Application for Inclusion of Oral Ibuprofen Suspension fileIbuprofen is now widely recognised...

25Ih October 2004

The Secretary of the Expert Committee on the Selection and Use of

Essential Drugs and Medicines Policy World Health Organization 20 Avenue Appia CH-I211 Geneva 27

Essential Medicines Policy, Access and Rational Use

Dear Secretary

With this letter I am sending a completed application plus supporting documentation for the inclusion of paediatric ibuprofen in the WHO model list of essential drugs.

The International Ibuprofen Foundation (IIF) is now recognised as a leading authority on this important medicine. Its tolerance and effectiveness were fully covered at our conference at the Royal College of Physicians in London on April 15116, 2002. Participants were international scientists of considerable reputation and their presentatinns can be seen on our website at ~.ibupmfen-fo?lndationcom

Ibuprofen is now widely recognised worldwide as a highly effective analgesic antipyretic and anti-inflammatory medicine with a high safety profile in adults and also in paediatric use. It is freely available over the counter in Europe, the Americas and following a change in regulatory requirements, in Australia and New Zealand.

We believe that the case for the inclusion of paediatric ibuprofen on your list of essential drugs is substantial. We would be happy to enlarge upon the documentation here if this would be of help to your expert committee.

If this would be of practical benefit the IIF would be happy to come to Geneva to answer questions from the committee members.

I hope we may receive a favourable response and look forward to hearing from you

Yours sincerelv

G N H E N D E R ~ ~ L? i recto r ,SSnera I 1nternat:onai ibuprofen Foundation

Application for Inclusion of Oral Ibuprofen Suspension To The WHO Model List of Essential Medicines

APPLICATION BY THE INTERNATTONAL IBUPROFEN FOUNDATION (XF)

FOR THE INCLUSION OF IBUPROFEN SUSPENSION IN THE WHO MODEL

LIST OF ESSENTIAL MEDICINES

Summary statement of the proposal for inclusion

This is an application for inclusion of Paediatric Ibuprofen in the WHO list of essential

medicines. Ibuprofen is currently included in the Model formulary for the treatment of

pain and this application supports the inclusion of paediatric ibuprofen suspension for the

treatment of pyrexia.

Name of the organization(s) consulted and/or supporting the application

Various key Paediatricians around the world have been consulted and have given their

endorsement to this application. These include Professor John Pearn, Professor of

Paediatrics & Child Health at The University of Queensland, Australia and Doctor Dipak

Kanabar, Consultant Paediatrician at Guy’s and St. Thomas’ Hospital, London. A

supportive statement is included from both.(Appendix 11).

Professor John Van den Anker, Executive Director, Children’s National Medical Centre

at George Washington University School of Medicine and Health Sciences, Washington,

USA and Erasmus MC-Sophia Children’s Hospital, Rotterdam has also given his support

to this application.

Two of the Companies who market this drug have also been approached. Both Boots

Healthcare International and Wyeth Consumer Health have given their full support to this

application.


International Non proprietary Name of the mdiciiie

The International Non proprietary Name of the medicine is Ibuprofen.

Whether listing is requested as an individual medicine or as an example of a

therapeutic group

The application is being made so that the drug can be listed as the individual drug,

paediatric ibuprofen suspension and not as the therapeutic group antipyretics or NSAID.

Information supporting the public health relevance

Fever has been recognised as an important sign of disease since the beginning of recorded

history. Opinion has changed substantially about whether patients are better with or

without fever. In ancient times it was considered that fever was the body’s defence

mechanis= and shculd not be tretited. A change in this view occurred in the wake of

experiments by the French physiologist, Claude Bernard, who demonstrated that animals

died when their body temperature was raised 5 - 6 degrees Celsius above normal. These

findings? combined with the beginning of thermometer use in medical practice, resulted

in a dramatic shift in opinion and fever became generally regarded as a threat to health.

However it’s important to realise that the main purpose of using an antipyretic is to

control those symptoms associated with fever which have a negative impact on the

child’s wellbeing such as headache, rigors, nausea and vomiting and febrile convulsion.

Parents the world over have a preferred method of treating high temperature in their

children and when it comes to pharmacological methods, two main treatments seem to be

used. either paracetamol or ibuprofen. Fever is one of the most common symptoms in

children and is responsible Cor 1O-JO”a of visits to the General Practitioner or

Applicstion for Inclusion of Oral Ibuprofen Suspension To The WHO Model List of Essential Medicines

Paediatrician. Parents are frightened when their child develops a fever w-hich is further

compounded by seeing their child in distress. It has been demonstrated that undue fear of

the effects of fever among parents of infants and young children is common and has led

to overly aggressive treatment. This has included treating children with temperatures

below 38 degrees Celsius, waking sleeping children to administer antipyretics and using

physical methods that are both uncomfortable and ineffective. Symptomatic treatment

with rapid onset is often required to avoid any distress or discomfort, dehydration and

febrile seizures. The efficacy of ibuprofen in the treatment of pyrexia has been studied in

many comparator and placebo-controlled studies and these are discussed extensively

below. For all licensed dosages ibuprofen has been shown to be at least as effective as

paracetamol in treating fever. Recent studies have shown that ibuprofen is superior in

effectiveness to paracetamol in treating fever and again these are discussed below. The

tolerability of ibuprofen when used as a short term antipyretic is similar to that of

paracetamol and again details of this are indicated in the studies below. The safety

profiles of both drugs are excel!ent yet not al! children will respond to each drug, it

therefore being important to offer choice. Aspirin is limited in the paediatric population

due to concerns over the association with Reye's syndrome.

All of this means that in terms of public health relevance it is essential that both

paracetamol and ibuprofen are available for the treatment of fever in children.

Treatment details

The posology detailed in the table below is based on a dose of 7-0-30mg/kg daily or 7.5-

1 Omgikg per single dose.

Doses should be given approxi~narely every 6-8 hours. or with a minimum interval of 4

hours benveen each dose.

Age

Babies 3-6 months

Babies 6-12 months

Children 1-3 years

Children 3-6 years

Average weight (kg) /Uni t dose Sr frequency ir. 24 hours

(approx)

5.6-7.6

7.7-9

10-15

16-20

2.5 mi 3 times a day

2.5 ml 3-4 times a day

5 m l 3 times a day

7.5 m l 3 times a day

Children 7-9 years

I I I I

21-29 110 ml3 times a day

There are a variety of dosing devices available to administer paediatric ibuprofen

suspension including a dosing spoon and dosing syringe that is available calibrated with

weight or volume. This will enable children who may be malnourished to be dosed

safely.

Children 10-12 years

Summary of comparative effectiveness in a variety nf c!inical settings:

- Identification of clinical evidence

Data Source

The following electronic databases were searched from their inception through October

2004 to identify randomised controlled trials, systematic reviews and meta-analyses

examining the efficacy of ibuprofen in fever. Medline, Embase, Cochrane Database,

Database of Abstracts Of Reviews Of Effects, Adis Clinical Trials Insight, Biosis

previews, British Nursing Index, CBIB, Derwent Drug File, International Pharmaceutical

Abstracts. Pharm-Line, Cinahl, Pascal. SCZZ- SciSearch. In implementing the search

strategy we used the following key words in combination: ibuprofen, Nurofen, Brufen,

Motrin. Ad\ il. isobutylphenyl, propionic acid, antipyretic, antipyresis. pyrexia, fever.

hypothermia. child. infant. paediatric. pediatric. The electronic search strategy is

30-40 115 m13 times a day


provided in appendix 1 . Hand searches o f reference lists of identified studies did not

provide any additional data

- Inclusion and Exclusion Criteria

We included studies with children aged less than 16 years receiving either ibuprofen or a

comparator antipyretic for the treatment of fever. Systematic reviews and meta-analyses

that included studies which satisfied these criteria were also included. Studies addressing

both fever and pain were also included however data representing the analgesic affect of

ibuprofen were excluded. Otherwise relevant studies measuring the antipyretic effect of

ibuprofen were excluded if no comparator therapy was used.

- Results

Following the electronic search 509 results were initially identified. From these, 150

results were eliminated from title checking using over inclusive methodology which also

included elimination of duplications. Following abstract reviews, and where abstracts

were not available papers were sourced, 3 1 papers were identified as meeting the

inclusion criteria. These are presented in the following tabulated summary.

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Application for Inclusion of Oral Ibuprofen Suspension T o The WHO Model List of Essential Medicines

Srimmary of comparative evidence on safety -

Disorders I

Nervous System Disorders

Renal and Urinary Disorders

Heparobiliary IDisorders

Blood and

-Estimnte of totulpatient e.uposure to date

Paediatric ibuprofen has been available since 1997 and is now marketed in more than 60

countries. Such a diverse international market makes it difficult to obtain valid global

patient exposure. In 1997 child specific ibuprofen accounted for 7.0% of the global child

specific non-prescription analgesics market, approximating to a value of f72.4 million

which is the equivalent of 27 million packs of product. This market share increased to

12.0% by 2003, approximating a value of L141.2 million which is the equivalent of 48

million packs of product.

Data was unavailable for the prescription market but the value is estimated to be the

equivalent of the non-prescription analgesics market.

Source- Euromonitor

Rare:

Very rare:

diarrhoea, flatulence, constipation and vomiting

gastro-intestinal ulcers, sometimes with bleeding and perforation can occur.

Uncommon: Headache

Very rare: Decrease of urea excretion and oedema can occur. Also, acute renal failure. Papillary necrosis, especially in long-term use, and increased serum urea concentrations have been reported.

Very rare'. liver disorders, especially in long-term treatment.

Vcry rare: 1 haematopoietic disorders (anaemia, leucopenia.

I

1

- Dmcripiieic?r? Q,f adxrs2 efi2cts,+eac;imis

The list of thc Following adverse effects relates to those experienced with ibuprofen.

Gastrointestinal IUncommon: \abdominal pain, dyspepsia and nausea.

Very rare:

Uncommon:

Very rare

\ /

epidermal necrolysis can occur.

In patients with existing auto-immune disorders (such as systemic lupus erythematosus, mixed connective tissue disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed

Hypersensitivity reactions with urticaria and pruritus.

severe hypersensitivity reactions. Symptoms could be: facial, tongue and larynx swelling, dyspnoea, tachycardia, hypotension, (anaphylaxis, angioedema or severe shock).

Exacerbation of asthma and bronchospasm.

kin an( ubcutaneous )isorders

nmune Systen lisorders

Iypersensitivity .eactions

\d Very rare: Isevere forms of skin reactions such as erythema muitiforme and;

The frequencies are defined as follows and as defined by the ICH guidelines:

Very common: >:/IO

Commoii: ::: 00, :::I 0

Uncommon: >I / l , nnn , i/in,nnn, <i / i ,nno

Very Rare: <1/10,000, including isolated reports.

- Identification of variation in safety due health sy! ms and. rtient factors

No issues in variation in safety due to health systems have been identified; however

particularly in the developing countries there are possible issues with malnutrition and

dehydration within the patient population.

The issue of malnutrition can be addressed by dosing the child according to weight as

detailed in the dosing table presented earlier. The availability of a dosing syringe

calibrated with weight or volume will enable children who may be malnourished to be

dosed safely.

,,\buprnf;.,j $(&J5. P T?, u - - - - Application for Inclusion of Oral Ibuprofen Suspension

To The WHO Model List of Essential Medicines

As a precautionary measure as in the use of all NSAIDs including aspirin and ibuprofen

we recommend that all children be adequately hydrated before receiving paediatric

ibuprofen suspension. During periods of dehydration, which may occur in children with

high temperature or malnourishment, there is a small possibility of reversible pre-renal

acute renal insufficiency. In circumstances of severe volume depletion and reduced renal

glomerular filtration vasoconstrictor agents such as angiotensin I1 and noradrenaline are

generated. The vasodilator prostaglandins, PGE2 and PGI, modulate the effects of the

vasoconstrictor agents in the kidney by causing compensatory vasodilation8. Therefore

inhibition of prostaglandin synthesis may elicit a temporary affect on this compensatory

mechanism. However, this is reversible on stopping the NSAID and does not normally

occur in healthy indi~iduals '~.

Renal function was monitored in a subgroup of children (285 of 27 065) who were

admitted to hospital while participating in a randomised double-blind trial of 5 or 10

mgikg of ibuprofen or paracetamol 12 mg/kg for the treatment of febrile illness'*. There

was no difference between the treatments in blood urea nitrogen levels, serum creatinine

concentrations or the incidence of serum creatinine concentrations > 62 micromolil. The

authors concluded these data suggest that the short-term risk of less severe renal

impairment associated with short-term use of ibuprofen in children is small and not

significantly different from that with paracetamol. There was also no difference between

ibuprofen and paracetamol in the risk of admission for acute renal failure 1 9 .

Much ibuprofen safety data in premature infants have also become available in the last

few years. It is important to note that premature infants present as an extremely

vulnerable population since prematurity is associated with a relatively high risk of serious

complications including renal pathology. Approximately 95% of pretenn infants are

admitted io neonatal intensive care units. In developed countries complications include

respirarory distress syndrome (50 - 60% of infants), PDA (30 - 30%); nosocomial

inkction (IO - 15%). intraventricular hemorrhage (lo%), death (9 - 15%) and

Application for Inclusion of Oral Ibuprofen Suspension I


neurodevelopmental delay 3’. The fact that ibuprofen is so well tolerated in these

vulnerable infants with high initial plasma levels, low protein binding and slow

elimination lends strong support for its safety in children aged 3 months and above who,

by comparison, are relatively healthy.

Var~arigou’~ concluded that treatment with ibuprofen in pre-term infants was not

connected with any neurological, intestinal, renal, hepatic or haematological

complications. Furthermore D a d concluded that ibuprofen reduced the incidence of

bronchopulmonary dysplasia without any renal, biochemical or haematological effect,

Romagnoli” found that ibuprofen did not have any direct effect on cerebral and renal

blood flow velocities in premature infants. Therefore, ibuprofen did not increase the risk

of either cerebral or renal hypoxia, with no effect on blood flow velocities in either the

anterior cerebral artery or renal artery, in these infants. This was also supported by further

blood flow velocity studies undertaken by Lago”. In a study examining the effects of

both ibuprofen and indomethacin in pretem infants treated for PDA, ibuprofen was

found not tc significaiily reduce mesenteric blood flow velocity compared with

indomethacin. Heyman’” showed oral ibuprofen to be effective and safe in PDA closure

with serum creatinine levels within normal range at all times. Subsequently there was no

contraindication for a second or third dose of ibuprofen when required. Good tolerability

was also demonstrated in PDA studies undertaken by Supappanachart” and Akisu’.

Supappanachart determined that following orally administered ibuprofen, infants had

serum creatinine levels that were not significantly different from pre-treatment levels.

Akisu also found that ibuprofen was not associated with significant side effects in pre-

term infants


- Summary of comparative safety against comparators

Many comparative studies have been conducted with ibuprofen which look at efficacy as

well as safety. The studies reviewed for the purpose of this application are those using

paracetamol as the key comparator. This is because paracetamol is one of the most

widely used paediatric medications and has an excellent safety profile. The first study

reviewed is a randomised double-blind clinical trial with over 84,000 subjects. The

second study is a multicentre open label prospective study with over 30,000 subjects.

These two studies provide an invaluable insight into the practical use of ibuprofen in a

clinical setting. The third is a meta-analysis which itself reviews 17 key comparative

clinical trials

Dr Samuel M. Lesko of Boston University and the Northeast Regional Cancer Institute,

Scranton, Pennsylvania, reported on the results fiom the Boston University Fever

Designed and conducted by the Slone Epidemiology Unit at the university, and

guided by an Independent Advisory Committee, it investigated the risk of rare and

serious adverse events after using ibuprofen suspension in febrile children.

In the Boston Study, 1,735 primary care physicians enrolled 84,192 children into a

randomised double-blind clinical trial. The children had to have febrile illnesses, be aged

between six months and 12 years, weigh between seven and 50 kg, be able to take

medication by mouth and be in the care of a parent or guardian who could follow written

instructions in English. Children known to be sensitive to ibuprofen or paracetamol were

excluded from the study.

Randomisation was to one of three treatment groups: paracetamol 12 mgikg, ibuprofen 5

mg/kg, and ibuprofen (10 mg/kg). The primary outcomes sought were admission to

hospital for the events seen in adults taking NSAIDs, such as acute gastrointestinal

bleeding, acute renal failure and anaphylaxis. There were approximately 28,000 children


in each treatment group. The median treatment age was 40 months, and 52 percent were

male

Two children died during the trial. The deaths were judged not to be related to

participation in the study. One was the result of a car accident and one was due to

complications of bacterial meningitis.

