Full text of DOI:10.2165/00044011-200121120-00004

Clin Drug Invest 2001; 21 (12): 821-825
1173-2563/01/0012-0821/$22.00/0
CLINICAL USE
© Adis International Limited. All rights reserved.
Premarketing Surveillance of Oral
Ibuprofen Solution in Febrile Children
M. Berkovitch,1 J. Press,2 M. Bulkowstein,1 L. Even,3 J. Barash,4 R. Brik,5 D. Tasher,6
R. Marom,7 A.S. Luder,8 Y. Hecht,9 M. Rubinshtein,10 M. Mosleh,5 S. Ben-Shachar,11
R. Talmor,12 A. Zviel,12 A. Kiro,12 L. Piglansky,12 V. P i n s k 12 and Y. Uziel12
1 Clinical Pharmacology Unit, Assaf Harofeh Medical Center, Zerifin, Israel
2 Pediatric Emergency Unit, Soroka Medical Center, Beer-Sheva, Israel
3 Department of Pediatrics, Western Galilee Hospital, Nahariya, Israel
4 Pediatric Daycare, Kaplan Medical Center, Rehovot, Israel
5 Department of Pediatrics, Rambam Medical Center, Haifa, Israel
6 Department of Pediatrics, The E. Wolfson Medical Center, Holon, Israel
7 Department of Pediatrics, Ha’Emek Medical Center, Haifa, Israel
8 Department of Pediatrics, Sieff Hospital, Haifa, Israel
9 Department of Pediatrics, Carmel Medical Center, Haifa, Israel
10 Pediatric Emergency Department, Shiba Medical Center, Tal-Hashomer, Israel
11 Department of Pediatrics, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israel
12 Department of Pediatrics, Sapir Medical Center, Kfar-saba, Israel
Objective: Ibuprofen is as effective as paracetamol (acetaminophen) as an anti-
pyretic and analgesic agent in paediatric patients. Ibuprofen is considered to be
well tolerated; however, there are reports on gastrointestinal bleeding or renal
adverse effects among children treated with ibuprofen. Oral ibuprofen suspension
was recently registered and approved by the Ministry of Health in Israel as an
antipyretic and analgesic agent. Before distribution of the drug to pharmacies,
we aimed to follow possible adverse effects among children receiving ibuprofen
suspension in several paediatric wards and clinics.
Abstract
Design: Children with fever needing antipyretic medication received ibuprofen
oral suspension 5 to 10 mg/kg/dose. In each case the age of the patient, gender,
diagnosis, number of ibuprofen doses, duration of treatment and any adverse
reactions were reported.
Results: 1564 children from 14 paediatric wards (11 hospitals) and from five
paediatric and family clinics participated in the study; 882 males and 682 females.
The patients, aged 3.6 4.2 years (range 1 month to 16.5 years), received
2.4 3 (range 1 to 22) doses of ibuprofen suspension for 1.56 2.11 (range 1 to
20) days. Adverse reactions were reported among 26 patients (1.66%) [95%
confidence interval (CI) 1.1-2.4]; 18 children (1.15%) [95% CI 0.7-1.8] vomited
immediately after the administration of the drug and it was not readministered.
Two children (0.12%) [95% CI 0.02-0.46] had abdominal pain that resolved spon-
taneously, two patients reported nausea, and two other children had diarrhoea.
Eight children (0.51%) reported experiencing a ‘bitter taste’from the medication,

822
Berkovitch et al.
of whom one patient discontinued the medication while the other seven continued
it.
Conclusions: The adverse reactions following administration of oral ibuprofen
suspension reported in our study were low in frequency, mild and disappeared
spontaneously. However, continuing reporting on its tolerability is needed.
In Israel, paracetamol (acetaminophen) is the
Children with fever needing antipyretic medica-
tion participated in the study. Those with known
allergy to aspirin or to NSAIDs were excluded,
as were children with renal impairment, acute or
chronic liver disease and children with bleeding
disorders. Each child received ibuprofen suspen-
sion 5 to 10 mg/kg/dose, not more than four doses
per day. Ibuprofen (Nurofen® for Children1, Boots
Healthcare International, Nottingham, England)
was supplied directly by the importer.
In each case in the paediatric ward, a special
form was completed, and after discharge of the
child the form was transferred to one centre that
collected all the data. In the paediatric and family
clinics, the primary-care physician enrolled
children during an office visit for a febrile illness.
