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NUROFEN FOR PAIN AND FEVER RELIEVE IN CHILDREN

รศ.พญ.จุฬธิดา โฉมฉาย

กมุารแพทย์และ ผู้ เช่ียวชาญด้านพิษวิทยา อาจารย์พิเศษ ภาควิชากมุารเวชศาสตร์ คณะแพทยศาสตร์ศริิราชพยาบาล

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Formulation and Properties

The 1st ibuprofen-based for babies and children

For babies and children from 3 months up

Effective relief pain and fever for 8 hours

Ibuprofen B.P. 100 mg in 5 ml Oral suspension

Orange flavour, Alcohol Free

PK/PD Profile

Ibuprofen Paracetamol

Time to peak concentration (min) 54 27

Time to max effect (min) 183 133

Onset of action (min) 69 109

TI (TD50/ED50) 20 10

Kelly MT. et al. Clin Pharmacology 1992 (52):2 p181-89

Serious Adverse Effects Ibuprofen vs. Paracetamol

Serious AE includes GI bleed, renal failure and anaphylaxis

There was no difference in serious adverse events between

ibuprofen and paracetamol

Risk of GI bleed for ibuprofen (7.2/100,000). No difference from

paracetamol

No association with Reye‘s Syndrome in a large study (41,810)

Association of ibuprofen and invasive Group A Strep after

varicella infection is inconclusive.

Ibuprofen and paracetamol safety in pediatric pain and fever.

Current Medical Research and Opinion 2009 25(9). 2207-22

Adverse effects requiring discontinuation of medication

Ibuprofen vs. Paracetamol

Southey E., Weiser K and Kleijnen J. Systemic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever. Curr Med Opinion,2009;25:9: 2207 -2222

There was no increased risk of medication discontinuation in

ibuprofen vs. Placebo group ( RR 0.59 [95%CI 0.18-

1.92])

Meta-analysis of ibuprofen vs. Paracetamol (Ashraf 1999) in

20,111 children showed increased incidence of AE

in younger (< 2yrs) 17.5% vs. 15%, p< 0.001

and older children (>2 and < 12 yrs old) 11.9% vs. 10.7%, p =0.04

Other adverse reactions Ibuprofen vs. Paracetamol

Southey E., Weiser K and Kleijnen J. Systemic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever. Curr Med Opinion,2009;25:9: 2207-2222 .

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Relative risk (RR) for children experiencing adverse events with ibuprofen is

comparable to paracetamol is RR 1.03 (95% CI: 0.98, 1.10).

All three treatment groups had similar outcomes, with a rare occurrence of

serious AEs .

Ibuprofen has no difference to paracetamol or placebo in terms of GI

symptoms, asthma or renal adverse effects.

Southey E., Weiser K and Kleijnen J. Systemic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever. Curr Med Opinion,2009;25:9: 2207-2222 .

As well tolerated as Paracetamol and Placebo

Systemic reaction with Ibuprofen VS Paracetamol

Risk Ratio (95% CI) = 1.03 (0.98, 1.10) Heterogenecity: Chiz = 16.13, df = 15(p=0.37)

Systemic reactions Ibuprofen vs. Paracetamol

Southey E., Weiser K and Kleijnen J. Systemic review and meta-analysis of the clinical safety and tolerability of ibuprofen compared with paracetamol in paediatric pain and fever. Curr Med Opinion,2009;25:9: 2207-2222 .

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Lesko SM, Mitchell AA. An assessment of the safety of paediatric ibuprofen. A practitioner-based randomised clinical trial. JAMA 1995; 273: 929-33.

Comparable Safety in other AE

Ibuprofen and paracetamol were found to have a similarly low incidence of AEs overall

and the same GI tolerability.

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Kanabar D, Dale S, Raw at M. A review of ibuprofen and acetaminophen use in febrile children and the occurrence of asthma-related symptoms. Clin Ther 2007; 29: 2716-23.

Low risk for asthmatic children

In a literature review of children with asthma

Ibuprofen had a low risk of asthma related morbidity in children.

Ibuprofen may in fact offer a protective effect in comparison to paracetamol.

IBUPROFEN FOR FEVER

Why treat fever in children?

Dehydration

Discomfort and anorexia

Parental anxiety

Unneccessary healthcare visits

Febrile convulsion

Options for treating fever in children

Tepid sponge

Medications

Paracetamol

Ibuprofen

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F. Pelen et al., "Treatment of fever: monotherapy with Ibuprofen. Ibuprofen pediatric suspension containing 100 mg

5 ml, multicentre acceptability study conducted in hospital.", ANN PEDIAT, 45(10), 1998, pp. 719-728

Fast Onset of Action Start reducing fever in 15 mins

Open multi-centre hospitals based study of 351 children in France

Ibuprofen (10mg/kg) had a fast onset for fevers >38.5 and <40.5°C

(p<0.001 in all fevers, p<0.00034 in high fevers)

Ibuprofen had an early, significant antipyretic effect from 15 minutes to 12 hours after

administration in all pediatric fevers (orange line) and in fevers over 39.5°C (red line).