Fewer than 800 children were hospitalised during the study, the admission rate being

similar for all three groups. There were remarkably few primary outcomes. Four children

were admitted for gastrointestinal (GI) bleeding, all of whom were in an ibuprofen

treatment group. All the bleeds were mild, not needing surgery or transfusion, and

responding to conservative management. This was a risk of GI bleeding of 7.2 per

100,000 courses of treatment. This rate was not significantly different from that in the

paracetamol group.

There were no episodes of renal failure, but because of concern that ibuprofen might

increase the risk of milder renal impaimmi, Lhr: Study aulhors searched tiit. medical

records of 288 hospitalised children for blood urea nitrogen (BUN) and creatinine levels

on, or within 24 hours of admission. The three treatment groups did not differ

significantly in either measurement. It is concluded that the short-term use of ibuprofen

does not increase the risk of renal impairment relative to that of paracetamol.

Hospitalisation for cellulitis or for abdominal pain did not vary significantly for each of

the three treatment groups. Physician visits to children with abdominal pain after

analgesics ranged from 1 I O to 120 per 100,000 treatments, the differences between the

randomised groups being insignificant.

There were 1879 asthmatic children in this study and data from this population were

examined. There was no difference in the risk of hospitalisation due to asthma between

ibuprofen and paracetamol (Relative Risk [RR] = 0.63). There was no difference in the

risk of adverse events related to asthma occurring in asthmatic children treated with

u

Application for Inclusion of Oral Ibuprofen Suspension T o The WHO Model List of Essential Medicines

ibuprofen or paracetamol. The risk of hospitalisation due to asthma in the ibuprofen

group was less than 0.09%. There was a similar result among children treated for fever

with paracetamol. Further to this, outpatient physician visits for asthma were less

common in the ibuprofen treated children (RR = 0.56) than the paracetamol treated

children. This could suggest a beneficial anti-inflammatory effect of ibuprofen in

asthmatic children

The results from the Childrens Analgesic Medicine Project (CAMP)’ complements these

results. It was a multicentre open label prospective study comparing the safety of

ibuprofen suspension with paracetamol suspension in children with fever and/ or pain.

The intent of the study was to document clinical prescribing practices and patient use of

the medicines in a naturalistic setting outside the restrictions of a randomised clinical

trial. The trial also examined whether the use of childrens ibuprofen created a higher risk

for either serious or non serious AEs relative to paracetamol. 424 paediatricians enrolled

4 i ,8 i 0 chiidren aged I month to 18 years at 69 US clinics.

A total of 30,144 children took at least one dose of either drug and were included in the

analysis. Approximately 20,000 were treated with ibuprofen and 10,000 treated with

paracetamol. There was no increased incidence of serious AEs with either drug. For both

age groups there were no serious AEs that occurred in 2 1% of treated subjects. There

were no cases of Reyes Syndrome, anaphylaxis, renal failure, gastric bleeding,

necrotising fasciitis, Stevens Johnson Syndrome or any other serious disease related to

the use of either drug. Four,children died during the trial, all occurring in children < 2

years. The deaths were judged not to be related to participation in the study. The deaths

were attributed to Herpes encephalitis, sepsis due to S.pnentoniae, medullo blastoma, and

sudden infant death syndrome. There was a slightly higher overall incidence of AEs with

the ibuprofen group14.896 1’s 12.996. This may have been due to the preference of the

physicians to treat sicker children with ibuprofen as well as the disproportionate use of

Application for Inclusion o f Oral Ibuprofen Suspension To The WHO Model List ofEssentia1 Medicines

ibuprofen increasing the likelihood of observing AEs within the ibuprofen treatment

group.

The absence of both serious AEs and rare non-serious events confirms the safety of

ibuprofen suspension in children of all ages. Overall ibuprofen exhibited a similar AE

profile to paracetamol.

A recent meta-analysis" by Dr David Perrott and his colleagues from Sydney Childrens

hospital further supports these result. They performed a meta-analysis to investigate the

relative efficacy of the two drugs in treating pain, fever and their safety compared with

each other and placebo.

Electronic databases were searched from their inception until May 2002 for randomised

controlled trials of ibuprofen and paracetamol for paediatric pain and fever. 127 studies

of potential relevance were identified and 17 blinded randomised controlled trials with

chiidren aged less tinan 18 years, receiving eirher drug to treat fever or moderate IO severe

pain were selected. All 17 data sets were used for the analysis on safety.

The principal outcome measure for safety was the risk ratio for minor and major harm for

ibuprofen vs paracetamol treatment. Minor harm was defined as the occurrence of an AE

not leading to withdrawal from the study such as nausea or sweating. The risk ratio for

minor harm was calculated by dividing the number of minor harm events per patient for

the ibuprofen treatment arm by the corresponding figure for the paracetamol treatment

arm.

Major harm was defined as the occurrence of an AE causing withdrawal from the study

such as abdominal pain or vomiting. The risk ratio for major harm was calculated by

dividing the proportion of patients experiencing major harm of minor harm in the

ibuprofen rreatment ann by the corresponding proportion in the paracetamol treatment

Application for lnclusion of Oral Ibuprofen Suspension To The WHO Model List of Essential Medicines

arm. The risk ratios for minor and major harm for each drug compared with placebo was

also calculated

For the minor and major harm analyses, a risk ratio of 1 indicated that the drugs did not

differ in safety. Risk ratios greater than 1 indicate that ibuprofen was less safe than

paracetamol, and values less than 1 indicate tlic converse.

' h e point-estimate for the risk ratio was 0.96 (0.68-1.36) for minor hami and 1.00 (0.55-

1.82) for major harm. As the 95% CIS contained values on either side

of 1 .00, these data provide no clear evidence that the dniys differed from each other in

safety. There was also no evidence that the risk ratio varied in magnitude across the

individual studies

i. Nine studies reported minor and major harm data for a placebo arm. I hese data were

used tc calculate risk ratios for minor and major harm compared with placebo. For minor

harm. rhc risk r:ltio for paracetamol :s p!acebo was 0.79 (YJYOLI. 0.42 -i .48); the risk

ratio for ibuprofen vs placebo was 1.17 (95% C1. 0.68-2.03). For major harm, the risk

ratio for paracetamol vs placebo was 0.90 (95% CI_ 0.25- 3.29); the risk ratio for

ibuprofen vs placebo was 1.51 (95% CI. 0.45-5.05). Although for both minor and major

harm the risk ratic point-estimatcs were closc to i for both drug placebo comparisons, the

\\-idth of the 05% CIS suggests that these data are inconclusive as to safety. especially for

major harm.

,_-",<.

In summary these data do not provide any evidence to suggest that treatment with

ibuprofen and paracetamol are less safe than each other or placebo. ie both were more

effective than placebo and equally safe at the studied dosages. In addition the wide

therapeutic index of ibuprofen is also beneficial. The therapeutic index of ibuprofen is 20

(therapeutic dose of 10 mglkg and toxic dosc is between 300 and 400 mg/kg). By


contrast. the therapeutic indcx of paracetamol is only about 10 (therapeutic dose of 15

Drug Highest cost (US$/ml)

mg/kg and toxic dose of 150 mg/kg). Ibuprofen therefore has a therapeutic index at least

twice as high as that of paracetamol, w-hich is already licensed for children from 3

months. Unlike aspirin and paracetamol, the effects of ibuprofen in overdose are

predictable from its pharmacology at therapeutic doses. The large majority of patients

who take an overdose of ibuprofen suffer no symptoms or only mild symptoms".

Additionally in the developing world there are many children who are malnourished and

therefore will have depleted glutathione storages resulting in an increased risk of

hepatotoxicity related to acetaminophen

Lowest Cost Median Cost (US$/ml) (US$/rnl)

Summary of available data on comparative cost and cost-effectiveness within the

pharmacological class or therapeutic group.

The costs for ibuprofen and paracetamol have been sourced from the International Drug

Price Indicator Gdide (accessible fr=m the Wor!d wide Web) and were taken on 25'"

October 2004. The cost of ibuprofen has been provided and also the cost of paracetamol

to enable comparison. Since this is an application for paediatric ibuprofen then the costs

of suspension have been used.

Paracetamol 0.0086 0.0006 0.0032

I I I I ~l Ibuprofen 0.0025 0.0105

In order to give a comparative cost the maximum possible dose that a child could take for

a self-limiting illness has been used.


Drug

Paracetamol

______ Maximal daily Cost per ml Total cost pcr dose for 16 year (USYml) day treatment old child (US$) _ _ _ _ _ _ ~ ~ 49 0.0032 7

I Ibuprofen 1 0.630

Summary of regulatory status of the medicine

Ibuprofen is available for paediatric use, either with or without medical prescription, in

more than 6 1 countries. They include the following: Argentina, Austria, Australia,

Bulgaria, Botswana, Belgium, Brazil, Canada, China Colombia, Cyprus, Czech Republic,

Denmark, Finland, Egypt, France, Georgia, Germany, Greece, Hong Kong, Hungary,

India, Indonesia. Ireland. Israel, Italy, Japan, Jordan, Kazakhstan, Lebanon, Luxembourg,

Malaysia. Malta, Mexico, Morocco, Namibia. Netherlands: New Zealand, Philippines,

Poland, Puerto Rico, Portugal, Romania, Russia, Saudi Arabia, Serbia, Singapore, Slovak

Republic, South Africa. South Korea, Spain, Sweden, Swaziland, Taiwan, Thailand,

Turkey, United Kingdom, Ukraine, USA, Uzbekistan and Venezuela.

Availability of pharmacopoeial standards

A monograph for ibuprofen is available in the British Pharmacopoeia, European

Pharmacopoeia and the United States Pharmacopoeia. Ibuprofen tablets are also listed in

the International Pharmacopoeia.

Applicat ion f o r Inclusion of O r a l Ibupro fen Suspens ion To The WHO Model List of Essent ia l Medicines

PROPOSED TEXT FOR WHO MODEL FORMULARY

Paediatric Ibuprofen Suspension

Oral suspension 20mg/ml

Uses:

pyrexia

Contraindications:

Patients with a known hypersensitivity to ibuprofen or any other constituent of the medicinal product.

Patients with a history of bronchospasm, asthma, rhinitis, or urticaria associated with aspirin or other non-steroidal anti-inflammatory drugs (NSAIDs).

Patients with a history of, or existing gastrointestinal ulceration or bleeding.

Patients with severe hepatic failure, severe renal failure or severe heart failure

During the last trimester of pregnancy.

Precautions:

Caution is required in patients wirh:

undesirable effects section) systemic lupus erythematosus as well as those with mixed connective tissue disease (see

gastrointestinal disorders and chronic inflammatory intestinal disease (ulcerative colitis,

hypertension andor cardiac impairment

renal impairment

hepatic dysfunction

dehydration

Crohn's disease)

Bronchospasm may be precipitated in patients suffering from, or with a history of, bronchial asthma or allergic disease.

The elderly are at increased risk of the consequence of adverse reactions.

Undesirable effects may he rniniinised by using the minimum effective dose for the shortest possible duration.


There is some evidence that drugs which inhibit cyclo-oxygenasel prostaglandin synthesis may cause impairment of female fertility by an effect on ovulation. This is reversible on withdrawal of treatment.

Age Average weight (kg) Unit dose & frequency in 24 hours

(approx) Babies 3-6 months 5.6-7.6 2.5 m l 3 times aday

Babies 6-12 months 7.7-9 2.5 ml3-4 times a day

Children 1-3 years 10-15 5 m13 times a day

Children 4-6 years 16-20 7.5 m13 times a day

Children 7-9 years 2 1-79 10 m13 times a day

Children 10-12 years 30-40 /15ml3 timesaday I I

Dosage: The dosage detailed in the table below is based on a dose of 20-30mg/kg daily or 7.5-lOmg'kg

per single dose.

Doses should be given approximately every 6-8 hours, or with a minimum interval of 4 hours

between each dose

I

Reiial and Urinary Very rare: Disorders

Decrease of urea excretion and oedema can occur. Also. acute renal failure. Papillarq. necrosis, especially in long-

iterm use, and increased serum urea concentrations have

Undesirable Effects

The list of the following adverse cffects relates to those experienced with ibuprofen

Gastrointestinal

Disorders Rare: diarrhoea, flatulence, constipation and vomiting

perforation can occur.

I Nervous System Uncommon: Headache Disorders


Hepatobiliary Very rare: liver disorders, especially in long-term treatment. Disorders

Blood and V q rare: haematopoietic disorders (anaemia, leucopenia, Lymphatic system thrombocytopenia, pancytopenia, agranulocytosis). First Disorders signs are: fever, sore throat, superficial mouth ulcers, flu-

like symptoms, severe exhaustion, nose and skin bleeding.

Skin severe forms of skin reactions such as erythema multiforme Subcutaneous and epidermal necrolysis can occur. Disorders

Immune System Very rare: In patients with existing auto-immune disorders (such as Disorders systemic lupus erythematosus, mixed connective tissue

disease) during treatment with ibuprofen, single cases of symptoms of aseptic meningitis, such as stiff neck, headache, nausea, vomiting, fever or disorientation have been observed