After 3 to 7 days of treatment, the parents were
contacted to determine the occurrence of adverse
effects. In each case the age of the patient, diag-
nosis, dose of ibuprofen, number of ibuprofen
doses, duration of treatment and adverse reactions
were reported.
drug of choice for the treatment of fever in chil-
dren. Its efficacy as an antipyretic has been well
established in numerous clinical studies. However,
its adverse effect on hepatic function has raised a
few questions about its safety, even in therapeutic
doses.[1,2]
Ibuprofen is a nonsteroidal anti-inflammatory
drug (NSAID) with antipyretic and analgesic prop-
erties. In 1989 the Food and Drug Administration
approved ibuprofen for use as an antipyretic in
children. During the last decade, several studies
have shown that the efficacy of ibuprofen is at least
and not less than that of paracetamol as an anti-
pyretic and analgesic agent forpaediatricpatients.[3-7]
The safety of ibuprofen was also investigated and
reported.[8-12]
Ibuprofen administered to children is con-
sidered to be well tolerated;[8,10,13,14] however,
there are reports on gastrointestinal bleeding or
renal adverse effects among children treated with
ibuprofen.[8,15,16]
Ibuprofen suspension was recently registered
and approved as an antipyretic and analgesic by the
Ministry of Health in Israel to treat children above
the age of 6 months.
In this premarketing surveillance we aimed to
investigate possible adverse reactions among
children receiving oral ibuprofen suspension, in
various paediatric wards and clinics, before the
drug arrived at the various pharmaceutical sale-
points.
Patients were recruited from 14 paediatric wards
in 11 hospitals in Israel (Assaf Harofeh Medical
Center, Sapir Medical Center, Carmel Medical
Center, Wolfson Medical Center, Sieff Hospital,
Western Galilee Hospital, Kaplan Medical Center,
Ha’emek Medical Center, Sourasky Medical
Center, Shiba Medical Center and Rambam Medi-
cal Center) and from five paediatric and family
clinics.
Statistical Analyses
Patients and Methods
Continuous data, such as the age of the patients,
number of ibuprofen doses, and duration of
The study was approved by the ethics committee
of the Ministry of Health. Children were recruited
from 14 paediatric wards and five paediatric and
family clinics in Israel.
1 Trade name is used for identification purposes only and
does not imply product endorsement.
© Adis International Limited. All rights reserved.
Clin Drug Invest 2001; 21 (12)

Oral Ibuprofen in Febrile Children
823
Table I. Risk of adverse reactions induced by ibuprofen (n = 1564)
therapy, are described as mean standard devia-
tion.
The frequency of adverse reactions is reported
as a percentage and 95% confidence interval (CI).
Symptom
No. (%)
Total adverse drug reactions
Risk 95% CI
26 (1.66%)
1.1-2.4
Vomiting
18 (1.15%)
0.7-1.8
Risk 95% CI
Results
Diarrhoea
2 (0.12%)
0.02-0.46
The 1564 children who participated in the study
were aged 3.6 4.2 years (range 1 month to 16.5
years); there were 882 males and 682 females.
1318 children were recruited from hospitals and
246 children were recruited from paediatric and
family clinics. The patients received 2.4 3 (range
1 to 22) oral doses of ibuprofen suspension for 1.56
2.11 (range 1 to 20) days. The eight most com-
mon diseases for which ibuprofen was adminis-
tered are shown in figure 1.
Risk 95% CI
Abdominal pain
Risk 95% CI
2 (0.12%)
0.02-0.46
Nausea
2 (0.12%)
0.02-0.46
Risk 95% CI
CI = confidence interval.
was treated with three doses of ibuprofen, devel-
oped a mild macular rash over the body and the
extremities, which appeared after the first dose of
ibuprofen, and disappeared within several hours.
He was also treated with oral penicillin for
follicular tonsillitis. One 6-year-old child who was
admitted to the hospital for hypertension investi-
gation, had a ‘strange feeling’ after the second
dose of ibuprofen.
Eight children (0.51%) reported experiencing a
‘bitter taste’ from the medication, of whom one
patient discontinued the medication while the other
seven continued it.
Adverse reactions were reported among 26
patients (1.66%) [95% CI 1.1-2.4]. The most
common adverse event was vomiting − 18 children
(1.15%) [95% CI 0.7-1.8] vomited immediately
after the administration of the drug and it was not
readministered. Two children (0.12%) [95% CI
0.02-0.46] had abdominal pain that resolved
spontaneously, two patients (0.12%) [95% CI
0.02-0.46] reported nausea, and two other children
had diarrhoea (table I). One 7-year-old child, who
350
300
250
200
150
100
50
Twenty-two patients, younger than 6 months of
age, who did not respond to paracetamol, received
ibuprofen. They were aged 3.5 months 5 weeks
(range 4 weeks to 5 months), and received 2.1
2.5 (1 to 12) doses for 1.7 1.1 (1 to 5) days. No
adverse effects were reported among this group of
patients.
