective than ibuprofen/placebo, with significantly more patients in the alternating group becoming afebrile at 6 h compared with those in the ibuprofen/placebo group (83.3% vs 57.6%; p = .018); this difference was also significantly greater at 7 and 8 h (p < .001 for both time points). Patients treated with alternating doses of ibuprofen and acetaminophen also had a significantly longer time to recurrence of fever versus ibuprofen alone (mean ± SD: 7.4 ± 1.3 h vs 5.7 ± 2.3 h; p < .001) and a significantly greater decline in rectal temperature at 7 (p = .026) and 8 (p = .002) hours.

Sarrell et al.⁴⁷ conducted a randomized, double-blind, 3-arm, parallel-group study in febrile children aged 6–36 months comparing acetaminophen alone versus ibuprofen alone versus an alternating regimen of ibuprofen and acetaminophen. Prior to beginning randomized treatment, patients in each treatment group received a loading dose of either acetaminophen or ibuprofen. Alternating acetaminophen and ibuprofen, regardless of which medication was given first, was significantly more effective than acetaminophen or ibuprofen monotherapy with respect to mean rectal temperature, rate of fever reduction, additional antipyretic medication needed (all p < .001), and fever recurrence at day 5 (p = .02). Measures of the child’s stress, as well as absenteeism from daycare (and hence work absenteeism for the parent), were also significantly reduced in the alternating group (p < .001 for all measures).

Discussion

This review explored the antipyretic efficacy and tolerability of acetaminophen versus ibuprofen, as well as treatment regimens using both drugs reported in randomized studies in children. The data indicate that physician-directed acetaminophen and ibuprofen dosing provide equivalent fever reduction and that ibuprofen may be modestly superior at OTC doses. Limited data suggest that combined or alternating use of acetaminophen and ibuprofen may provide greater fever reduction compared with either agent alone.

Although our main focus was the comparative efficacy of acetaminophen and ibuprofen in the treatment of pediatric fever, antipyresis alone is not the most meaningful outcome, as there is little evidence that fever itself is harmful⁴⁸. Indeed, according to the American Academy of Pediatrics, improvement in the child’s overall comfort level should be the goal of antipyretic treatment². Despite this recommendation, very few studies in this review^{18,20,25,29,41,47} assessed the clinical response of children, including measures of comfort or stress, or parental impression of the child’s well-being.

In recent years, the practice of alternating acetaminophen with ibuprofen or combining the 2 drugs to reduce pediatric fever has become increasingly common. The studies reviewed here generally support the antipyretic advantages of alternating and/or combining acetaminophen and ibuprofen versus the use of either antipyretic as monotherapy. Studies evaluating the efficacy of alternating or combining regimens of acetaminophen and ibuprofen showed superiority versus either drug alone in some, but not all cases. Additional studies are needed to investigate combined and alternating strategies and to determine if one is more advantageous than the other. The only study to investigate both approaches found no difference between the 2 dosing strategies¹¹. Additional investigations should include assessments for school/work absenteeism, family stress, child discomfort, sleep, and fluid intake, among others. Regardless of whether acetaminophen and ibuprofen were administered in an alternating or a combined manner, the regimens were well tolerated and the observed safety profiles were similar to those seen with antipyretic monotherapy. Clinicians must weigh these advantages against the additional costs and potential risks of such therapy, including the possibility that such use, with different dosing intervals, might lead to confusion and result in accidental excessive dosing by parents or use where contraindicated (e.g. ibuprofen use with renal dysfunction/dehydration or accidental or intentional overdose of acetaminophen), contributing to “fever phobia” or failure to diagnose or monitor for signs of serious underlying diseases.

This review has some limitations. First, the studies included in this review varied in design, for instance, in terms of patient characteristics including age; method of temperature measurement; efficacy and tolerability endpoints assessed; dosing regimens tested; and study duration; these variations precluded our ability to conduct a formal systematic review. Secondly, the review may be limited by publication bias whereby studies having positive outcomes are more likely to be reported. Further, most of the studies were of short duration (often less than 8 h) with limited follow-up, and not all included systematic assessment of tolerability, both of which may have limited the incidence of adverse events reported.

Conclusions

Although the overall antipyretic efficacy of OTC oral tablet and syrup formulations of acetaminophen and ibuprofen in febrile children at physician-directed doses is similar, ibuprofen may have modest advantages over acetaminophen at OTC doses in terms of faster onset of antipyresis, overall efficacy, and duration of fever reduction, but provides only limited clinical benefit. Both acetaminophen and ibuprofen are well tolerated and effective when caregivers follow the labelling information on dosing. Combining or alternating acetaminophen with ibuprofen, given their differential mechanisms of action, metabolism, and end-organ toxicities, appears to provide some antipyretic efficacy advantages in children versus either agent alone and appears to be well tolerated. Given that improvements in patient comfort or distress are arguably more meaningful outcomes than antipyresis, per se, a systematic evaluation of these patient-centered outcomes during treatment with acetaminophen or ibuprofen may prove helpful in determining the best course of action in the management of pediatric fever.

Transparency

Declaration of funding

This manuscript was funded by Pfizer. The study sponsor had no role in the conceptualization or drafting of this article.

Declaration of financial/other relationships

IMP has served as a paid consultant for the Consumer Healthcare Products Association, Evidera, Johnson & Johnson, and Pfizer and as a consultant for GlaxoSmithKline within the past 3 years. PDW has served as a paid consultant on previous trials of acetaminophen and ibuprofen and as an expert witness in FDA hearings involving manufacturers of acetaminophen and ibuprofen. He has also served as a paid consultant for the Consumer Healthcare Products Association.

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Author contributions

Both authors were responsible for project conceptualization, data curation and formal analysis, and manuscript review and editing. Both authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

Acknowledgements

Medical writing support was provided by John H. Simmons, MD, and Duprane Pedaci Young, PhD, of Peloton Advantage, LLC, an OPEN Health company, and was funded by Pfizer.