and Very rare:

~~~

Hypersensitivity Uncommon: Hypersensitivity reactions with urticaria and pruritus. Reactions severe hypersensitivity reactions. Symptoms could be:

facial, tongue and larynx swelling, dyspnoea, tachycardia, ,hypotension, (anaphylaxis, angioedema or severe shock).

Very rare


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36. Van Esch A, Van Steensel-Moll HA, Steyerberg EW, Offringa M, Habbema JDF, Derksen-Lubsen G. Antipyretic efficacy of ibuprofen and acetaminophen in children wit!i febrile seizures. 3 r c h Pediatr A#dolesc Med 1995;14?:632-637.

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38. Varvarigou A, Bardin CL et al. Early ibuprofen administration to prevent patent ductus arteriosus in premature newborn infants. JAMA. 1996 Feb 21;275(7):539-44

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40. Vinh H, Parry CM et al. Double blind comparison of ibuprofen and paracetamol for adjunctive treatment of uncomplicated typhoid fever. Pediatr-Infect-Dis-J 2004: 23:

41. Volans G. Monaghan J, Colbridge M. Ibuprofen overdose. Int J Clin Pract Suppl.

12. Wahba H, The .4ntipyretic Effect of Ibuprofen and Acetaminophen in Children,

43. Walson PD, Galletta G. Braden NJ, Alexander L. Ibuprofen, acetaminophen, and

34. Thoden-W-R, Bomhofen-J. Antipyretic efficacy of ibuprofen and acetaminophen in

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226-230.

2003 Apr(135):54-60

Pharmacotherapy 2004; 24: 280-284

piacebo treatment o t febrile children. Clin Pharmacoi 'rher 1989;46:9-17.

q s s - I Application for Inclusion of Oral Ibuprofen Suspension


44. Walson PD, Ibuprofen versus paracetamol for the treatment of fever in children. Br Clin Pract Suppl. 1990 Aug;70: 19-2 1.

45. Walson PD, Galletta G, Chomilo F, Braden NJ, Sawyer LA, Scheinbaurn ML Comparison of multidose ibuprofen and acetaminophen therapy in febrile children. Am J Dis Child. 1992;146(5):626-32.

46. Wilson G, Guerra, AJMS, Santos NT. Comparative study of the antipyretic effect of ibuprofen (oral suspension) and paracetamol (suppositories) in paediatrics. J Int Med Res 1984;12:250-254,

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48. Wong A, Sibbald A et al. Antipyretic effects of dipyrone versus ibuprofen versus acetaminophenin children: results of a multinational, randomized, modified double- blind study. Clin-Pediatr.2001 4016 (3 13-324)


APPENDIX I ELECTRONIC SEARCH STRATEGY AND RESULTS

OCTOBER 2004

!'

ELECTRONIC SEARCH STRATEGY AND RESULTS OCTOBER 2004

I MEZZ 2 MEZZ 3 MEZZ

4 MEZZ 5 MEZZ

6 MEZZ 7 MEZZ 8 MEZZ 9 MEZZ 10 MEZZ I I MEZZ 12 MEZZ 13 MEZZ 14 MEZZ 15 MEZZ

16 MEZZ 17 MEZZ

I S MEZZ 19 MEZZ 20 MEZZ 21 MEZZ 22 EMZZ 23 EMZZ 24 EMZZ

25 EMZZ 26 EMZZ

27 EMZZ 28 EMZZ 29 EMZZ 30 EMZZ 31 EMZZ 32 EMZZ 33 EMZZ 34 EMZZ jj EMZZ 36 EM22

5686 IBUPROFEN 157 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL 25 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ

ACID

1692062 (CHILD$? OR INFANT$I OR PAEDIATRIC$I OR PEDIATRIC$I)

545 4 AND 5 124438 PYREXI$l OR FEVER$3 OR HYPERTHERMI$ 4168 ANTIPYRETIC$I OR (ANTI ADJ PYRETIC$l) 167 ANTIPYRESIS OR (ANTI ADJ P Y E S I S )

81 634 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 181049 7 OR 8 O R 9 OR 10

5722 1 OR 2 OR 3

1 4 6 6 A N D I I

95 12 AND 13 2638 4.TL OR 4.MJ.

216648 (CLINICAL ADJ TRIAL$I) OR CLINICAL-TRIALS# OR (CLIN ADJ TRIAL).DE.

0 CLINICAL-TRIAL# 129709 (RANDOMIZ$ OR RANDOMIS$) NEAR (TRIAL$l OR STUDY OR

95851 DOUBLE ADJ BLIND$2 332298 15 OR 16 OR I7 OR 18

STIJDIES,!

37 14 AND 19 58 14 NOT 20

17528 IBUPROFEN I834 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL 29 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ

ACID

1029887 (CHILD$3 OR INFANT$l OR PAEDIATRIC$I OR PEDIATRIC$I)

17543 22 OR 23 OR 24

1762 25 AND 26 104267 PYREXI$I OR FEVER$3 OR HYPERTHEMI$ 4167 ANTIPYRETIC$I OR (ANTI .4DJ PYRETIC$I)

71 538 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 1 3 0 3 2 8 2 8 O R 2 9 O R 3 0 O R 3 1

148 ANTIPYRESIS OR (ANTI ADJ PYRESIS)

387 27 AND 32 7513 25.TI. OR25.MJ. I39 33 AND 34

356607 (CLINICAL ADJ TRIALS]) OR CLINICAL-TRIALS# OR

37 EMZZ 38 EMZZ

39 EMZZ 40 EMZZ 41 EMZZ 42 EMZZ 43 DDNS 44 DDNS 45 DDNS

46 DDNS 47 DDNS

48 DDNS 49 DDNS 50 DDNS 51 DDNS 52 DDNS 53 DDNS 54 DDNS 55 DDNS 56 DDNS 57 DDNS

58 DDNS 59 DDNS

60 DD~NS 61 DDNS 62 DDNS 63 DDNS 64 IPAB 65 IPAB 66 IPAB

67 IPAB 68 IPAB

69 IPAB 70 IPAB 71 lPAB 72 IPAB 73 IPAB 74 IPAB 75 IPAB 76 IPAB 77 IPAB 78 IP.AB

(CLIN ADJ TRIAL).DE. 342290 CLINICAL-TRIAL# 150262 (RANDOMIZ$ OR RANDOMISS) NEAR (TRIAL$I OR STUDY OR

S9379 DOUBLE ADJ BLIND$2 455058 36 OR 37 OR 38 OR 39

STUDIES)

55 35 AND 40 134 35 NOT 41

8106 IBUPROFEN 41 4 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL

3 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ ACID

8122 43 OR 44 OR 45 68643 (CHILD$3 OR MFANT$l OR PAEDIATRIC$I OR

PEDIATRIC$l) 604 46 AND 41

26030 PYREXI$l OR FEVERS3 OR HYPERTHERMIS 34747 ANTIPYRETIC$I OR (ANTI ADJ PYRETIC$l)

9860 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 65053 49 OR 50 OR 51 OR 52

236 48 AND 53 8122 46.TI. OR 46.MJ. 236 54 AND 55



0 CLINICAL-TRIAL# 75302 (RANDOMIZS OR RANDOMISS) NEAR (TRIALS1 OR STUDY OR

68043 DOUBLE ADJ BLINDTI 2 1 8 8 1 8 5 7 O R S 8 O R 5 9 O R 6 0

STUDIES)

79 56 AND 61 157 56 NOT 62

1499 IBUPROFEN 136 NUROFEN OR BRUFEN OR iviOTWI OR ADVIL 5 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPlONIC ADJ

AClD

23055 (CHILD$3 OR INFANT$I OR PAEDIATRIC$l OR PEDIATRIC$l)

1502 64 OR 65 OR 66

89 67 AND 68 3 173 PYREXI$I OR FEVER$3 OR HYPERTHERMI$ 9787 ANTIPYRETIC31 OR (ANTI ADJ PYRETIC$I)

973 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE

47 69 AND 74

47 75 AND 76


13339 70 OR 71 OR 72 OR 73

1502 67.TI. OR 67.MJ.

7342 (CLINICAL ADJ TRIALSI) OR CLINICAL-TRIALS# OR (CLIN ADJ TRIAL).DE.

79 IPAB SO IPAB

S I IPAB 82 IPAB 83 IPAB 84 !PAR 85 BlZZ 86 BIZZ 87 BIZZ

88 BIZZ 89 BIZZ

90 BIZZ 91 BIZZ 92 BIZZ 93 BIZZ 94 BIZZ 95 BIZZ 96 BIZZ 97 BIZZ 98 BIZZ 99 BIZZ

100 BIZZ 101 BIZZ

102 BIZZ IO3 BIZZ 104 BIZZ 105 BIZZ 106 LINE 107 LINE 108 LINE

IO9 LINE 110 LINE

1 1 1 L N ? 112 LINE 113 LINE 114 LINE 115 LINE I I6 LINE 117 LINE I 1 8 LINE 119 LINE 110 LINE

121 LINE

0 CLINICAL-TRIAL# I1 157 (RANDOMIZ$ OR RANDOMISQNEAR (TRIAL$I OR STUDY OR

IO807 DOUBLE ADJ BLIND$? STUDIES)

23155 78 OR 79 OR 80 OR 81 1 I 77 AND 82 36 11 NOT 83

133 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL 37 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ

6900 lBUPROFEN

ACID

1035852 (CHILD$3 OR INFANT$I OR PAEDIATRIC$I OR PEDIATRIC$ I)

544 88 AND 89 140310 PYREXI$I OR FEVER$3 OR HYPERTHEMI$ 4220 ANTIPYRETIC$l OR (ANTI ADJ PYRETIC$l)

26927 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 162009 9 1 OR 92 OR 93 OR 94

6962 85 OR 86 OR 87

I 81 ANTIPYRESIS OR (ANTI ADJ PYRESIS)

131 90 AND 95 6962 %.TI. OR 8S.MJ. 131 96 AND 97


0 CLINICAL-TRIAL# 78451 (RANDOMIZ$ OR RANDOMIS$) NEAR (TRIAL$I OR STUDY OR

STUDIES) 56884 DOUBLE ADJ BLIND$? I66927 9 9 0 R 100 OR IO1 OR IO2

30 98 AND 103 101 98NOT 104 850 IBUPROFEN

6 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL 0 '2' ADJ '4' ADJ ISOBLITYLPHENYL ADJ PROPIONIC ADJ

ACID 851 I06 OR IO7 OR 108

19001 (CHILD$3 OR INFANT$I OR PAEDIATRIC$I OR PEDIATRIC$I)

124 IO9 AND 110 2466 PYREXI$I OR FEVER$3 OR HYPERTHERMI$

88 ANTIPYRETIC$l OR (ANTI ADJ PYRETIC$I) 4 ANTIPYRESIS OR (ANTI ADJ PYRESIS)

592 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 2825 1 12 OR I I3 OR 1 I4 OR 115

37 I l l AND 116 851 109.TI. OR 109 MJ. 37 I17 AND 1 I S

(CLIN ADJ TRIAL).DE. 11718 (CLINICAL 4DJ TRIAL$I) OR CLINICAL-TRIALS# OR

0 CLINICAL-TRIAL#

122 LEVE

123 LINE 124 LINE 125 LINE 126 LINE I27 ACZZ 128 ACZZ 129 ACZZ

130 ACZZ 131 ACZZ

132 ACZZ 133 ACZZ 134 ACZZ 135 ACZZ 136 ACZZ 137 ACZZ 138 ACZZ 139 ACZZ 140 ACZZ 141 ACZZ

142 ACZZ 143 ACZZ

144 ACZZ 145 ACZZ 146 ACZZ 147 ACZZ 148 AC89 149 AC89 150 AC89

I 5 1 AC89 152 AC89

153 AC89 154 AC89 155 AC89 156 AC89 157 AC89 158 AC89 159 AC89 160 AC89 161 AC89 162 AC89

163 AC89 164 AC89

1085 1 (RANDOM!Z$ OR RANDOMIS$) NEAR (TR!AL$ I OR STUDY OF. STUDIES)

735 DOUBLE ADJ BLIND$2 15984 l20OR121 O R 1 2 2 O R 1 2 3

7 I I9 AND 124 30 1 I9 NOT 125 2 1 19 IBUPROFEN

64 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL 0 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPlONIC ADJ

ACID 2121 127 OR 128 OR I29

42552 (CHILD$3 OR INFANT$I OR PAEDIATRIC$I OR PEDIATRIC$l)

202 130AND 131 9557 PYREXI$I OR FEVER$3 OR HYPERTHERMI$ 9008 ANTIPYRETIC$I OR (ANTI ADJ PYRETIC$l)


2121 I3O.TI. OR 130.MJ.

49037 (CLINICAL ADJ TRIAL$l) OR CLINICAL-TRIALS# OR


94 132 AND 137

94 138 AND 139

(CLIN ADJ TRIAL).DE. 0 CLINICAL-TRIAL#

63688 (RANDOMIZ$ OR RANDOMIS$) NEAR (TRIAL$I OR STUDY OR

33 179 DOUBLE ADJ BLIND$2 89757 141 OR 142 OR 143 OR 144

STUDIES)

30 I40 AND I45 64 140 NOT 146


ACii) 446 148 OR 149 OR 150

2306 (CHILD$3 OR INFANT$I OR PAEDIATRlC$I OR PEDIATRICS 1)

43 151 AND 152 1867 PYREXI$l OR FEVER$3 OR HYPERTHERMB 125 ANTIPYRETIC$l OR (ANTI ADJ PYRETIC$l)

465 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 2159 154OR 155OR 156OR 157

446 IjI.T!.OR 151.MJ.

1055 (CLINICAL ADJ TRIAL$l) OR CLINICAL-TRIALS# OR


15 153 AND 158

15 159AND 160


1584 (RANDOMES OR RANDOMIS$) NEAR (TRLAL$I OR STUDY OR

165 AC89 166 AC89 167 AC89 168 AC89 169 CDSR 170 CDSR 171 CDSR

172 CDSR 173 CDSR

174 CDSR 175 CDSR 176 CDSR 177 CDSR 178 CDSR 179 CDSR I 8 0 CDSR 181 CDSR 182 CDSR 183 CDSR

184 CDSR 185 CDSR

186 CDSR 187 CDSR 188 CDSR i s 9 CDSR 190 DARE 191 DARE 192 DARE

193 DARE 194 DARE

195 DARE 196 DARE 197 DARE 198 DARE 199 DARE 200 DARE 201 DARE 202 DARE 203 DARE 204 DARE

205 DARE 206 DARE

STUDIES) 4946 DOUBLE ADJ BLIND$2 6430 162 OR 163 OR 164 OR 165

6 161 AND 166 9 161 NOT 167 14 IBUPROFEN 0 NIJROFEN OR BRUFEN OR MOTKN OR ADVIL 0 '2' ADJ 'q ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ

14 I69 OR I70 OR 171 ACID

619 (CHILD$3 OR INFANT$I OR PAEDIATRIC$I OR PEDIATRIC$I)

5 172AND 173 49 PYREXI$I OR FEVER$3 OR HYPERTHEMI$ 5 ANTIPYRETIC$I OR (ANTI ADJ PYRETIC$l) 0 ANTIPYRESIS OR (ANTI ADJ PYRESIS)

21 FEVER# OR (BODY ADJ TEMPERATURE) O R FEBRILE 64 175 OR 176 OR 177 OR 178

1 174AND 179 4 172.TI. OR 172.MJ. 0 180AND 181

( C L N ADJ TRIAL).DE. 476 (CLINICAL ADJ TRIALS]) OR CLINICAL-TRIALS# OR

0 CLINICAL-TRIAL# 2063 (RANDOME$ OR RANDOMIS$) NEAR (TRIALS1 OR STUDY OR

STUDIES) I60 DOUBLE ADJ BLIND$:

2097 183 OR 184 OR 185 OR 186 0 152AND 187 0 i82NOT I88 26 IBUPROFEN 0 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL 0 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ

26 I90 OR 191 OR 192 790 (CHILD$3 OR INFANT$I OR PAEDIATRIC$I OR

ACID

PEDIATRIC$I) 5 193 AND 194

66 PYREXI$I OR FEVER$3 OR HYPERTHEMI$ 3 ANTIPYRETIC$I OR (ANTI ADJ PYRETIC$I) 0 ANTIPYRESIS OR (ANTI ADJ PYRESIS)

30 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 87 196 OR 197 OR 198 OR 199 2 195 AND 200

26 193 TI. OR 193.MJ. 2 201 AND 202

(CLIN ADJ TRIAL).DE. 1261 (CLINICAL ADJ TRIAL$I) OR CLINICAL-TRIALS# OR

0 CLINICAL-TRIAL$ 2696 (RANDOMIZ$ OR RANDOMISS) NEAR (TRIALS1 OR S rUDY OR

STUDLES)

207 DARE 496 DOUBLE ADJ BLIND$2 208 DARE 2907 204 OR 205 OR 206 OR 207 209 DARE 2 203 AND 208 210 DARE 0 203 NOT 209 211 BNID 12 IBUPROFEN 212 BNID 0 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL 213 BNID

214 BNID 12211 O R 2 1 2 O R 2 1 3 21 5 BNID 10740 (CHILD$3 OR INFANT$I OR PAEDIATRIC$I OR

216 BNID 5 2 1 4 A N D 2 1 5 2 17 BNID 218 BNID 6 ANTIPYRETIC$l OR (ANTI ADJ PYRETIC$]) 219 BNID 0 ANTIPYRESIS OR (ANTI ADJ PYRESIS) 220 BNID 236 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 221 BNID 222 BNID 3 216 AND 221 223 BNID 12 214.T1. OR214.MJ. 224 BNID 3 222 AND 223 225 BNID 187 (CLINICAL ADJ TRLAL$I) OR CLINICAL-TRIALS# OR

226 BNID 0 CLINICAL-TRIAL# 227 BNID

228 BNID 41 DOUBLE ADJ BLIND$2 229 BNID 981 225 OR 226 OR 227 OR 228 230 BNID 0 224 AND 229

232 "AH, 7 I8 IBUPROFEN 233 NAHL 26 NUROFEN OR BRUFEN OR MOTRIN OR ADVIL 234 NAHL

235 NAHL 729 232 OR 233 OR 234 236 NAHL 362745 (CHILD$3 OR INFANT$I OR PAEDIATRIC$i OR

237 NAHL 246 235 AND 236 238 NAHL 5243 PYREXBI OR FEVER$3 OR HYPERTHEMI$ 239 NAHL 187 ANTIPYRETIC$l OR (ANTI ADJ PYRETIC$I) 240 NAHL 37 ANTIPYRESIS OR (ANTI ADJ PYRESIS) 241 NAHL 3766 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 242 NAHL 7394 238 OR 239 OR 240 OR 241 243 NAHL 87 237 AND 242 244 NAHL 179 235.TI. OR 235.MJ. 245 NAHL 20 243 AND 244 246 NAHL 38462 (CLINICAL ADJ TRIAL$I) OR CLINICAL-TRIALS# OR

247 NAHL 0 CLINICAL-TRIAL# 248 NAHL 33362 (RANDOMIZ$ OR RANDOMIS$) NEAR(TRIAL$I OR STUDY OR

249 NAHL 107345 DOUBLE ADJ BLIND$?

0 '2' ADJ '4' i\DJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ ACID

PEDIATRIC$I)

16 1 PYREXI$ 1 OR FEVER$3 OR HYPERTHEMI$

337 21 7 OR 21 8 OR 219 OR 220

(CLIN ADJ TRIAL).DE.

821 (RANDOME$ OR RANDOMIS$) NEAR (TRIAL$I OR STUDY OR STUDIES)

231 BNID 3 224 NOT 230

0 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ ACID

PEDIATRIC$I)

(CLIN ADJ TRIAL).DE.

STUDIES)

250 NAIHL 251 NAHL 252 NAHL 253 PASC 254 PASC 255 PASC

256 PASC 257 PASC

258 PASC 259 PASC 260 PASC 261 PASC 262 PASC 263 PASC 264 PASC 265 PASC 266 PASC 267 PASC

268 PASC 269 PASC

270 PASC 271 PASC 272 PASC 273 PASC 214 CBIB 275 CBIB 216 CBIB

277 CBIB 278 CBIB

279 CBIB 280 CBlB 281 CBIB 282 CBIB 283 CBIB 284 CBIB 285 CBlB 286 CBlB 287 CBIB 288 CBIB

289 CBlB 290 CBIB

291 CBlB 292 CBIB

21 I997 246 OR 247 OR 218 OK 249 I 1 245 AND 250

2495 IBUPROFEN 9 245 NOT 2.5 1

22 NUKOFEN OR BRUFEN OR MOTRIN OK ADVIL 15 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ

ACID 2506 253 OR 254 OR 255

486254 (CHILD$3 OR INFANTK OR PAEDIATRIC$l OR PEDIATRIC$I)

221 256 AND 251 3 1032 PYREXI$I OR FEVER$3 OR HYPERTHERMI$ 2920 ANTIPYRETIC$I OR (ANTI ADJ PYRETIC$I)


2506 256.TI. OR 256.MJ.

48466 (CLINICAL ADJ TRIAL$I) OR CLINICAL-TRIALS# OR


70 258 AND 263

70 264 AND 265


57791 (RANDOMIZ$ OR RANDOMIS$) NEAR (TRIAL$I OR STUDY OR

36321 DOUBLE ADJ BLIND$2 110809 267 OR 268 OR 269 OR 270

STUDIES)

21 266AND271 49 266 NOT 272

3015 IBLTPROFEV 20 NUROFEN OK BRUFEN~ OR MOTTRIN OR ADVIL 19 '2' ADJ '4' ADJ ISOBUTYLPHENYL ADJ PROPIONIC ADJ

ACID 3028 274 OR 275 OR 276

381606 (CHILD$3 OR INFANT$I ORPAEDIATRIC$I OR PEDIATRIC$I)

298 217 AND 278 35322 PYREXI$I OR FEVER$3 OR HYPERTHEMI$

841 ANTIPYRETIC$I OR (ANTI ADJ PYRETlC$l) 77 ANTIPYRESIS OR (ANTI ADJ P Y E S I S )

13 100 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 45444 280 OR 281 OR 282 OR 283

3028 277.TI. OR 277.MJ.

59901 ( C L N C A L ADJ TRIAL$l) OR CLINICAL-TRIALS# OR

88 279 AND 284

88 285 AND 286

(CLIN ADJ TR1AL):DE. 0 CLINICAL-TRIAL#