0
itis
Discussion
Otitis
ection
al inf
ection
onsillitis
T
ile illness
Meningitis
Pneumonia
act inf
y tr
ebr
Vir
Ibuprofen is currently administered not only as
an antipyretic, but also in the treatment of juvenile
rheumatoid arthritis,[17] for tonsillectomy and post-
operative pain,[9,18,19] and for the acute treatment
of migraine in children.[20] In a study performed by
Lesko and Mitchell,[8] where the safety of paracet-
F
inar
Acute gastroenter
Ur
Indication
Fig. 1. The eight most common diagnoses for which oral
ibuprofen solution was administered in the children (n = 1564)
included in this study.
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Clin Drug Invest 2001; 21 (12)

824
Berkovitch et al.
amol and ibuprofen among paediatric patients was
compared, 4 of 55 785 children, randomised to
ibuprofen treatment, had acute gastrointestinal
bleeding. The risk of acute gastrointestinal bleed-
ing was 7.2 per 100 000 (95% CI 2-18 per 100 000),
as compared with a risk of zero per 100 000 (95%
CI 0-11 per 100 000) among those treated with
paracetamol. However, the difference was not
statistically significant (p = 0.31).[8] None of the
children hospitalised with gastrointestinal bleed-
ing required a blood transfusion, and no special
procedures were performed to attempt to identify
the source of bleeding.[8] For acute renal failure,
anaphylaxis and Reye’s syndrome, the observed
risk for each among the 55 785 children
randomised to treatment with ibuprofen was zero
per 100 000 (95% CI 0-5.4 per 100 000).[8] In this
study, relative to paracetamol-treated children,
they found no evidence of a significantly increased
risk for acute gastrointestinal bleeding, acute renal
failure, anaphylaxis or Reye’s syndrome among
ibuprofen-treated children.[8] The same authors
reported on the safety of paracetamol and
ibuprofen among children younger than 2 years of
age, and found that the risk of serious adverse
clinical events was small and did not vary by choice
of medication.[14] In another study by Lesko and
Mitchell,[13] the authors concluded that the risk of
acute renal complications after short-term use of
ibuprofen is small and cannot easily be differen-
tiated from the risk among children given para-
cetamol.[13]
In another study, Noyola et al.[21] did not find
any complications associated with the use of para-
cetamol or ibuprofen in children with enteric fe-
ver.[21] On the other hand, there are reports on renal
complications after the long- and short-term use of
ibuprofen or other NSAIDs among children.[12,15,16]
Not one of the 1564 children in our study had renal
failure; however, we did not aim to measure blood
urea nitrogen or creatinine, nor did we evaluate
specifically for renal failure, which is a limitation
of our study. There were no reports of gastro-
intestinal bleeding in our patients. The most
common adverse effect described in our study was
vomiting; 18 children (1.15%) [95% CI 0.7-1.8]
vomited immediately after the first dose of
ibuprofen. The vomiting cannot be attributed to the
medication only; firstly, some of the children had
vomiting related to the infection itself; secondly,
there are children who have a known tendency
to vomit during oral drug administration. The
ibuprofen was not readministered to these 18
patients; they received paracetamol orally or rec-
tally. Theoretically, even if vomiting is attributed
to the drug only, the risk of vomiting after
ibuprofen administration is only 1 per 100 patients
(95% CI 0.7-1.8). Eight children reported experi-
encing a ‘bitter taste’ from the medication, of
whom seven continued taking it. The ibuprofen
solution administered in our study is sugar-free
and contains an orange flavour and ingredients
such as sodium saccharin, citric acid, sodium citrate
and others, which are probably not responsible for
the ‘bitter taste’ of the medication some children
experienced.
Excluding the 18 patients who vomited imme-
diately after ingestion of ibuprofen, the number of
children with adverse reactions was small − six pa-
tients (0.38%) [95% CI 0.3-0.6]. These six patients
had gastrointestinal complaints, such as nausea
(n = 2), abdominal pain (n = 2) or diarrhoea (n = 2)
[table I]. None of the 1564 children had gastro-
intestinal bleeding. The risk of gastrointestinal
problems as a result of ibuprofen administration is
small − 3.8 per 1000 patients (95% CI 0.3-0.6).
Although the study was designed for short-term
treatment with ibuprofen, there were children in
our study who received the drug for almost 3
weeks, with a total number of 22 doses. No adverse
reactions were reported among these children.
Ibuprofen should not be administered to
children younger than 6 months of age, because of
lack of experience in this age group with the
drug. However, in several wards, when paraceta-
mol treatment was not effective, ibuprofen was
administered to children younger than 6 months of
age, and even a 1-month-old infant received the
medication. No adverse effects were observed
among these 22 young children.
