EurJ Clin Pharmacol (1994) 46:197-201

Springer-Verlag 1994

Comparative efficacy and tolerance of ibuprofen syrup

and acetaminophen syrup in children with pyrexia associated
with infectious diseases and treated with antibiotics
E. A u t r e t 1, G. Breart s , A . P. Jonville 1, S. Courcier 2, C. Lassale 2, J. M. G o e h r s 2
1 Clinical Pharmacology Department, Bretonneau Hospital, Boulevard Tonnele, Tours, France
2 Clinical Research Department of Boots Pharma, Courbevoie, France
3 INSERM U 149,Paris, France

Received: 8 June 1993/Accepted: 12 December 1993

Abstract. A double-blind, randomised, parallel group tablished safety record, which is equal to that of aspirin
study has been done comparing the efficacy and tolera- and acetaminophen. The antipyretic properties of ibu-
bility of 7.5mg/kg ibuprofen syrup (n =77) and profen in children have been demonstrated and compared
10 mg-kg-1 acetaminophen syrup (n = 77) in 154 children with various other antipyretic agents [5]. Its antipyretic ef-
(6 months to 5 years) with fever ( > 38 C) associated with fectiveness seems to be very similar to that of acetami-
infectious diseases and treated with antibiotic therapy. nophen, but most of these trials have been carried out with
The area under the percentage reduction in tempera- a single dose and without associated antibiotic therapy.
ture curve captured the net effect of each drug and pro- The objective of the present study was to evaluate the
vided the best estimate for comparison of efficacy during antipyretic action of ibuprofen in children younger than
a defined period. Temperature evolution over time was 5 years of age under the common condition prescription
not significantly different between the two groups. Never- for one of an antipyretic, i.e., in association with an anti-
theless, the temperature reduction over the first 4 h of biotic.
treatment (H0-H4) was significantly higher after ibu-
profen (60%) than acetaminophen (45%). Both ibu-
profen and acetaminophen were well tolerated. Subjects and m e t h o d s
In conclusion, significant antipyretic activity, good
tolerability and its availability as a syrup make ibuprofen Study population
an effective means of fever control in children.
To be enrolled in the study, children had to be aged 6 months to
K e y words: Ibuprofen, Fever, Acetaminophen; children, 5 years, hospitalised for hyperthermia of infectious origin, and re-
quiring, in addition to antipyretic treatment, an antibiotic, which
infections disease, adverse effects could be either amoxycillin or amoxycillin-clavulanic acid
(AUGMENTINR). Initial rectal temperature was at least 38C.
Written informed consent from the parents or the legal guardian was
Fever is common in children. Parents learn from their doc- required. The protocol was approved by the Ethics Committee of
tors about its treatment, including cool baths, removing the University Hospital of Tours on 3 October 1989.
excess clothing and the use of antipyretic drugs. Aspirin
and acetaminophen are the antipyretic drugs usually used
to treat paediatric pyrexia, with a present preference for Table 1. Entry profile of children studied, mean with (SD)
acetaminophen owing to the risk of Reye's syndrome with Ibuprofen Acetaminophen
aspirin, which has made led to contra-indication of this (n = 77) (n = 77)
drug for the treatment of childhood pyrexia in the United
Age (month) 24.8 (15.2) 22.9 (15.1)
States and in the United Kingdom [1-3]. Ibuprofen is a Malen (%) 47 (61%) 43 (55.8%)
non-steroidal antiinfiammatory drug (NSAID) derived Body weight (kg) 11.8 (3.1) 11.5 (3.3)
from propionic acid. Because of its antiinflammatory and Temperature (C) 39.02 (0.72) 39.04 (0,76)
analgesic properties it is used in the treatment of chronic Diagnosis a (n):
rheumatic diseases in children [4]. It is available over the Bronchopulmonary
counter for adults in the United States because of its es- infection 20 28
URTP 78b 63
Other aetiology 20 21
Correspondence to: E. Autret, Departement de Pharmacologie Cli-
nique, H6pital Bretonneau, Boulevard Tonnel6, F-37044Tours, Not mutually exclusive; bmore than one site per patient was
France possible
198
40 temperature was above 37.8C, up to a maximum of 30 mg.kg 1
-24 h -1 for ibuprofen and 40 mg.kg-24 h-1 for acetaminophen.
The first antibiotic treatment and the first antipyretic treatment
39,04 were taken at the same time. Concomitant medication with anti-
2
39
3;o . 8,oo
"~-~ 38,35
pyretic agents was not allowed during the study or during the 6 h be-
fore inclusion in it. If, despite the therapeutic scheme proposed,
E o~3807 :38.04~ + , , hyperthermia persisted or produced undue distress, the patient with-
38 drew or was withdrawn from the study and could then receive
5:
acetaminophen.