93814 (IWNDOMIZ$ OR RANDOMIS) NEAR (TRlAL$I OR STUDY OR

501 73 DOUBLE .4DJ BLIND$? STUDIES)

I61 2.53 288 OR 289 OR 290 OR 291

293 CBIB 294 CBIB 295 SCZZ 296 SCZZ 297 sczz 298 SCZZ 299 SCZZ

300 SCZZ 301 SCZZ 302 SCZZ 303 SCZZ 304 SCZZ 305 SCZZ 306 SCZZ 307 SCZZ 308 SCZZ 309 SCZZ

310 SCZZ 311 SCZZ

312 sczz 313 sczz 314 SCZZ 315 SCZZ 316

317 318 319

320 321

34 287 AND 292 54 287 NOT 293


ACID 733 1 295 OR 296 OR 297

773408 (CHILD$3 OR INFANT$I OR PAEDIATRIC$I OR PEDIATRIC$ I )

667 298 AND 299 72500 PYREXI$I OR FEVER$3 OR HYPERTHEMI$ 1598 ANTIPYRETIC$I OR (ANTI ADJ PYRETIC$I) 169 ANTIPYRESIS OR (ANTI ADJ PYRESIS)

23 160 FEVER# OR (BODY ADJ TEMPERATURE) OR FEBRILE 91482 301 OR 302 OR 303 OR 304

146 300 AND 305 7331 298.TI. OR 298.MJ. 146 306 AND 307


0 CLINICAL-TRIAL# 144780 (RANDOMIZ$ OR RANDOMIS$) NEAR (TRIAL$l OR STUDY OR

75865 DOUBLE ADJ BLIND$2 250342 309 OR 310 OR 31 I OR 312

STUDIES)

47 308 AND 313 99308NOT314

370 ..COMBINE 20.41.62.83.104.125.146.167.1 88,209,2?0.251,772.293

194 DUPLICATES FROM STATEMENT 0316 176 KEPT FROM STATEMENT 03 16 803 ..COMBINE 21,42,63,84,105,126,147,168,189,~l0,23l,252,273,294 ,315

294 DUPLICATES FROM STATEMENT 0319 509 KEPT

,3 I4

FROM STATEMENT 03 19

Search line 318 - ibuprofen + fever + children + clinical trials 1 MEZZ

TI Efficacy and safety of acetaminophen vs ibuprofen for treating children's pain or fever: a meta-analysis.

2 EMZZ TI How safe is ibuprofen in febrile asthmatic children?

3 AC89 TI Carprofen: n new nonsteroidal antiinflammatory drug. Pharmacology,

clinical efficacy and adverse effects.

4 DARE

TI Treating fever in children: paracetamol or ibuprofen? (Structured abstract).

5 NAHL T1 Antipyretic efficacy and safety of ibuprofen and acetaminophen in

children.

6 PASC TI Comparison of Benzydamine hydrochloride and Salvia officinalis as an

adjuvant local treatment to systemic nonsteroidal anti-inflammatory drug in controlling pain after tonsillectomy, adenoidectomy, or both: An open-label, single-blind, randomized clinical trial.

7 MEZZ Tl Double blind comparison of ibuprofen and paracetamol for adjunctive

treatment of uncomplicated typhoid fever.

8 EMZZ TI Fever and pain: Ibuprofen suppositories for small children.

9 DDNS TI A meta-analysis comparison of ibuprofen (IBU) and indomethacin (INDO)

for closure of patent ductus arteriosus (PDA).

I O IPAB TI Multicenter parallel comparison of the efficacy and tolerability of

ibuprofen vs metaizole.

!! RIZZ TI Orai ibuprofen and intravenous indomethacin for treatment of patent

ductus arteriosus in newborn infants: retrospective study.

12 ACZZ TI Pragmatic randomised controlled trial of two prescribing strategies for

childhood acute otitis media.

13 AC89 TI Ibuprofen overdose and exposure in utero: results from a postmarketing

voluntary reporting system.

14 DARE TI The nursing management of fever in children: a systematic review

(Structured abstract).

15 NAHL TI Evidence-based practice. Alternating acetaminophen and ibuprofen in the

febrile child: examination of the evidence regarding efficacy and safety

16 MEZZ TI Asthma morbidity after the short-term use of ibuprofen in children.

17 DDNS TI Analgesic efficacy of rectal acetaminophen and ibuprofen alone or in

combination for pediatric day-case adenoidectomy.

18 AC89 T! Hepatic toxicity of nonsteroid;! antiinflammatory drugs.

19 NAHL TI Ibuprofen was more protective against asthma morbidity than

acetaminophen in asthmatic children with fever.

20 MEZZ TI The safety of ibuprofen suspension in children

21 AC89 TI Suprofen.

22 MEZZ TI A general overview of the use of ibuprofen in paediatrics.

23 EMZZ TI The Antipyretic Effect of Ibuprofen and Acetaminophen in Children

24 DDNS TI Effects of postoperative, nonsteroidal, anti-inflammatory drugs on

bleeding risk after tonsillectomy. Meta-analysis of randomized, controlled trials.

25 IPAB TI Assessment of the safety of pediatric ibuprofen: practitioner-based

randomized clinical trial.

26 AC89 Ti Fentiazac suspension inthe treatment of acute inflammation of the upper

respiratory tract in children.

21 MEZZ TI Oral ibuprofen and indomethacin for treatment of patent ductus

arteriosus in premature infants: a randomized trial at Ramathibodi Hospital.

28 EMZZ TI Intramuscular dipyrone versus oral ibuprofen or nimesulide for reduction

of fever in the outpatient setting.

29 DDNS TI Evidence on the use of paracetamol i n febrile children

30 BlZZ TI Antipyretics in pediatric practice

31 AC89 TI Clinical pharmacokinetics of nonsteroidal antiinflammatory drugs.

32 NAHL TI A study of the efficacy of antipyretic drugs in the prevention of

febrile seizure recurrence.

33 CBIB TI Symptomatic intravenous antipyretic therapy: Efficacy of metamizol,

diclofenac, and propacetamol.

34 MEZZ TI Treating fever in children: paracetamol or ibuprofen?

35 DDNS TI Valdecoxib provides similar efficacy and improved upper GI safety

compared with nonspecific NSAIDs in elderly patients with osteoarthritis (OA) or rheumatoid arthritis (RA).

36 IPAB TI Placebo-controlled model for assaying systemic analgesics in children

37 NAHL TI Paracetamol or ibuprofen in febrile children.

38 CBIB TI Comparison of oral versus normal and high-dose rectal acetaminophen in

the treatment of febrile children,

39 MEZZ TI Effectiveness and tolerability of ibuprofen-arginine versus paracetamol

in children with fever of likely infectious origin.

40 BIZZ TI How did such a bad report get published in the EJCP? Trial of

paracetamol, ibuprofen and nimesulide in children with upper respiratory infections (B. Ulukol et al., EJCP November 1999, 55: 615-618).

41 ACZZ

complications.

42 NAHL

TI Ibuprofen for tonsillectomy pain in children: efficacy and

TI Clinicians' forum. Managing a child's pain and fever.

43 MEZZ TI Antipyretic effects of dipyrone versus ibuprofen versus acetaminophen in

children results of a multinational, randomized, modified double-blind study.

44 DDNS TI Safety and efficacy of ibuprofen versus indomethacin in preterin infants

treated for patent ductus arteriosus: a randomised controlled trial.

45 NAHL TI Ibuprofen suspension: pediatric antipyretic.

46 PASC TI Treatment of fever : monotherapy with ibuprofen. Ibuprofen pediatric

suspension containing 100 mg/5 ml(*), Multicentre acceptability study conducted in hospital.

Traitement de la fievre en monotherapie, ibuprofene suspension pediatrique a 100 mg/5 ml(*), etude multicentrique d'acceptabilite menee en milieu hospitalier.

47 MEZZ

paracetamol.

48 DDNS

TI Antipyretic effects of nimesulide, paracetamol and ibuprofen-

TI Premarketing surveillance of oral ibuprofen solution in febrile children.

49 NAHL TI The many uses of ibuprofen

50 MEZZ TT (haluat ion of thc antipyretic safety and accuracy of TWO pediatric

ibuprofen formuiations).

51 EMZZ TI Ibuprofen versus paracetamol in febrile asthmatic children.

52 DDNS TI Double-blind, placebo-controlled analgesic study of ibuprofen or

rofecoxib in combination with paracetamol for tonsillectomy in children

53 NAHL

children's fever. TI Pediatric ibuprofen: researchers study safety of ibuprofen use for

54 CBlB TI Antipyretic efficacy of an initial 30-mdkg loading dose of

acetaminophen versus a 15-mgkg maintenance dose.

55 MEZZ TI Pharmacokinetic-Pharmacodynamic Modelling of the antipyretic effect of

two oral formulations of ibuprofen.

56 EMZZ

TI !buprofen in !iquid form fer the treatment of fever and pain in children.

57 DDNS TI Reactogenicity of DTPa-HBVIHib vaccine administered as a single

injection vs DTPa-HBV and Hib vaccines administered simultaneously at separate sites, to infants at 2, 4 and 5 months of age.

58 MEZZ TI Parents' fear regarding fever and febrile seizures.

59 EMZZ TI lbuprofene in pediatrics

60 DDNS TI Analgesia after ambulatory amygdalectomy in the child. Comparison

between tramadol and propacetamol-paracetamol. (Fr.).

61 PASC TI Tube placement : A prospective, randomized double-blind study

62 MEZZ

two years old.

63 DDNS

TI The safety of acetaminophen and ibuprofen among children younger than

TI A comparison of ibuprofen and indomethacin for closure of patent ductus arteriosus.

64 CEiE TI Acetaminophen controlled-release sprinkles versus acetaminophen

immediate-release elixir in febrile children.

65 SCZZ TI Over-the-counter analgesics and antipyretics: A critical assessment.

66 MEZZ

counter dose.

67 EMZZ

TI Gastrointestinal safety and tolerance of ibuprofen at maximum over-the

TI Invasive group A streptococcal infection and nonsteroidal antiinflammatory drug use among children with primary varicella.

68 DDNS TI Pharmacokinetic-pharmacodynamic modelling of the antipyretic effect of 2

oral formulations of ibuprofen.

69 MEZZ TI Towards evidence based emergency medicine: best BETS from the Manchester

Royal Infirmary. Paraceramol or ibuprofen in febrile children.

70 BIZ2 TI Antipyretic therapy: Clinical trials 1990 through 1995

71 CBIB TI Morphine-sparing effect of acetaminophen in pediatric day-case surgery.

72 MEZZ TI Randomized. controlled trial of ibuprofen syrup administered during

febrile illnesses to prevent febrile seizure recurrences.

13 EMZZ

care setting.

74 DDNS

TI The antipyretic use of acetaminophen versus ibuprofen in a pediatric

TI Renal safety profile of rofecoxib, a specific inhibitor of COX-2, in controlled clinical trials.

75 CBIB TI Acetaminophen has greater antipyretic efficacy than aspirin in

endotoxemia: A randomized, double-blind, placebo-controlled trial,

76 MEZZ TI Equivalent antipyretic activity of ibuprofen and paracetamol in febrile

children.

I1 DDNS TI Effects of indomethacin and ibuprofen on mesenteric and renal blood flow

in preterm infants with patent ductus arteriosus.

78 MEZZ TI Renal function after short-term ibuprofen use in infants and children

79 EMZZ TI Safety profile of ibuprofen suspension in young children.

80 CBIB TI Treatment of fever: monotherapy with Ibuprofen. Ibuprofen pediatric

suspension containing 100 mg 5 ml, multicentre acceptability study conducted in hospital.

81 MEZZ T1 A comparison of ibuprofen versus acetaminophen with codeine in the young

tonsillectomy patient.

82 EMZZ TI Assessment of the efficacy and safety of paracetamol. ibuprofen and

nimesulide in children with upper respiratory tract infections.

83 MEZZ

TI Eva!uation of ibuprofen ve r su aspirin and paracetamol on efficacy and comfort in children with fever.

84 EMZZ TI Ibuprofen or acetaminophen for management of fever in children?

85 CS!B TI What we don't know about paracetamol in children

86 MEZZ TI Comparing efficacy and tolerability of ibuprofen and paracetamol in

fever.

87 ACZZ TI Ibuprofen or acetaminophen for the acute treatment of migraine in

children: a double-b!ind, randomized, placebo-controlled, crossover study.

88 MEZZ TI When a randomised controlled trial is needed to assess drug safety. The

case of paediatric ibuprofen.

89 DDNS TI Treatment of pain with sustained-release tramadol 100, 150, 200 rng:

results of a post-marketing surveillance study.

90 CBIB TI Antipyretic activity and safety of ibuprofen tablets in the treatment of

fever in adults: Multicentre study among general practitioners.

91 MEZZ

febrile seizures. TI Antipyretic efficacy of ibuprofen and acetaminophen in children with

92 EMZZ TI Integrated pharmacokinetic-pharmacodynamic model for acetaminophen,

I

ibuprofen, and placebo antipyresis in children.

93 CBIB TI Paracetamol plasma and cerebrospinal fluid pharmacokinetics in children.

94 MEZZ TI An assessment of the safety of pediatric ibuprofen. A practitioner-based

randomized clinical trial.

95 EMZZ TI Paracetamol and ibuprofen for treatment of fever in Malawian children

aged less than five years.

96 BIZZ

TI CLINICAL AND LABORATORY OBSERVATIONS RANDOMIZED DOUBLE-BLIND MULTICENTER

CONTROLLED TRIAL OF IBUPROFEN VERSUS ACETAMINOPHEN

PLACEBO FOR TREATMENT OF SYMPTOMS OF TONSILLITIS AND

CHILDREN.

97 ACZZ

PARACETAMOL AND

PHARYNGITIS IN

TI Renal function following short-term ibuprofen use in febrile children

98 MEZZ TI Comparative efficacy and tolerance of ibuprofen syrup and acetaminophen

syrup in children with pyrexia associated with infectious diseases and treated with antibiotics.

99 EMZZ TI Treatment of fever: Monotherapy with ibuprofen. Ibuprofen pediatric

suspension containing 100 mg/S rnl(*), multicentre acceptability study conducted in hospital.

100 DDNS TI The effect of nonsteroidal antiinflammatory drugs on electrolyte

homeostasis and blood pressure in young and elderly persons with and without renal insufficiency.

101 MEZZ TI Efficacy of ibuprofen in pediatric patients with fever.

102 EMZZ TI Temperature, age, and recurrence of febrile seizure.

103 DDNS TI Comparative effects of nabumetone, sulindac and ibuprofen on renal

function.

104 BIZ2 TI A RANDOMIZED DOUBLE-BLIND MULTICENTER CONTROLLED TRIAL OF IBUPROFEN FOR

ACUTE OTITIS MEDIA IN CHILDREN.

105 MEZZ TI Comparison of inultidose ibuprofen and acetaminophen therapy in febrile

children.

106 EMZZ TI Antipyretic activity and safety of ibuprofen tablets in the treatment of

fever in adults: Multicentre study among general practitioners.

107 DDNS TI Suppression of renal inflammation with vitamins A and E along wtih non-

steroidal anti-inflammatory agetits in ascending pyelonephritis in rats.

108 CBIB TI Postoperative analgesia with preoperative oral ibuprofen or

acetaminophen in cliildren undergoing myringotomy.

109 MEZZ TI Antipyretic efficacy of ibuprofen vs acetaminophen.

110 EMZZ TI Ibuprofen prophylaxis for adverse reactions to diphtheria-tetanus-

pertussis vaccination: A randomized trial.

111 MEZZ TI Single-dose, placebo-controlled comparative study of ibuprofen and

acetaminophen antipyresis in children.

112 EMZZ TI Informed consent, parental awareness, and reasons for participating in a

randotnised controlled study.

113 DDNS TI A randomized, double-blind, multicentre controlled trial of ibuprofen

versus acetaminophen and placebo for symptoms of acute otitis media in children.

114 CBIB TI Antipyretic efficacy of tiaprofenic acid in febrile children.

. ._ I 1 3 ivIEZZ

TI A dose ranging study of ibuprofen suspension as an antipyretic.

116 DDNS TI Pediatric ibuprofen and leukopenia

117 MEZZ TI A double-blind comparison of ibuprofen and paracetamol in juvenile

pyrexia.

118 DDNS TI Confounders of antipyretic drug pharmacodynamics.

119 MEZZ TI A double-blind dose-ranging trial with paediatric ibuprofen

120 EMZZ TI Ibuprofen and/or acetaminophen: What price for 'eutliennia'? (1)

