Table 1.

Summary of clinical trials of paracetamol for treatment of fever in children

Study (design; setting)	Patients (N; age range)	Treatments (n)	Regimen	Efficacy endpoint	Efficacy results (PARA vs. comparator)	Adverse events (PARA vs. comparator)
Versus NSAIDs
Autret-Leca et al. [34]. (R, DB [1st dose]/OL [3 days], MC, PG; GP)	Fever (304; 0.25–12 years)	PARA 15 mg/kg (150) IBU 10 mg/kg (151)	Repeat dose for 3 days	AUC0-6 h	Mean AUC0–6 h −7.66 vs. −7.77 °C/min (P = 0.82)	Any AE 10.6% vs. 11.2% Infections 4.6% vs. 3.3% GI disorders 2.6% vs. 2.6% Respiratory disorders 2.6% vs. 2.6%
Carabano et al. [35]. (PG; NR)	Fever, ≥38 °C (166; NR)	PARA 15 mg/kg (80) IBU 7 mg/kg (86)	Single dose	Change in temperature after drug administration	At 1 h 37.80 vs. 37.66 °C (P = 0.22) At 2 h 37.29 vs. 37.09 °C (P = 0.14) At 3 h 37.28 vs. 37.12 °C (P = 0.64) At 4 h 37.46 vs. 37.40 °C (P = 0.72)	NR
Celebi et al. [59]. (R, PG; ED)	Fever (301; 1–14 years)	PARA 15 mg/kg (112) IBU 10 mg/kg (84) KETO 0.5 mg/kg (105)	Repeat dose for 48 h	Change in temperature after drug administration	At 30 min 38.4 vs. 38.5 vs. 38.4 °C At 60 min 38.0 vs. 38.1 vs. 37.9 °C At 120 min 37.7 vs. 37.7 vs. 37.6 °C At 4–6 h 37.5 vs. 37.4 vs. 37.3 °C	Early (< 6 h) vomiting 3.8% vs. 9.6% vs. 13.5% Late (6–48 h) vomiting 1.3% vs. 5.8% vs. 2.7%
PITCH [60]. (R, SB, MC, PG; OP)	Fever, ≥37.8 °C and ≤41.0 °C (156; 0.5–6 years)	PARA 15 mg/kga (52) IBU 10 mg/kgb (52) PARA + IBU (52)	Repeat dose for 48 h	Time without fever in the first 4 h	Time without fever in the first 4 h 219 vs. 211 vs. 202 min Time without fever in the first 24 h 1078 vs. 1029 vs. 1051 min	Diarrhea 19.2% vs. 17.3% vs. 23.1% Vomiting 11.5% vs. 5.8% vs. 3.8% Rash 3.8% vs. 3.8% vs. 1.9%
Wong et al. [40]. (R, DB, MC, PG; NR)	Fever, ≥ 37.8 °C and ≤ 40.5 °C (628; 0.5–6 years)	PARA 12 mg/kgc (210) DIPYR 15 mg/kg (209) IBU 5/10 mg/kgd (209)	Single dose	Patients with a temperature reduction of ≥1.5 °C	Temperature reduction of ≥1.5 °C 77% vs. 86% vs. 83% Time to temperature reduction of ≥1.5 °C 109 vs. 103 vs. 120 min Normal (≤37.5 °C) temperature 68% vs. 82% vs. 78% (both P = 0.004 vs. PARA)	Drug-related AEs 15% vs. 17% vs. 27% Vomiting 3.8% vs. 4.3% vs. 2.9% Diarrhea 2.4% vs. 1.4% vs. 1.4%
Versus PL
Gupta et al. [38]. (R, DB, PC; tertiary care)	Fever, ≥ 37.6 °C and ≤ 40.5 °C (210; 0.5–6 years)	PARA 15 mg/kg (103) PL (107)	Single dose	Fever clearance time [time to normal (≤37.5 °C) temperature]	Median fever clearance time 32 vs. 36 h (P = 0.23)	AE in first 6 h 8.7% vs. 0%
Kramer et al. [61]. (R, DB, PC; home)	Fever, ≥ 38 °C and < 41 °C (225; 0.5–6 years)	PARA 10–15 mg/kg (123) PL (102)	Multiple dose q4 h	Duration of fever	Mean duration of fever 34.7 vs. 36.1 h	NR
Parenteral PARA (i.e., PROP)
Reymond et al. [84]. (Two studies; R, OL, PG; hospital)	Fever (10/24; NR)	Study 1 PROP 30 mg/kg (5) ASA 15 mg/kg (5) Study 2 PROP 30 mg/kg (11) PROP 15 mg/kg (13)	Single dose	Change in temperature	Study 1: change in temperature −1.99 vs. −2.31 °C Study 2: change in temperature −1.79 vs. −2.11 °C	Burning sensation during PROP infusion in 45% of patients
Drug-dosage comparison
Treluyer et al. [36]. (R, DB, PG; NR)	Fever, 39–40.5 °C (121; 0.33–9 years)	PARA 30 mg/kg LD (62) PARA 15 mg/kg MD (59)	Single dose	Rectal temperature	Time to rectal temperature <38.5 °C 110.7 vs. 139.4 min (P = 0.05)	Any AE 9.7 vs. 8.5%

AUC _0–6h area under the temperature reduction curve-absolute difference in tympanic temperature from baseline at 6 h, ASA aspirin, DB double blind, DIPYR dipyrone, ED emergency department, GI gastrointestinal, GP general practice, IBU ibuprofen, KETO ketoprofen, LD loading dose, MD maintenance dose, NR not reported, NSAIDs non-steroidal anti-inflammatory drugs, OL open label, OP outpatient, PARA paracetamol, PL placebo, PC placebo-controlled, PG parallel group, PROP propacetamol, q4 h Every 4 h, R randomized, SB single blind

^aEvery 4–6 h

^bEvery 6–8 h

^cDosed according to age; average was 12 mg/kg

^d5 mg/kg for T0 < 39.2 °C; 10 mg/kg for T0 ≥ 39.2 °C