37.42
37,31
37
0 1 2 4 6 8 12 Evaluations
Efficacy. The rectal temperature (C) was measured with a mercury
Time (h)
thermometer, specific to each child, at the time of first administration
Fig. 1. Mean temperature after ibuprofen ( ) and acetaminophen of the study medication (H0) and 1,2, 4, 6, 8,12, 24, 36, 48, 60 and 72 h
(+) after that first dose. The main criterion for assessment of efficacy was
the area under the percentage reduction in temperature curve com-
pared to the initial temperature during the first 12 h of treatment. Ac-
80
73 cessory criteria were the percentage of the reduction in temperature
70 between H0 and H4, the mean fall in temperature between H0 and
60 H4, and the time of maximum antipyresis (temperature < 37C).
60 When the temperature fell below 37 C the value chosen for calcula-
E 49 tions was 37 C, as suggested by E. Autret and G. Breart.
50

= 40 Tolerability. Adverse experiences were recorded throughout the

.9 study. In addition, to assess long-term tolerability, in the child was
= 30
"o still hospitalised 7 days after inclusion a questionnaire was given to
the family or to the nursing staff, so that any delayed adverse events
= 20
g 21 could be detected. The implication of the study treatment in the oc-
10 i i i i i i currence of adverse events was analysed by the investigator and by
1 2 4 6 8 12 the co-ordinator before the study was unblinded.

Time (h)
Statistical methods
1~g.2. Area under the percentage reduction in temperature curves.
Ibuprofen; + acetaminophenl H4, 95 % CI [ - 2.3; 43.1]; H6, 95 % The percent reduction at time i was defined as:
CI [ - 3 . 3 ; 73.1]; H8, 95% CI [-8.6; 91.4]; H12, 95% CI [-21.3;
115.7] T0-T i
Pi = T0_37oc

with
Exclusion criteria
To= Temperature at entry into the study
Tt = Temperature at time i (minimum 37 C)
Children were excluded from the study if they had ingested any anti-
T0-37 C = Maximum possible reduction
pyretic drug up to 6 h before the study started, if they had a history of
hypersensitivity to non-steroidal antiinflammatory drugs (including According to the above formula patients whose temperature
aspirin), to acetaminophen or to penicillins. Additional exclusions reached or fell below 37 C had 100 % reduction.
included any condition that might interfere with drug absorption or The area under the Pi was computed using the trapezoidal rule.
distribution, or severe hyperthermia with neurological and/or Student's t test was used to compare means, and the chi-square test
haemodynamic disorders. Children treated with anti-epileptic medi- to compare percentages, 95 % confidence intervals (CI) for the dif-
cation were also excluded. ference between the ibuprofen and the acetaminophen groups were
computed.

Treatments
This double-blind study was carried out on a multicentre basis at
14 hospitals in France. Patients were randomly assigned to one of
2 parallel treatment groups. The sample size (75 patients per group)
was calculated be able to a difference of 100 % h - 1between the area
under the percentage reduction in temperature curves (AUC), or a
fall in temperature of 30 %, in the first 4 hours of drug administration
(H0-H4) with c~= 0.05 and fl = 0.1. Patients were randomised to re-
ceive either ibuprofen syrup 30 m g - m l - 1 or acetaminophen syrup
40 rag- ml - ~. Both syrups were identical with regard to content, fla-
vour and taste. All medications were supplied b~ B oots Pharmaceu-
ticals (UK). Ibuprofen was given at 7.5 mg. kg- /dose and acetami-
nophen at 10 rag- kg - 1/dose. The first dose was followed 6 h later by
a second dose administered regardless of the degree of hyperther-
mia. The following doses were given at regular intervals of 6 h if the
Results
Entry profile
One hundred and fifty-four patients were included in the
study, 77 in t h e i b u p r o f e n g r o u p a n d 77 i n t h e a c e t a m i -
n o p h e n g r o u p . N i n e p a t i e n t s (4 i n t h e i b u p r o f e n a n d 5 i n
the acetaminophen groups) did not follow the protocol,
b u t t h e y h a v e b e e n t a k e n i n t o a c c o u n t in t h e a n a l y s i s ac-
counting the principle of intention-to-treat. All patients
w e r e f o l l o w e d u p to H72. F o r 3 p a t i e n t s (for w h o m o n l y
H 0 a n d H 1 d a t a w e r e a v a i l a b l e ) t h e m a i n a s s e s s m e n t crite-
r i o n c o u l d n o t b e c o n s i d e r e d as n o e x t r a p o l a t i o n w a s