(rnulti ple letters).

121 DDNS TI Acute and chronic effects of nonsteroidal antiinflammatory drugs on

glomerular filtration rate in elderly patients,

122 MEZZ TI Ibuprofen, acetaminophen, and placebo treatment of febrile children

I23 DDNS T! Efficacy and safety of ibuprofen (! 0 mgkg), acetaminophen (! 5 mdkg),

and placebo in the relief of orthodontic pain in children.

124 MEZZ TI A single-blind parallel group study investigating the antipyretic

properties of ibuprofen syrup versus acetylsalicylic acid syrup in febrile children.

125 EMZZ TI Ibuprofen: Proven efficacy in treatment of febrile seizures.

126 DDNS TI Nonsteroidal antiinflammatory drug-induced gastroduodenal injury in

children.

127 MEZZ TI Antipyretic activity of ibuprofen and paracetamol in children with

pyrexia.

128 EMZZ TI Efficacy and safety of acetaminophen vs ibuprofen in the febrile child,

129 DDNS Ti ibuprofen treatment of patent ductus arteriosus.

130 SCZZ TI EVALUATION OF THE ANTIPYRETIC EFFECT OF KETOROLAC, ACETAMINOPHEN, AND

PLACEBO IN ENDOTOXIN-INDUCED FEVER.

131 MEZZ TI A comparative study of two dosage levels of ibuprofen syrup in children

with pyrexia.

Id2 EMZZ TI Safety of ibuprofen use in febrile children.

133 SCZZ TI IBUPROFEN IN THE TREATMENT OF POSTOPERATIVE PAIN IN SMALL CHILDREN - A

STUDY. RANDOMIZED DOUBLE-BLIND-PLACEBO CONTROLLED PARALLEL-GROUP

154 DDNS TI An assessment of the safety of pediatric ibuprofen.

135 SCZZ T1 TREATMENT OF FEVER N CHILDHOOD

136 DDNS TI Prophylactic oral acetaminophen or ibuprofen are not effective for

postoperative pain relief in children undergoing myringotomy.

137 DDNS TI Intravenous immunoglobulin in the treatment of systemic juvenile

rheumatoid arthritis: a randomized placebo controlled trial.

138 SCZZ TI PEDIATRIC LABELING REQUIREMENTS - IMPLICATIONS FOR PHARMACOKINETIC

STUDIES.

139 EMZZ TI Short-term ibuprofen use is safe in children with fever.

140 DDNS TI Development and use of a gastropathy index for ranking the safety of

non-steroidal anti-inflammatory drugs in the elderly.

141 EMZZ TI Ibuprofen as an antipyretic drug in childhood.

142 DDNS TI Comparison of Ibuprofen, .4cetaminophen and Placebo Treatment of Fever in

Children.

143 EMZZ TI Safety of paracetamol and ibuprofen in febrile children

144 DDNS TI Efficacy and Safety of Nabumetone Versus Diclofenac, Naproxen,

Ibuprofen, and Piroxicam in the Elderly.

145 DDNS TI Safety Experience With Nabumetone Versus Diclofenac, Naproxen Ibuprofen,

and Piroxicam in Osteoarthritis and Rheumatoid Arthritis.

146 DDNS TI Efficacy of Nabumetone Versus Diclofenac, Naproxen, Ibuprofen. and

Piroxicam in Osteoarthritis and Rheumatoid Arthritis.

147 sczz TI A NEW CLINICAL BIOASSAY FOR ANTIPYRESIS

148 sczz

TI IBLJPRGFEN IN CI-IILDREN WIT: I CYSTIC-FIBROSIS - PMAR?v~ACOXINETICS AND

ADVERSE-EFFECTS

149 DDNS TI A Placebo-Controlled Model for Assaying Systemic Analgesics in Children.

150 DDNS TI Renovascular Effects of Nonprescription Ibuprofen in Elderly

Hypertensive Patients with Mild Renal Impairment.

151 EMZZ TI Ibuprofen versus paracetamol for the treatment of fever in children

152 DDNS TI Pharmacokinetics and Pharmacodynamics of Ibuprofen Isomers and

Acetaminophen in Febrile Children.

153 EMZZ

paracetamol.

154 DDNS

TI Comparative evaluation of the antipyretic efficacy of ibuprofen and

TI Single-Dose Pharmacokinetics of Ibuprofen and Acetaminophen in Febrile Children.

155 EMZZ TI Induction of prostaglandin synthesis as the mechanism responsible for

the chills and fever produced by inksiiig amphotericiu B.

156 EMZZ TI Fentiazac suspension in the treatment of acute inflammation of the upper

respiratory tract in children.

157 DDNS TI Efficacy of Ibuprofen Versus Paracetamol in Juvenile Pyrexia

158 DDNS TI Randomized, Double-Blind, Multicenter, Controlled Trial of Ibuprofen

Versus Acetaminophen (Paracetamol) and Placebo for Treatment of Symptoms of Tonsillitis and Pharyngitis in Children.

159 DDNS TI Randomized, Double-Blind, Multicentre, Controlled Trial of Ibuprofen for

Acute Otitis Media in Children.

160 DDNS TI Sore Throat Pain Model for the Evaluation of Analgesics in Children

161 DDNS TI Comparative Study of Suspensions of lbuprofeii and Paracetamol in Soft

Tissue Injuries i n Children.

162 DDNS TI Recombinant Interferon beta: A Phase 1-11 Trial in Children with

Recurrent Brain Tumors.

163 DDNS Ti Pharmacokinetics/Dynamics (PKIPD) of Ibuprofen (IBU) Isomers vs

Acetaminophen (APAPI in Febrile Children.

164 DDNS TI Effect of NSAIDs on Inulin Clearance in Healthy Elderly Persons.

165 DDNS TI Ibuprofen Suspension in the Treatment of Juvenile Rheumatoid Arthritis.

166 DDNS TI Efficacy, Safety and Pharmacodynamics of ibuprofen in Pediatric Patients

with Fever.

167 DDNS TI Pharmacodynamics of Ibuprofen (IB) Antipyresis in Children.

168 DDNS TI Renal Effects of Nonsteroidal Anti-Inflammatory Drugs in the Elderly

169 DDNS TI Ibuprofen Suspension in the Treatment of JRA: Results of the Double-

Blind, Aspirin Controlled Trial.

170 DDNS TI Ibuprofen (I) in Elderly Hypertensive Patients with Mild Renal

Impairment.

171 DDNS TI Treatment of Nephrogenic Diabetes insipidus with Prostaglandin Synthesis

Inhibitors.

172 DDNS TI Postextraction Pain Relief in Children: a Clinical Trial of Liquid

Analgesics.

173 DDNS TI Aluminum Ibuprofen Analgesia Following Extractions in Children

174 DDNS TI A Comparison of Aluminum Ibuprofen Suspension and Acetaminophen Elixir

in the Treatment of Fever in Children.

175 DDNS TI Comparative Evaluation of .\ntipyretic Activity of Ibuprofen and Aspirin

in Children with Pyrexia of Varied Aetiology.

176 DDNS Ti Comparative Study of the Antipyretic Effect of Ibuprofen (Oral ..

Suspension) and Paracetamol (Suppositories) in Paediatrics

Search line 321 - iboprofen + h e r + chi!dren 1 MEZZ TI Ibuprofen or acetaminophen i n children? As the debate continues. the

evidence may favor ibuprofen.

2 EMZZ TI Effect of recent antipyretic use on measured fever in the pediatric

emergency department.

3 DDNS TI Genetic predisposition to acute gastrointestinal bleeding after NSAIDs

use.

4 IPAB TI The use of non-opioid analgesics and antipyretics among infants and

children in Finland from 1990 to 2002.

5 BIZZ TI The use of recombinant activated factor VI1 for controlling life-

threatening bleeding in Dengue Shock Syndrome.

6 ACZZ TI Current medication choices in iuvenile rheumatoid arthritis 11 - uodatc

of a survey performed in i993

7 BNID TI Managing fever and pain in children. (Use of paracetamol and ibuprofen

for children treated at home by parents. 13 refs).

8 NAHL TI Advisor forum. Liver damage concerns in childhood fever treatment.

9 PASC TI Antipyretique activity of ibuprofen syrup in children emergency unit

Evaluation de la reponse antipyretique a 30 minutes de I'ibuprofene suspension aux urgences pediatriques.

10 CBIB

considerations.

1 1 MEZZ

TI The febrile patient: Diagnostic. prognostic and therapeutic

TI How safe is ibuprofen in febrile asthmatic children?

12 EMZZ TI Oral ibuprofen and intravenous indomethacin for treatment of patent

ductus arteriosus i n newborn infants: Retrospective study.

13 BlZZ TI Prescribing habits of general practitioners in the treatment of

chi ldhod :espiratory-tract infections.

14 LINE TI Evidence based paediatrics: evidence based management of seizures

associated with fever.

15 ACZZ TI Intravenous ketorolac in the treatment of fever

16 AC89 TI Adverse reactions to nonsteroidal antiinflammatory drugs: diclofenac

compared with other nonsteroidal antiinflammatory drugs.

17 BNID TI Managing the febrile child. (Review of latest evidence on aspirin,

ibuprofen and paracetamol).

18 NAHL TI Pain and fever in children

19 MEZZ TI The antipyretic effect of ibuprofen and acetaminophen in children.

20 DD” TI Relationship between selective cyclooxygenase-2 inhibitors and acute

myocardial infarction in older adults.

21 LINE TI Primary care treatment of pain and fever.

22 ACZZ TI Intramuscular ceftriaxone in the treatment of childhood meningitis due

to Haemophilus influenzae type F

23 AC89 TI Update on ibuprofen: review article.

24 BNID TI Treating fever in children: paracetamol or ibuprofen? (Mini-review of

the research literature. 33 refs).

25 NAHL TI Clinical update. Managing fever and pain in children

26 CBIB

TI Renal complications of non-steroidal anti-inflammatories.

27 MEZZ TI Acute renal failure after treatment with non-steroidal anti-inflammatory

drugs.

28 EMZZ TI Ibuprofen and acute renal failure in a toddler

29 DDNS TI Potential interaction between acenocoumard and diclofenac, naproxen and

ibuprofen and role of CYP2C9 genotype.

30 IPAB TI Systematic review of prevalence of aspirin induced asthma and its

implications for clinical practice.

31 LINE TI Licensed drugs in the treatment of childhood fever in Italy

32 NAHL TI How often do pediatricians recommend alternating acetaminophen and

ibuprofen for fever?

33 CBIB TI When body temperature changes, does rectal temperature lag?

34 MEZZ TI Fcver phobia revisited

35 EMZZ TI Unsubstantiated alarmist declarations need to be examined (1)

36 IPAB TI Pediatric OTC medications.

31 BIZ2 TI Platelet activity in sickle cell vaso-occlusive episodes.

38 ACZZ TI Antiepileptic hypersensitivity syndrome in children

39 AC89 TI Clinical experience and results of treatment with suprofen in

pediatrics. 3rd communication: antipyretic effect and tolerability of repeat doses of suprofen and paracetamol syrup in hospitalized children. A single blind study.

40 PASC TI The effect ofrecalling paracetamol on hospital admissions for poisoning

in Western Australia.

41 MEZZ TI Antipyretic efficacy and safety of ibuprofen and acetaminophen in

children.

42 EMZZ TI Effectiveness of Pretreatment in Decreasing .4dverse Events Associated

with Pamidronate in Children and Adolescents.

43 DDNS T1 Cerebral malaria. Optimising management.

44 NAHL TI Commentary on Acetaminophen and ibuprofen: fever control and overdose

(original article by Murphy K appears in PED NURS 1992; 18(4):428-32).

45 MEZZ TI Alternating acetaminophen and ibuprofen in the febrile child:

examination of the evidence regarding efficacy and safety.

46 EMZZ TI No evidence for practice of alternating doses of paracetamol and

ibuprofen in children with fever.

41 DDNS TI Effect of selective cyclooxygenase 2 inhibitors and naproxen on short-

term risk of acute myocardial infarction in the elderly.

48 LINE -_ 1.

I I muprofen or acetaminophen (paraceiamoij for management of h e r in children?

49 ACZZ TI Allergic reactions due to ibuprofen in children.

50 CBIB TI Underdosing of acetaminophen by parents and emergency department

utilization.

51 MEZZ TI Ibuprofen and increased morbidity in children with asthma : fact or

fiction?

52 EMZZ TI Fever phobia revisited (2)

53 DDNS TI The risk of peptic ulcer in elderly acute and chronic users of aspirin

and other nonsteroidal antiinflammatory drugs: the role of gastroprotective drugs.

54 IPAE TI Caution is key in pediatric pain relief.

55 BiZZ TI Black widow bites in children.

56 LINE TI Antipyretic therapy. Physiologic rationale, diagnostic implications, and

clinical consequences.

57 AC89 TI Analgesic overdosage an overview of the problem

58 NAHL TI Ibuprofen suspension for children.

59 MEZZ TI Ibuprofen was more protective against asthma morbidity than

acetaminophen in asthmatic children with fever.

60 DDNS TI Paracetamol in childhood. Current state of knowledge and advice for

rational use for postoperative analgesia. (Ger.).

61 IPAB TI Treatment of otitis media with observation and a safety-net antibiotic

prescription.

62 BIZ2 TI Kecombinant Activated Factor Vi1 in Controliing Life-T'nrearening

Bleeding in Dengue Shock Syndrome.

63 ACZZ TI Aseptic meningitis in a child after systemic treatment with high dose

cytarabine.

64 AC89 TI Nonsteroidal antiinflammatory drugs as analgesics

6 5 MEZZ TI Fever: to treat or not to treat. Counterpoint.

66 EMZZ TI Antipyretique activity of ibuprofen syrup in children emergency unit.

67 DDNS TI Macrophage activation syndrome following initiation ofetanercept in a

child with systemic onset juvenile rheumatoid arthritis.

68 IP.4B TI Feverish debate.

69 BIZZ TI Ethnic differences in parental antipyretic use

70 LINE TI Evaluation of ibuprofen versus aspirin and paracetamol on efficacy and

comfort in children with fever.

71 ACZZ TI Patent ductus arteriosus in the premature neonate: current concepts in

pharmacological management.

12 PASC TI Simple febrile seizures in children.

Convulsions febriles simples de I'enfant : expliquer et rassurer les parents plutot que prescrire.

13 CBIB TI Population pharmacokinetics of high dose ibuprofen in cystic fibrosis

74 MEZZ TI Fever: to treat or not to treat. Point

IS EMZZ TI Polyarthritis and mediterranean spotted fever ( 2 )

76 DDNS TI Determinants and sequelae associated with utilization of acetaminophen

versus rradirionai nonsreroidai antiinflammatory drugs in an elderly population.

I1 IPAB TI Nonsteroidal anti-inflammatory drugs for postoperative pain - A focus on

children.

7 8 LINE TI Comparing efficacy and tolerability of ibuprofen and paracetamol in

fever.

I 9 CBIB TI Kawasaki disease with facial nerve paralysis

80 MEZZ TI Childhood fever revisited

81 EMZZ Ti Use of ibuprofen in pediatrics.

82 DDNS TI Observational study of upper gastrointestinal haemorrhage in elderly

patients given selective cyclo-oxygenase-? inhibitors or conventional non-steroidal anti-inflammatory drugs.

83 IPAB TI When your child has a headache

84 BIZZ TI Poisoning in children 2: Painkillers.

85 LINE TI Reliability of health information for the public on the world wide web:

systematic survey of advice on managing fever in children at home.

86 ACZZ TI Asthma morbidity following short-term use of acetaminophen and ibuprofen

in asthmatic children.

87 CBIB TI Management of fever: Making evidence-based decisions.

88 MEZZ TI (Current opinions on embryotoxic and teratogenic effects of ibuprofen)

89 EMZZ TI Effect of antipyretics on polymorphonuclear leukocyte functions in

children.

90 DDNS TI Indomethacin and ibuprofen effect on IL-lra production by mononuclear

ceiis of preterm newborns and aduirs.

91 IPAB TI Asthma and analgesics.

92 LINE TI Ibuprofen or paracetamol for children's fever?

93 ACZZ TI Severe ehrlichiosis in an adolescent taking trimethoprim-

sulfamethoxazole.

94 CBIB TI The safety of ibuprofen suspension in children