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Clin Drug Invest 2001; 21 (12)

Oral Ibuprofen in Febrile Children
825
6. Wilson JT, Brown RD, Kearns GL, et al. Single-dose, placebo-
controlled comparative study of ibuprofen and acetamino-
phen antipyresis in children. J Pediatr 1991; 119 (5): 803-11
7. Walson PD, Galletta G, Chomilo F, et al. Comparison of multi-
dose ibuprofen and acetaminophen therapy in febrile chil-
dren. Am J Dis Child 1992; 146 (5): 626-32
8. Lesko SM, Mitchell AA. An assessment of the safety of pedia-
tric ibuprofen: a practitioner-based randomized clinical trial.
JAMA 1995; 273 (12): 929-33
9. Harley EH, Dattolo RA. Ibuprofen for tonsillectomy pain in
children: efficacy and complications. Otolaryngol Head Neck
Surg 1998; 119 (5): 492-6
10. Steans A, Manners PJ, Robinson IG. A multicentre, long-term
evaluation of the safety and efficacy of ibuprofen syrup in
children with juvenile chronic arthritis. Br J Clin Pract 1990;
44 (5): 172-5
It is important to note that in the US paracetamol
and ibuprofen are commonly being used in an
alternating manner, for the management of fever.[22]
There is presently no scientific evidence that this
combination is safe or achieves faster antipyresis
than either agent administered alone.[22] There is
evidence that the improper use of these agents may
cause harm.[22] Until properly controlled studies
have assessed the risk of combining these two
products, practitioners should proceed with cau-
tion.[22]
11. Kustra RP, Scott CS, Retsch-Bogart GZ. Safety of acute and
chronic ibuprofen therapy in children. J Pediatr Pharm Pract
1996; 1 (1): 30-5
Conclusion
12. Schaller S, Kaplan BS. Acute nonoliguric renal failure in chil-
dren associated with nonsteroidal antiinflammatory agents.
Pediatr Emerg Care 1998; 14 (6): 416-8
13. Lesko SM, Mitchell AA. Renal function after short-term
ibuprofen use in infants and children. Pediatrics 1997; 100
(6): 954-7
14. Lesko SM, Mitchell AA. The safety of acetaminophen and
ibuprofen among children younger than two years old. Pedi-
atrics 1999; 104 (4): e39
15. Moghal NE, Hulton SA, Milford DV. Care in the use of
ibuprofen as an antipyretic in children. Clin Nephrol 1998;
49 (5): 293-5
The oral ibuprofen solution was well tolerated
and associated with only minor adverse reactions.
The number of adverse reactions in our study,
including the 18 children who vomited after
administration of ibuprofen, was small (1.66%).
They were mild and disappeared spontaneously.
However, larger cohorts and continuing reporting
on the tolerability of the drug are needed.
16. Flato B, Vinje O, Forre O. Toxicity of antirheumatic and anti-
inflammatory drugs in children. Clin Rheumatol 1998; 17 (6):
505-10
17. Giannini EH, Brewer EJ, Miller ML, et al. Ibuprofen suspen-
sion in the treatment of juvenile rheumatoid arthritis. Pediat-
ric Rheumatology Collaborative Study Group. J Pediatr 1990;
117 (4): 645-52
18. St Charles CS, Matt BH, Hamilton MM, et al. Comparison of
ibuprofen versus acetaminophen with codeine in the young
tonsillectomy patient. Otolaryngol Head Neck Surg 1997;
117 (1): 76-82
Acknowledgements
The study was supported by Teva-Abic Marketing Ltd,
Netanya, Israel. The authors wish to thank Ms Hanna Gotlieb
and Ms Pnina Mugami from Teva-Abic Ltd and Ms Malka
Guttman from the Clinical Pharmacology Unit, Assaf
Harofeh Medical Center, for supporting and encouraging this
study.
19. Kokki H, Hendolin H, Maunuksela EL, et al. Ibuprofen in the
treatment of postoperative pain in small children: a random-
ized double-blind-placebo controlled parallel group study.
Acta Anaesthesiol Scand 1994; 38 (5): 467-72
20. Hamalainen ML, Hoppu K, Valkeila E, et al. Ibuprofen or ac-
etaminophen for the acute treatment of migraine in children:
a double-blind, randomized, placebo-controlled, crossover
study. Neurology 1997; 48 (1): 103-7
21. Noyola DE, Fernandez M, Kaplan SL. Reevaluation of anti-
pyretics in children with enteric fever. Pediatr Infect Dis J
1998; 17 (8): 691-5
22. Mayoral CE, Marino RV, Rosenfeld W, et al. Alternating
antipyretics: is this an alternative? Pediatrics 2000; 105 (5):
1009-12
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Correspondence and offprints: Dr M. Berkovitch, Clinical
Pharmacology Unit, Assaf Harofeh Medical Center, Zerifin,
Israel.
E-mail: mberkovitch@asaf.health.gov.il
© Adis International Limited. All rights reserved.
Clin Drug Invest 2001; 21 (12)