95 EMZZ TI Information and education for the general public.

96 DDNS TI Rofecoxib in a child w,ith nonsteroidal anti-inflammatory drug induced

urticaria and angioedema.

91 IPAB TI Risks and benefits of nonsteroidal anti-inflammatory drugs in children -

A comparison with paracetamol.

98 BIZZ TI Comparison of incidence of reported adverse events with pretreatment for

pamidronate administration in children.

99 LPJE TI Antipyretic efficacy of ibuprofen and acetaminophen in children with

febrile seizures.

100 CBIB TI Pharmacokinetics of intravenous and rectal ketoprofen in young children.

101 EMZZ TI Antipyretic poisoning.

102 DDNS TI Ibuprofen induced acute renal failure in an infant.

103 IPAB TI Evidence-based management of seizures associated with fever.

104 BIZZ

community TI Fever: Knowledge, attitude and management in the Latin American

in5 LTNE Ti ibuprofen oral suspension - cniia.

106 PASC TI Pediatric ibuprofen use increases while incidence of Reye's syndrome

continues to decline.

107 CBIB TI Development of oral acetaminophen chewable tablets with inhibited bitter

taste.

108 EM22 TI Emergency department visits for poisoning: Epidemiological changes in

the last I0 years.

109 DDNS TI Toxicity of over-the-counter cough and cold medicines.

I10 IPAB TI Crying shame.

1 1 1 BIZ2 TI Alternating antipyretics to treat fever in children: Parental practices.

112 LINE TI Fever: definition and management in children

113 MEZZ TI (Analysis of prognostic factors for the antipyretic response to

ibuprofen).

114 EMZZ TI Antithermics: Modes of use in the Primary Attention System. Experience

in a municipium of Buenos Aires conurbation (Argentina).

115 DDNS TI Fixed drug eruption due to naproxen; lack of cross-reactivity with other

propionic acid derivatives.

116 BIZZ

Prescription.

117 LINE

TI Treatment of otitis media with observation and a Safety-Net

TI The febrile child.

118 ACZZ TI Drug-induced liver disease

119 PASC TI Pharmacology of antipyretic drugs for their use in pediatrics,

n rharmacologie des aniipyreiiqut-s : appiicatiuns a ieur uiiiisation eii pediatrie. XXXIIe Congres de I'Association des pediatres de langue francaise - Societe francaise de pediatrie. Congres annuel.

120 MEZZ TI Acetaminophen and ibuprofen dosing by parents

121 EMZZ TI Antipyretics in children

122 DDNS TI Invasive group A streptococcal infection and nonsteroidal

antiinflammatory drug use among children with primary varicella.

123 IPAB TI Drug treatment ofjuvenile arthritis: accepted therapeutic options.

124 BIZZ TI Pediatric fever and Nurofen as anti-peretic.

125 LINE TI Headache.

126 ACZZ TI Pharmacodynamics of ibuprofen antipyresis in children.

127 MEZZ TI Alternating antipyretics: is this an alternative?

128 DDNS TI Analysis of nonsteroidal antiinflammatory drugs in meconium and its

relation to persistent pulmonary hypertension of the newborn.

129 lPAB TI Caregiver knowledge: assessment of common pediatric illnesses and over

the counter medications.

130 BIZ2 TI Home management of sickle pain: A daily diary study of analgesic usage

by children and adolescents with sickle cell disease.

131 ACZZ TI Acetaminophen in the management of background pain in children post-

burn.

132 CBIB TI Acetaminophen toxicity in children.

133 MEZZ TI Assessment of the efficacy and safety of paracetamol, ibuprofen and

nimesiilide in children with upper respiratory tract infections.

134 EMZZ TI An epidemiological investigation of a sustained high rate of pediatric

parapneumonic empyema: Risk factors and microbiological associations.

I35 DDNS TI Methotrexate as a possible trigger of macrophage activation syndrome in

systemic juvenile idiopathic arthritis.

136 lPAB TI Ibuprofen and paracetamol: relative safety in non-prescription dosages

137 LINE TI Counter prescribing for patients at risk. Pregnancy and breastfeeding.

138 MEZZ TI Paracetamol and ibuprofen for treatment of fever in Malawian children

aged less than five years.

139 EMZZ TI Premarketing surveillance of oral ibuprofen solution in febrile

children.

140 DDNS

children. (Ger.). TI First experience with ibuprofen suspension in the treatment of fever in

141 IPAB TI Safety of acute and chronic ibuprofen therapy in children

142 ACZZ TI A n assessment of the safety of ibuprofen suspension among ambulatory

children (the Boston University Fever Study): rationale and design.

143 MEZZ TI Pyloric channel stricture secondary to high-dose ibuprofen therapy in a

patient with cystic fibrosis.

144 EMZZ T1 Poststreptococcal reactive arthritis.

145 DDNS TI Preventive treatment for recurrent febrile seizures.

146 IPAB TI What's the best pain reliever? Depends on your pain

147 ACZZ TI Non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity

in children with juvenile arthritis.

148 MEZZ TI Integrated pharmacokinetic-pharmacodynamic model for acetaminophen,

ibuprofen, and placebo antipyresis in children.

149 EMZZ Ti Alternating antipyretics: Is this an alternative? (3).

150 DDNS TI No association between non-steroidal anti-inflammatory drugs, alone 01

with prophylactic anticoagulants. and blood transfusion following knee replacement surgery.

151 IPAB TI Ibuprofen: proven efficacy in treatment of febrile seizures

152 LINE TI Cooling the feverish child.

I53 CBlB TI Perforated peptic ulcer in an infant.

154 MEZZ

TI Combined antipyretic therapy: another potential source of chronic acetaminophen toxicity.

155 DDNS TI Antipyretic efficacy of ibuprofen and acetaminophen in children with

fever.

156 IPAB T I Ibuprofen: child

157 BlZZ TI (Untitled).

158 ACZZ TI Home antipyretics use in febrile children brought to the emergency

department.

159 CBIB TI Pliarmacokineticipharmacodynamic modeling of antipyretic and anti-

inflammatory effects of naproxen in the rat.

160 MEZZ TI Reevaluation of antipyretics in children with enteric fever.

161 EMZZ TI Exacerbation of asthma by ibuprofen in a very young child ( I ) .

162 DDNS TI Over-the-counter analgesics and antipyretics: a critical assessment.

163 IPAB TI Pediatric ibuprofen and leukopenia.

164 ACZZ TI Pediatric postoperative pain management

165 MEZZ TI Circulating leptin levels during acute experimental endotoxemia and

antiinflammatory therapy in humans.

166 EMZZ TI Home antipyretic use in children brought to the emergency department.

167 DDNS TI Non-steroidal anti-inflammatory drug-induced gastrointestinal toxicity

in a practice-based cohort of children with juvenile arthritis.

168 IPAB T I New OTC drugs and devices: selected review

169 ACZZ

T! Peri-operative use ofnonsteroidiil anti-inflammatory drugs in children: analgesic efficacy and bleeding.

170 MEZZ TI Care in the use of ibuprofen as an autipyretic in children

!7! EMZZ TI Incidence of Reye's syndrome in France: A hospital-based survey

172 DDNS TI Non-steroidal anti-inflammatory drug-induced central nervous system

toxicity in a practice-based cohort of children with juvenile arthritis.

173 IPAB TI Headache: classic opportunity for advice and sales

174 BIZZ TI Use of dipyrone i n a community clinic population

175 PASC TI Advilo children and infants, Nurofeno children and infants

(ibuprofene in pediatrics).

Advilo eufants et nourrissons, Nurofen<SUDo enfants et nourrissons (ibuprofene en pediatrie).

176 CBIB TI Diagnostic implications and clinical consequences of antipyretic

therapy.

177 MEZZ TI Acetaminophen: a clarification.

178 EMZZ TI Are we losing good drugs?

179 DDNS TI Effects of rheumatic disease and corticosteroid treatment on calcium

metabolism and bone density in children assessed one year after diagnosis, using stable isotopes and dual energy X-ray absorptiometry.

I80 IPAB TI Study on the awareness of the use of medicines among high school

students aged 13-16 years in a co-educational school in North India.

181 BIZZ TI Right thigh pain.

I82 LINE TI Cystitis.

(83 CBIB TI Toxicities of drugs used in the management of fever.

184 ME22 TI Ibuprofen use in pediatric patients

IS5 EMZZ TI External cooling in the management of fever

186 DDNS

gastric ulcer.

187 BIZZ

TI Non-steroidal anti-inflammatory drugs, Helicobacter pylori and bleeding

TI Ibuprofen as an antipyretic substance.

188 CBIB TI Pharmacokinetics of rectal paracetamol after repeated dosing in

children.

189 MEZZ TI Ibuprofen and/or acetaminophen: what price for "euthermia"?

190 EMZZ TI Effect of antipyretic drugs in children with malaria.

191 DDNS TI Judging the effectiveness of analgesia for children and adolescents

during vaso-occlusive events of sick1e cell diseasc.

192 BIZZ TI Is recall of pregnancy exposures influenced by interview timing?

193 CBIB TI Pharmacokinetics of ibuprofen enantiomers in children with cystic

fibrosis.

194 EMZZ TI Use of ibuprofen in pediatric infections with febrile convulsion.

195 DDNS TI Hypersensitivity reaction to acetylcysteine and carbocisteine.

196 BlZZ

in 20 years? TI Fever phobia revisited: Have parental misconceptions about fever changed

197 MEZZ TI (Focus on the safety of ibuprofen at the analgesic-antipyretic dose).

198 EMZZ

TI Headache, emesis. and fexver i n a l?-year-o!d boy

199 DDNS T1 Pharmacokinetic/pharmacodynamic modelling of the antipyretic effect of

two oral formulations of ibuprofen: suspension and effervescent granules.

200 PASC TI Interactions of ibuprofen with influenza infection and hyperammonemia in

an animal model of Reye's syndrome.

201 CBIB T1 Home management of fever in children: Rational or ritual?

202 MEZZ TI Choice of antipyretic in children.

203 EMZZ TI Ibuprofen fulfills the expectations of pediatricians.

204 DDNS TI Effects of ibuprofen and indomethacin on the regional circulation in

newborn piglets.

205 IPAB TI Use of nonprescription medications in the treatment of pain.

206 CBIB TI Pediatric febrile seizures and childhood headaches in primary care.

207 MEZZ TI Ibuprofen suspension: pediatric antipyretic.

208 DDNS TI Fixed drug eruptions in children.

209 IPAB TI Management of minor pain with OTC medications.

210 BIZ2 TI Ibufen (Ibuprofen) in cases of fever due to pediatric acute respiratory

tract infections-clinical efficacy and safety of usage.

211 MEZZ TI Ibuprofen as an over-the-counter drug: is there a risk for renal injury?

212 EMZZ TI Tubulointerstitial nephritis and asymptomatic uveitis

213 DDNS TI Severe falciparum malaria in children: current understanding of

pathophysiology and supportive treatment.

214 IPAB TI Determination of ibuprofen by high performance liquid chromatography.

215 BIZZ TI NS.A.ID facial angioedema in a selected pediatric atopic population

216 PASC TI A dose ranging study of ibuprofen suspension as an antipyretic. Reply

217 CBIB TI Predicting concentrations in children presenting with acetaminophen

overdose.

218 MEZZ TI Effect of age on ibuprofen pharmacokinetics and antipyretic response

219 EMZZ TI Prevesical abscess secondary to pubis symphysis septic arthritis.

220 DDNS TI A major role for prostacyclin in nitric oxide-induced ocular

vasorelaxation in the piglet.

221 PASC TI Antipyretic efficacy of ibuprofen vs acetaminophen

222 MEZZ -T

I I Acetaminophen and ibuprofen: <ever coniroi and overdose.

223 EMZZ

complications.

224 BIZZ

TI Fever in burned children and its association with infectious

TI Invasive group A streptococcal infection and antipyretic use among children with primary varicella.

225 PASC TI Comparison of multidose ibuprofen and acetaminophen therapy in febrile

children.

226 CBIB TI Pharniacology of anti-inflammatories: application to their usage in

pediatrics.

277 MEZZ TI Pharmacokinetics and pharmacodynamics of ibuprofen isomers and

acetaminophen in febrile children.

228 EMZZ TI Ibuprofen as antipyretic in children

229 DDNS TI Drug-associated acute-onset vanishing bile duct and Stevens-Johnson

syndromes in a child.

230 MEZZ TI Ibuprofen safety

231 EMZZ TI Fever: A weapon of defence too often disregarded

232 DDNS TI Pain medication during terminal care of children with cancer.

233 BIZZ TI Pharmacokinetic-pharmacodynamic modelling of the antipyretic effect of

two oral formulations of ibuprofen.

234 ACZZ TI Comparative efficacy and tolerance of ibuprofen syrup and acetaminophen

syrup in children with pyrexia associated with infectious diseases and treated with antibiotics.

235 PASC TI Efficacy of ibuprofen in pediatric patients with fever.

236 MEZZ -I ̂ . I I singie-dose pharmacokinetics OT ibuprdtm arid acetaminophen in febrile

children.

237 DDNS TI NSAIDs associated with increased risk of congestive heart failure in

elderly patients taking diuretics.

238 ACZZ TI Use of medication by adolescents for the management of menstrual

discomfort.

239 MEZZ TI Ibuprofen lowers body temperature and metabolic rate of humans with burn

injury

240 EMZZ TI How did such a bad report get published in the EJCP? Trial of

paracetamol. ibuprofen and nimesulide in children with upper respiratory infections (B. Ulukol et al., EJCP November 1999, 55: 615-618) (2).

241 DDNS TI Effects of indomethacin and ibuprofen on regional perfusion in the

newborn piglet

242 BlZZ

in children. TI Comparative study of dipyrone, ibuprofen and acetaminophen antipyresis

243 .4czz TI Treatment of fever: monotherapy with ibuprofen. Ibuprofen pediatric

suspension containing 100 mg 5 ml, multicentre acceptability study conducted in hospital.

244 CBIB TI Combined antipyretic therapy: Another potential source of chronic

acetaminophen toxicity - Reply.

245 sczz TI Benefits and risks of antipyretic therapy

246 MEZZ TI Drugs for childhood fever

241 EMZZ TI Fever in children: Paracetamol is mostly sufficient

248 DDNS TI Comparative evaluation of the effects of indomethacin and ibuprofen on

cerebral perfusion and oxygenation in preterm infants with patent ductus arteriosus.

249 aizz TI Safety profile of ibuprofen suspension in young children

250 CBlB TI Recombinant interleukin-6 in the treatment of congenital

thrombocytopenia associated with absent radii.

251 MEZZ TI Ibuprofin safety

252 EMZZ TI Fever in critically i l l patients.

253 DDNS TI Nonsteroidal anti-inflammatory drugs (NSAIDs) associated liver disease

in Black and Hispanic elderly patients.

254 ACZZ TI A placebo-controlled model for assaying systemic analgesics in children.

255 MELZ TI Junifen suspension--ibuprofen for febrile children

156 DDNS TI Consumption of non-steroidal antinflammatory drugs and the development

of functional venal impairment in elderly subjects. Results of a cas- [control study.

257 BIZ2 TI Pharmacology of antipyretics: Applications to their use in pediatrics.

258 PASC TI Ibuprofen, acetaminophen, and placebo treatment of febrile children.

259 MEZZ TI Pharmacokinetics of ibuprofen in febrile children.

260 EMZZ TI Ibuprofen for children

261 DDNS TJ Suppression of fever and the acute-phase response in a patient with

juvenile chronic arthritis treated with monoclonal antibody to tumour necrosis factor-alpha (cA2).

262 ACZZ TI Pain management in children

263 PASC TI Ulcerative proctitis in juvenile systemic lupus erythematosus after

ibuprofen treatment.

264 MEZZ TI Ibuprofen versus paracetamol for the treatment of fever in children

265 EMZZ Ti A case-control study of necrotizing fasciitis during primary varicella

266 DDNS

year-old child.

261 PASC

TI Acetaminophen-induced urticaria and tolerance of ibuprofen in an eight-

TI Induction of prostaglandin synthesis as the mechanism responsible for the chills and fever produced by infusing amphotericin B.

7-68 CBIB TI Ibuprofen and/or acetaminophen: What price for "euthermia"? - Reply

269 MEZZ TI Paediatric ibuprofen--an overview

270 EMZZ

TI Paracetamol or ibuprofen in febrile children.

211 DDNS TI Nonsteroidal anti-inflammatory drugs and the risk of hospitalization for

acute renal failure.

272 ACZZ TI The use of non-steroidal anti-inflammatory drugs in paediatric rheumatic

diseases.

273 SCZZ TI Clinical pharmacokinetics of ibuprofen - The first 30 years.

274 MEZZ TI Ibuprofen: a monograph.

275 EMZZ TI Neurovascular emergencies: Always rectal administration of diazepam in -

first convulsive seizure in children.

276 DDNS TI Protective effect of chronic NSAID use on cognitive decline in older

persons.

217 EIZZ TI Fever in children: A survey of health care professionals' knowledge and

treatment preferences.

278 ACZZ -. _. I I muprofen and paraceiamoi: eKeciive antipyretics i n children wi:h

febrile seizures.

279 CBIB TI Clinical pharmacology of antipyretic agents.

280 MEZZ

paracetamol.

281 EMZZ

TI Comparative evaluation of the antipyretic efficacy of ibuprofen and

TI Combined antipyretic therapy: Another potential source of chronic acetaminophen toxicity (2) (multiple letters).

282 DDNS TI The toxicity of antirheumatic medications in children

283 ACZZ

adolescents. TI Serum-sickness-like reaction associated with minocycline therapy in

284 MEZZ

TI Ibuprofen for fever

285 EMZZ TI Home-based therapies for the common cold among European American and

ethnic minority families: The interface between alternative /complementary and folk medicine.

286 DDNS TI A survey of NSAID usage in hospital and community and serious NSAID

related gastrointestinal toxicity.

287 BlZZ TI Effects of risperidone in overdose.

288 ACZZ TI Heat stroke-like episode in a child caused by zonisamide.

289 CBIB TI Pharmacokinetics and protein binding of intravenous ibuprofen in the

prPmature newborn infant.

290 SCZZ TI Clinical pharmacology at antipyretic agents

291 MEZZ TI Hepatic granulomata. Presenting with prolonged

anti-inflammatory treatment.

292 DDNS

ver. Resc tion with

-.. r I I ivonsieroidai antiinllamniaiory drugs aid cogiiiiive d e c h in the

elderly.

293 CBIB TI Use of ibuprofen in juvenile chronic arthritis.

294 MEZZ TI Ibuprofen vs acetaminophen in children.

295 EMZZ TI Acetaminophen: A clarification ( 5 ) .

296 DDNS TI Comparative evaluation of indometacin (INDO) and ibuprofen (IBU) on

cerebral blood volume in very-low-birth-weight infants.

297 ACZZ TI Serum sickness-like disease after immunization with a recombiiiant

hepatitis B vaccine.

298 MEZZ TI Ibuprofen: an alternative for children's fevers,

299 DDNS TI Nonsteroidal anti-inflammatory drugs inhibit expression of the inducible

nitric oxide synthase gene.

300 BIZZ TI Hypothermia from Azithromycin? (and response).

301 ACZZ TI Antipyretic activity and safety of ibuprofen tablets in the treatment of

fever in adults: multicentre study among general practitioners.

302 CBIB TI Short-Term Ibuprofen Use Is Safe in Children with Fever.

303 EMZZ TI Symptomatic therapy of common febrile states in children.

304 DDNS TI How many elderly general practice patients taking regular non-steroidal

anti-inflammatory drugs can be converted to taking regular paracetamol?

305 BIZZ TI NUREFLEX children and infants (ibuprofen 10 milligrams per kilogram) in

fever of the hospitalized child: Multicentric trial of acceptability, tolerance and efficacy (intermediate analysis).

306 ACZZ TI Juvenile arthritis: a practical guide to drug therapy.

307 CBIB TI Acetaminophen and other antipyretic analgesic drugs: Optimal dosages in

pediatric patients.

308 MEZZ TI Comparative evaluation of antipyretic activity of ibuprofen and aspirin

in children with pyrexia of varied aetiology.

309 EMZZ TI Ibuprofen and skin and soft tissue superinfections in children with

varicella.

310 DDNS TI Experience with misoprostol therapy for NSAID gastropathy in children

31 I ACZZ TI Simultaneous pharmacokinetic-pharmacodynamic modeling of ibuprofen in

febrile children.

312 EIMZZ TI The role of ibuprofen in the treatment offever in pediatrics.

313 DDNS TI Epidural corticosteroid injections for acute radiculopathy in a 95-year-

old woman.

314 BlZZ TI A large population trial for pediatric ibuprofen: A new method for

evaluating risk in actual use.

315 ACZZ TI Attack treatment of migraine in children

316 MEZZ TI Measurement of antipyretic activity of ibuprofen and paracetamol in

children.

317 EMZZ TI Antipyretic therapy

318 DDNS TI Effect of NSAIDs on electrolyte homeostasis in elderly and young

persons.

319 BIZZ TI A recent case of congenital malaria in Singapore

310 ACZZ TI Integrated pharrnacokineticipharmacodynamic model for acetaminophen and

ibuprofen antipyresis in children.

321 MEZZ TI Oral antipyretic therapy.

322 EMZZ TI Evaluation of sponging and antipyretic medicztion to reduce body

temperature in febrile children.

323 DDNS TI Up-regulation of brain PGE? and PGF2-alpha receptors and receptor-

coupled second messengers by cyclooxygenase inhibition in newborn pigs.

324 BlZZ TI Confounders of antipyretic drug pharmacodynamics

325 SCZZ TI STEREOSELECTIVE DISPOSITION OF IBUPROFEN ENANTIOMERS IN INFANTS

326 EMZZ TI Acute renal failure associated with amoxicillin and ibuprofen in an l l -

year-old boy (2).

327 ODNS TI Nonsteroidal anti-inflammatory drugs inhibit expression of the nitric

oxide synthase gene in rat alveolar macrophages.

328 BlZZ TI Are inajor cardiovascular malformations defects of a single developmental

field?

329 ACZZ TI Safety of tion steroidal antiinflammatory drugs in pregnant patients with

rheumatic disease.

330 EMZZ '1'1 Childhood fever

331 DDNS TI Gastroduodenal damage in children treated with nonsteroidal

antiinflammatory drugs is a common occurrence.

332 BlZZ TI Lactic aciduria after ibuprofen treatment in febrile children.

333 ACZZ TI Efficacy and safety of ibuprofen (IOmdkg), acetaminophen (1 5mg/kg), and

placebo in the relief of orthodontic pain in children.

334 sczz TI ANTIBIOTIC-INDUCED MENINGITIS.

^ ^ - 5 3 3 C1VIL.L

TI Management of fever in children.

336 DDNS TI Increased risk of facial scars in children taking nonsteroidal -

antiinflaniinatory drugs.

331 ACZZ TI Parents' management of children's pain following minor surgery

338 EMZZ TI Pediatric ibuprofen and leukopenia (3).

339 DDNS TI Serum antioxidative enzyme activity and juvenile chronic arthritis.

340 BlZZ TI Evaluation of the antipyretic efficacy of single dose ibuprofen

suspension compared to acetaminophen elixir in febrile children.

34 1 ACZZ TI A n assessment of the safety of ibuprofen suspension among ambulatory

children (the Boston University Fever Study): results.

341 sczz TI EVALUATION OF THE RAT EMBRYO CULTURE SYSTEM AS A PREDICTIVE TEST FOR

HUMAN TERATOGENS.

343 EMZZ TI Rash and fever in a 3-year-old girl.

344 DDNS TI Nimesulide. An update of its pharmacodynamic and pharmacokinetic

properties, and therapeulic efficacy.

345 BIZZ TI A model for apparent antipyresis in placebo-treated febrile children.

346 ACZZ TI Pharmacokinetics/dynamics of ibuprofen isomers vs acetaminophen in

febrile children.

341 SCZZ TI PHARMACODYNAMIC MODELING OF NONSTEROIDAL ANTIINFLAMMATORY DRUGS -

ANTIPYRETIC EFFECT OF IBUPROFEN.

345 EMZZ TI Treatment of febrile children.

349 DDi<'S TI Cutaneous polyarteritis nodosa. Reports of two cases in children and

review of the literature.

350 ACZZ TI Clinical efficacy af nimesulide against paracetamol and ibuprofen for

the treatment of headache in children with upper respiratory tract infections.

351 SCZZ TI FEVER IN CHILDHOOD - ITS TREATMENT.

352 EMZZ TI FDA advisory panels endorse motrin for children

353 DDNS TI Correlation between NSAID accumulation and creatinine clearance in

elderly patients without and with renal insufficiency (RI).

351 BIZZ 1'1 Childhood fever: l a treatment

355 EMZZ T1 Use of ibuprofen in juvenile chronic arthritis.

356 DDNS TI Epidural Analgesia in the Management of Severe Vaso-Occlusive Sickle

Cell Crisis.

3 5 1 EMZZ TI Poststreptococcal reactive arthritis in children: A potential

predecessor of rheumatic heart disease.

358 DDNS TI Adverse Events Related to Drugs and Drug Withdrawal in Nursing Home

Residents.

359 EMZZ TI Alterations in the electroretinogram of newborn piglets by propionic

acid- derivative nonsteroidal antiinflammatory drugs but not by indomethacin and diclofenac.

360 DDNS TI Fixed Drug Eruptions in Children: A Series of 23 Cases with Provocative

Tests.

361 EMZZ TI The pharmacokinetics of ibuprofen after burn injury

362 DDNS TI Acute Flank Pain and Reversible Renal Dysfunction Associated with .~ iuonsreroidai Anri-inflammatory Drug %e.

363 SCZZ TI A PROBABILITY NOMOGRAM TO PREDICT RECTAL TEMPERATURE IN CHILDREN.

364 EMZZ TI Children with fever

365 DDNS TI Safety of Non-Steroidal Anti-Inflammatories Before Adenotonsillectomy.

366 DDNS TI The Relationship Between Phenazone (Antipyrine) Metabolite Formation and

Theophylline Metabolism in Healthy and Frail Elderly Women.

361 SCZZ TI PHARMACOKINETICS AND PHARMACODYNAMICS IN THE DESiGN OF CONTROLLED-

RELEASE BEADS WITH ACETAMiNOPHEN AS MODEL-DRUG.

368 DDNS

T! Concurrent Use of Nonstcroida! Anti-inflammatory Drugs and Oral Anticoagulants Places Elderly Persons at High Risk for Hemorrhagic Peptic Ulcer Disease.

369 SCZZ TI IST TRIMESTER MATERNAL MEDICATION USE IN RELATION TO GASTROSCHISIS.

370 DDNS TI Indomethacin Compromises, Hemodynamics During Positive-Pressure

Ventilation, Independently of Prostanoids.

371 EMZZ TI Antipyretic therapy in the febrile child.

372 DDNS TI Prospective Follow-up of Adverse Reactions in Breast-Fed Infants Exposed

to Maternal Medication.

373 DDNS TI A Prospective Study of Aspirin Use and Cataract Extraction in Women,

374 EMZZ TI Problematic of the febrile syndrome in the urgencies services. Facts for

a practical orientation.

375 DDNS TI Uses of Nonsteroidal Anti-Inflammatory Drugs in Pediatrics.

376 SCZZ TI INTERLEUKIN-6 AS AN ENDOGENOUS PYROGEN - INDUCTION OF PROSTAGLANDIN-E2

IN BRAIN BUT NOT IN PERIPHERAL-BLOOD MONONUCLEAR-CELLS

377 EMZZ TI Ibuprofen safety (2) .

378 DDNS TI Renal Effects of NSAIDs in Healthy Elderly Persons.

379 BlZZ TI PHARMACOKINETICS-DYNAMICS PK-PD OF IBUPROFEN IBU ISOMERS VS

ACETAMINOPHEN APAP N FEBRILE CHILDREN.

380 DDNS TI Integrated Pharmacokinetic (PKN)/Pharmacodynamic (PDN) Model for

Acetaminophen and Ibuprofen Anripyresis in Children.

381 DDNS TI Pain-Fever PliarmacokineticsiDynamics (PWPD) in Children.

382 BIZZ TI COMPARATIVE EFFICACY OF IBUPROFEN IBU AND ACETAMINOPHEN APAP IN FEBRILE

CHILDREN.

383 EiMZZ TI First trimester maternal medication use in relation te gastroschisis.

384 DDNS TI Prevention of Activation of HIV-1 by Antiviral Agents in OM-10.1 Cells

385 BIZZ TI EFFICACY SAFETY AND PHARMACODYNAMICS OF IBUPROFEN IN PEDIATRIC PATIENTS

WITH FEVER.

386 EMZZ T1 Ibuprofin safety (1).

387 DDNS TI Risk of Major Gastrointestinal (GI) Complications with Individual Non-

Steroid Anti-Inflammatory Drugs (NSAIDs).

388 BIZZ TI ANTIPYRETICS IN PEDIATRIC PRACTICE

389 EMZZ TI Management of childhood fever (34).

390 DENS TI Simultaneous Pharmacokinetic (PK)-Pharmacodynamic (PD) Modeling of

Ibuprofen in Febrile Children.

391 BIZZ TI PHARMACODYKAMICS OF IBUPROFEN IB ANTIPYRESIS IN CHILDREN.

392 EMZZ TI Management of childhood fever

393 EMZZ TI Single-dose, placebo-centrolled comparative study of ibuprofen and

acetaminophen antipyresis in children.

394 DDNS

Induced Fever.

395 EMZZ

TI Pharmacodynamics of Ibuprofen Input Rate on Antipyresis in Rats with

TI Pediatric rheumatology

396 DDNS

T! Paediatric P.heumato!ogy: Re-vieTw. The Use of Non-Steroidal h t i - Inflammatory Drugs i n Paediatric Rheumatic Diseases,

397 EMZZ TI Ibuprofen paediatric suspension

398 DDNS TI Paediatric Rheumatology: Original Paper. Gastro-Duodenal Damage Due to

Non-Steroidal Anti-inflammatory Drugs in Children.

399 BIZZ TI IBUPROFEN SUSPENSION IN CHILDREN.

400 EMZZ TI Determination of ibuprofen in human plasma by high-performance liquid

chromatography.

401 BIZZ TI VIEWS ON THE USE OF ANTIPYRETICS IN CHILDREN.

402 DDNS TI Amyloidosis of Juvenile Chronic Arthritis in Turkish Children,

403 BIZZ TI A COMPARATIVE STUDY OF 2 DOSAGE LEVELS OF IBUPROFEN SYRUP IN CHILDREN

WITH PYREXIA.

I C 4 sczz 1 I LuMPAiiiSON OF IBUPRSFEN, ACETAiviiKOPHEN AND PLACEBO-TREATiviEXiu'T OF FEVER IN

CHILDREN.

405 DDNS

-. - _ _

TI Non-Steroidal Anti-Inflammatory Drug-Induced Jejunal and Colonic Diaphragm Disease: A Report of Two Cases.

406 EMZZ TI Antipyretic analgesic overdosage in children. Comparative risks

407 DDNS TI Prevalence of Upper Gastrointestinal Lesions in Patients Taking Chronic

Nonsteroidal Anti-Inflammatory Drug Therapy.

408 DDNS TI Anticholinergic Effects of Drugs Commonly Prescribed for the Elderly:

Potential Means for Assessing Risk of Delirium.

409 EMZZ TI Paediatric antipyrerics. The story so far,

410 DDNS TI Toxicity of' Antirheumatic Medications in Children with Juvenile

Arthritis.

411 BIZZ TI A COMPARISON OF ALUMINUM IBUPROFEN SUSPENSION AND P.CETAMINOPHEN ELIXIR

IN THE TREATMENT OF FEVER IN CHILDREN.

412 SCZZ TI EICOSANOIDS IN HEALTH AND IN DISEASE - AN APPRAISAL.

413 BIZZ TI ANALGESIC-ANTIPYRETIC CHOICES FOR CHILDREN WITH ASTHMA A REVIEW OF

SAFETY AND RISK OF COMMON PREPARATIONS.

414 DDNS TI Colitis Induced by Nonsteroidal Anti-Inflammatory Drugs: Report of Four

Cases and Review of the Literature.

415 BIZZ TI COMPARATIVE STUDY OF THE CYTO GENETIC ACTIVITY OF ACETYL SALICYLIC-ACID

AND BRUFEN.

316 EMZZ TI Pharmacokinetics of common analgesics, anti-inflammatories and

antipyretics in children.

417 DDNS TI Risk for Serious Gastrointestinal Complications Related to Use of

Nonsteroidal Anti-Inflammatory Drugs: A Meta-Analysis.

418 BIZZ TI MEASUREMENT OF ANTI PYRETIC ACTIVITY OF IBUPROFEN AND PARACETAMOL IN

CHILDREN.

419 DDNS TI The Successful Medical Management of Gastric Outflow Obstruction

Associated with the Use of Son-Steroidal Anti-Inflammatory Drugs in the Elderly.

420 BIZZ TI ORAL ANTI PYRETIC THERAPY EVALUATION OF THE PROPIONIC-ACID ~~

DERIVATIVES IBUPROFEN KETOPROFEN FENOPROFEN AND NAPROXEN.

121 DDNS TI Paucity of Renal Complications Associated with Nonsteroidal

Antiinflammatory Drugs in Children With Chronic Arthritis

422 EMZZ TI Calcified thoracic disc with herniation of the nucleus pulposus in a

child.

423 DDNS TI Interactions of Ibuprofen, Influenza and Hyperammonemia in Reye's

Syndrome.

424 EMZZ TI Juvenile rheumatoid arthritis - a review

425 DDNS TI Factors i n the Duration and Discontinuation of Treatment with

Nonsteroidal Anti-Inflammatory Medications.

426 BIZZ TI OPTIMAL ANTI PYRESIS IN CHILDREN

427 EMZZ TI Improved high-performance liquid chromatographic assay of ibuprofen in

plasma.

428 DDNS TI Nonsteroidal Anti-Inflammatory Drugs and the Risk for Chronic Renal

Disease.

129 BIZZ TI ZPdL ATJT: P:'DE'T!C THERAPY EVALC'AT!ON OF !P,LI?P,OFEF!,

430 EMZZ TI Ibuprofen in children with infective disorders - antipyretic efficacy.

431 DDNS TI Drug Use During Breast-Feeding,

432 EMZZ TI Fever: To treat or not to treat

433 DDNS TI Allergic Drug Reactions: Identification and Management.

434 EMZZ TI Antipyretic activity of ibuprofen and paracetamol in children with

pyrexia.

435 DDNS TI Upper Gastrointestinal Lesions in Elderly Patients Presenting for

Endoscopy: Relevance oi"SA1D Usage.

436 EMZZ TI Non-steroidal anti-inflammatory drugs i n podiatric medicine and surgery

437 EMZZ TI Analgesic-antipyretic choices for children with asthma: A review of

safety and risk for common preparations.

438 DDNS TI Pattern and Prevalence of Non-Steroidal Anti-Inflammatory Drug Use in

Elderly Patients with Complicated Peptic Ulcer Disease.

439 DDNS TI Antipyretic Drug Disposition in Febrile Children.

440 EMZZ

with pyrexia.

441 DDNS

TI A comparative study of two dosage levels of ibuprofen syrup in children

TI A Case of Severe Pancytopenia Caused by Ibuprofen.

442 EMZZ TI Optimum management ofjuvenile chronic polyarthritis.

443 DDNS TI Nonsteroidal Anti-Inflammatorv Drug Use and Increased Risk for Peptic -

Ulcer Disease in Elderly Persons.

444 EMZZ T T X i - L r e - : * I I luunirleuluaroL"~iL uses 0f::SA:DS.

445 DDNS TI Naproxen-Associated Pulmonary Infiltrates with Eosinophilia (PIE

Syndrome).

446 EMZZ TI Antipyretic analgesics for children.

441 DDNS TI Determination of Ibuprofen in Plasma by High Performance Liquid

Chromatography.

448 EMZZ TI Comparative study of the antipyretic effect of ibuprofen (oral

suspension) and paracetamol (suppositories) in paediatrics.

449 DDNS TI Ketorolac, an Injectable Nonnarcotic Analgesic.

450 DDNS TI An Assessment of Drug Related Admissions to a Medicine for the Elderly

Unit.

451 EMZZ TI Clinical pharmacology of antipyretics in children.

452 DDNS TI Naproxen-Induced Pseudoporphyria: A Distinctive Photodermatitis

453 EMZZ T1 Treatment of fever in 1982: A review.

454 DDNS TI Aplastic Anaemia Associated with a Non-Steroidal Anti-Inflammatory Drug:

Relapse after Exposure to Another Such Drug.

455 EMZZ TI Analgesics and antipyretics in paediatric medicine

456 DDNS TI Transplacental Cardiovascular Effects of Four Popular Analgesics in

Rats.

457 EMZZ TI Arthritis & rheumatism

458 DDNS TI Nephrotic Syndrome Associated with Nonsteroidal Anti-Inflammatory Drug

Use in Two Children.

459 DDNS TI Pharmacokinetics of Misoprostol in the Elderly, in Patients with Renal

Failure and When Coadministered with NSAID or Antipyrine, Propranolol or Diazepam.

460 EMZZ TI Chronic juvenile arthritis. A study of 46 patients,

461 EMZZ TI Comparative efficacy of aspirin and acetaminophen in the reduction of

fever in children.

462 DDNS TI Non-Steroidal Anti-Inflammatory Drugs and Gastrointestinal Bleeding in

the Elderly.

463 EMZZ TI Mycoplasma pneumoniae infection with arthritis and a varicella-like

eruption

464 DDNS TI Elderly People Taking Uon-Steroidal Anti-Inflammatory Drugs are llnlikely

to Have Excess Renal Impairment.

465 EMZZ TI Ibuprofen and flurbiprofen.

466 DDNS TI Hematologic and Renal Safety of Choline Magnesium Trisalicylate

467 EMZZ TI Antipyretic analgesics for young children

468 EMZZ Ti Oral antipyretic therapy evaluation of the propionic acid derivatives

ibuprofen, ketoprofen, fenoprofen and naproxen.

469 DDNS Ti Immunological Effects of Antiinflammatory Drugs: Testing in MLC

470 EMZZ TI Brufen in the complex treatment of rheumatic fever in children

471 DDNS TI Liquid Chromatographic Method for Indomethacin and Other Inflammatory

Drugs.

472 EMZZ TI Rheumatic disease in children and adolescents

473 DONS -7 T T I I updaic on NSAiDs ill tile Elderly

414 EMZZ TI Optimal antipyresis in children

475 DDNS Ti Ibuprofen Antipyresis and Pharmacokinetics in Children

416 EMZZ TI Evolution ofjuvenile rheumatoid arthritis. A review of 101 patients.

477 DDNS Ti Revised Pharmacokinetic Constants for Use Under Systeme international

478 EMZZ TI Juvenile rheumatoid arthritis

479 DDNS TI Problem of Aspirin lnduced Asthma.

4S0 EhlZZ TI Lymphopenia and hepatic toxicity with ibuprofen

481 DDNS TI Death from Undiagnosed Peptic Ulcer Complications: A Continuing

Chsllenge.

452 EMZZ TI Pyrexia and antipyrexial treatment in children

463 DDNS TI Adenosine and Leukotrienes have a Regulatory Role in Lung Surfnctant

Secretion in the Newborn Rabbit.

484 EMZZ TI Oral antipyretic therapy. Evaluation of ibuprofen.

485 DDNS TI Choice of Non-Steroidal Anti-Inflammatory Drug in Persons Treated for

Dyspepsia.

486 EMZZ TI Drug therapy in juvenile rheumatoid arthritis, with a study of

azathioprine (Norwegian).

487 DDNS TI A Single-Blind Parallel Group Study Investigating the Antipyretic

Properties of Ibuprofen Syrup versus Acetylsalicylic Acid Syrup in Febrile Children.

455 EMZZ __ -. I I I ne use of ibuprofen in the controi of rheumalic [ever cases

489 DDNS TI Steady State Pharmacokinetics of Naproxen in Elderly Rheumatics Compared

with Young Volunteers.

490 DDNS TI The Use of Digoxin in 55 Residential Homes for Elderly People.

491 DDNS TI A Scoring System for Selection of Essential Drugs.

492 DDNS TI Hyponatremic Hypervolemia Caused by a Drug-Drug Interaction Mistaken for

Syndrome of Inappropriate ADH.

493 DDNS TI Evaluation of Renal Function in Elderly Patients Receiving "SAID'S

194 DDNS TI Repeat Prescribing ot"on-Steroidal Anti-Inflammatory Drugs.

495 DDNS TI Nonsteroidal Anti-inflammatory Drugs and Hospitalization for

Gastroesophageal Bleeding in the Elderly.

496 DDNS TI Human Fetal Ductus Arteriosus Constriction from Nonsteroidal

Antiinflammatory Drugs.

497 DDNS TI Cyclooxygenase Inhibition Reduces Placental Transfer: Reversal by

Carbacyclin.

498 DDNS TI Case Report Naproxen-Induced Pseudoporphyria.

499 DDNS TI Time-Dependent Inhibition of Platelet Cyclo-Oxygenase by Indomethacin is

Slowly Reversible.

500 DDNS TI Clinical Pharmacology of Pediatric Antipyretic Drugs.

501 DDNS TI Arachidonic Acid Metabolites Stimulate Phosphatidylcholine Secretion in

Primary Cultures of Type I1 Pneumocytes.

502 DDNS TI First-Trimester Drug Use and Congenital Disorders

5% DDNS TI Prostaglandin Synthesis in Rat Embryo Tissue; The Effect ofNon -

Steroidal Anti-Inflammatory Drugs In Vivo and Ex Vivo.

504 DDNS TI Juvenile Chronic Arthritis in Black and Indian South African Children.

505 DDNS TI Consumption Coagulopathy Associated with Systemic Juvenile Rheumatoid

Arthritis.

506 DDNS TI Familial Palindromic Rheumatism: A Possible Association with HLA.

507 DDNS TI The Hypermobility Syndrome.

508 DDNS TI Constriction of Fetal Ductus Arteriosus by Nan-Steroidal Anti -

Inflammatory Drugs.

509 DDNS

TI ,A. New Eereditary Type of Affection of Skin and Bones. (Russ.).

L


APPENDIX 11 STATEMENTS OF SUPPORT

Guy's and S t Thomas' NHS Foundation Trust

20''' October 2004

The Secretary Expert Committee Department of Essential Drugs and Medicines Policy (EDM) WHO Essential Medicine List World Health Organisation CH-I211 GENEVA 27 Switzerland

Dear Colleague

Ibuprofen for fever and pain management in children

For a number of years. I have. as a practising paediatrician and academic teacher at the above institution. been involved in the care of children who require safe and

agcd 6 months to 16 years.

I n this context, I have been very impressed by the relative safety and efficacy of Ibuprofen. compared with other available drugs; and we have gradually moved in our own practice to recorninend its use. In this context, and particularly in the context of llie very advantageous Therapeutic Index of Ibuprofen, I w-odd recommend its inclusion in the WIHO Essential Medicines List for the inaiiagement of pyrexial illnesses of childhood.

The reasons for my proposal to your esteemed committee are as follows:

'The literature supports the effect on childhood pyrexia is dose dependent for both ibuprofen and paracetamol and comparative studies with regard lo the rate o f recluction in temperature. degree and the duration of the reducrion. indicate that both the drugs have comparable antipyretic activity'.'.'. The acceptability and tolerability iix hot11 medicines are also hroactly similar ', however. there is some indicalion that Ihuprot'en may have a longer duration of effect'.

i l l .iiiclition. illere are instaii~es \+liere paracetamol may noi LicIiie\:e thc desired ;in1i!3yretic effect nilti o r the dowse recommendations may have been cscerded and ~ot i ie have concluded that ihiiprotkn ma! he p ~ ~ i c ~ i i a r l y iiseliii i n ii child \\lie c:iiiiinI

ui;e nor achieve satisfacrory antipyresis n i t h paracetamol alone

ii'iiplc ^.-* ^*. . -. C1^.^ "A,,... 1"..'.. f-.. 'L. :. a,.... ~~ ._.. I. I .I a ~ A p ~ & *i,a:p&. p u & u u u y UI UK intciLaici1i vii,il diseases ofcliiidreii

4

'l'lial is nor to say that paracetamol is ineffective and there is 110 evidcnce to my Iknowledge that oiie preparation is superior to another in terms of adverse effects Inowever. a large clinical trial involving 84 191 children aged 6 months to I7 years. receiving either paracetainol or ibuprofen revealed few serious adverse effects. giving a11 estimated popiilation risk o f less than 7.7 adverse events per 100,000 patients for the development of gastrointestinal bleeding, acute renal failure. anaphylaxis. or lie ye's s y tidro me5.

In a further randomised controlled study by Lesko et ai. ibuprofen was found to be less likely to exacerbate asthma symptoms when compared to paracetamol (children with known hypersensitivity to paracetamol or NSAIDS being excluded) '.

Ihuprofen also has the advantage that it can be ~ised for mild to moderate pain and reduction of inflammation, although I am aware that this latter property is weaker than its analgesic effect. Considering that children with pyrexia also have concurrent pain, iund [nay have an infective or inflammatory basis for their pyrexia. I can readily see the clinical advantage of using this agent in preference to paracetamol.

Other indications in my paediatric practice include the relief of pain due to headache including migraine, postoperative pain, musculoskeletal, joint and rheumatoid disorders, dental pain and dysmenorrhoea in teenagers.

I note that there is presently no disease / clinical indication heading for antipyretics in EMLib and would recommend that sucli a provision be made with the posology:

Ibuprofen liquid preparation: 5 - 10 mg /kg given 6 - Shourly (with a maximum daily dosz of40 mg / I& d a y ) and &.;en for a maximL:m o f 3 ~ 5 days.

Thank you for your kind consideration.

Yours sincerely

Dr Dipak Kanabar Consultant Paediatrician

References

I . Van Esch 4 . Van Steensel-Moll IHA> et al. Antipyretic efficacy of ibuprofen and acetaminophen in children with febrile seizures. Arch Pediutr Ado/ Mcd 1995. 149 : 632 - 637.

3. Sidler .I. Frey B, Baerlocher K. A double-blind comparison of ibuprofen and paracetamol in juvenile pyrexia. Br .JC/in Pract. 1990: 44 (suppl. 70): 22 - 25.

3 . Aindekar YK. Desai RZ: Antipyretic activity o f ibuprofen and paracetamol in children with pyrexia. Br. J. Clin. Pracf. 1985; 41: 140- 143.

4. Kauffinaii RE, Sawyer LA, Sclieinbautn ML. Antipyretic efficacy of ibuprofen vs acetaminophen. A.JDC 1992; 146: 622 - 625.

5. Lesko SM, Mitchell AA. An assessment of the safety ofpaediatric ibuprofen: a practitioner-based randomised clinical trial. J A M 1995; 273: 929 - 933.

6. Lesko SM, Louik C, Vezina RM, et al. Asthma morbidity after short-term use of ibuprofen i n children. Pediatrics 2002; 109: e20

THE UNIVERSITY OF QUEENSLAND A U S T R A L I A

School of Medicine

Discipline of Paediatrics and Child Health HEAD OF DISCIPLINE Professor Geoff Clegharn 3365 5329

Professor John Pearn 3365 5323 Assoc Pmf Pe!er Oa'?!es 3365 5305 Assoc Prof James Nixon 3365 5322 Or Roy Kimble 3365 5315 Dr Michael Nissen 3365 5021 Or Jane Peake 3365 5333

The University of Quaensland Level 3, RCH Foundation Bullding Royal Children's Hospital Herston Qld 4029 Australia Telephone +61 7 3365 5338 / 3365 5479 Facsimile +61 7 3365 5455

7"' October. 2004,

The Co-ordinator, WHO Essential Medicine List, World Health Organisation, Geneva, SWITZERLAND.

Dear Colleague,

Ibuprofen

For a number of years I have: as a practising paediatrician and academic teacher, been involved in the care of children who require safe and simple antipyretic amlgesia, p a r t i c ~ l d j j hi thz inisiiusent viral diseases of iliildhood.

In this context I have been very impressed by the relative safety and efficacy of Ibuprofen, coinpared with other available drugs; and we have gradually moved in our own practice to recommend its use. In this context, and partic.ularly in the context of the very advantageous Therapeutic hdes of Ibuprofen, I would recommend its inc!usion in the WHO Essential Medicines List.

Thank you for your kind consideration, 1

.m '--

Professor John Peam. Professor of Paediatrics & Child Health.

Application for Inclusion of Oral Ibuprofen Suspension fileIbuprofen is now widely recognised...

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