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Pelen F., Verrierre F., Cournot A,. Lasfargues G. Treatment of fever: monotherapy with ibuprofen. Ibuprofen pediatric suspension contain 100 mg/5ml. Ann Pediatr (Paris), 1998, 45,719-728.

Temperature lowering effects of ibuprofen (10mg/kg) observed in all paediatric fevers

(orange line) and in fevers over 39.5°C (red line) across 12 hours.

Ibuprofen has 2 hours longer duration of action than paracetamol (4-6 hours).

Long Duration of Action Reduce fever for up to 8 hours

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Kelley M, Walson P, et al. Clinical Pharmacology and Therapeutics 1992; 52: 181-9.

Long Duration of Action Reduce fever for up to 8 hours

A randomised, open-label, parallel design study involving 36 children aged from 6 months

to 11 years of age comparing Iburofen and Paracetamol.

There is significant effect of type of drug and time

Ibuprofen gave significantly greater mean temperature differences at 4, 5, 6, 7 and 8 hours

(p < 0.02)

Whilst this was not

the recommended

dose for ibuprofen,

these results have

been repeated in

other studies using

the recommended

dose.

3-arm RCT ibuprofen vs.

paracetamol vs.

Combined

Strong evidence for time

spent without fever in the

ibuprofen group and the

combined therapy group

paracetamol plus ibuprofen as combined therapy

Hay AD. Paracetamol plus ibuprofen for the treatment of fever in children: randomized controlled trial. BMJ, 2008;337;a1302.

Strong evidence suggested that paracetamol plus ibuprofen had a faster

effect than paracetamol

Ibuprofen alone had a faster effect than paracetamol alone

Giving paracetamol plus ibuprofen over 24 hours increased time without

fever by 4.4 hours compared with paracetamol and by 2.5 hours compared

with ibuprofen

Hay AD. Paracetamol plus ibuprofen for the treatment of fever in children: randomized controlled trial. BMJ, 2008;337;a1302.

Guideline for the treatment of fever

Children < 3 months with suspected fever should be seen by

a doctor

Children with fever longer than a few days should be

evaluated by a doctor

Ibuprofen should NEVER be recommended when children

present with fever ALONE

Children with fever and obvious source can safely receive

ibuprofen

Fever and ear pain or tooth pain

Fever and signs of HFM

IBUPROFEN FOR PEDIATRIC PAIN CONTROL

Drenel L. A., Gorelick H. M., Welsman J. S., et al. Ann Emerg Med. 2009;54:553-560

Friday H. J., Kanegaye T. J., McCaslin I., et al. Academic Emergency medicine. 2009;16:711-716

From Meta Analysis, literature

searches were performed using

PubMed/MEDLINE (until August 2009)

and EMBASE (through January 2008).

54 Clinical data supporting ibuprofen

analgesic efficacy compared to

paracetamol, 18 were conducted in

pediatric patients.

Studies concluded that ibuprofen was

superior to paracetamol for analgesic

relief.

Standardized Mean Difference

(acetaminophen-ibuprofen)

• Clark E., Plint A., Correll R., Gaboury I and Passi B. Acute pain relief in children with musculoskeletal trauma. Pediatrics, 2007; 119; 460-467 • Catherine A and Bryan V. Efficacy and Safety of ibuprofen and acetaminophen in children and adults: A meta -analysis and qualitative review. Ann Pharmacother, 2010;44:489-506.

More effective than paracetamol for “Pain relief”

The downside of paracetamol

USFDA issued a warning against preparations which mix

paracetamol with other analgesics

Paracetamol-induced liver injury

Paracetamol is metabolized via P450 MFO (toxic pathway) and

conjugation in the liver

In therapeutic dosing, metabolism via MFO accounts for a very

small percentage. NAPQI being generated are detoxified by

endogenous glutathione

Chronic supra-therapeutic overdose saturates conjugation pathway,

depletes glutathione and increases NAPQI generation

Result: hepatotoxicity

Mixed-formulation paracetamol accounts for 20% of all

paracetamol in the market (USA)

Consumer are unaware and often take paracetamol along

with these drugs

Hepatic injury from chronic overdose is not easily reversible

with NAC

USFDA recommends that mixed formulation paracetamol

limit paracetamol content to 325mg.

Chronic overdose of paracetamol

http://www.fda.gov/drugs/drugsafety/informationbydrugclass/ucm165107.htm

Summary Paracetamol remains the first-line drug for treating fever in

children and adults in Thailand

When DHF can be safely excluded, ibuprofen can be safely

used to treat fevers and musculoskeletal pain of short

duration

Ibuprofen and paracetamol have comparable safety data

Combined use of ibuprofen and paracetamol is more

efficacious can either one alone

Paracetamol has significant hepatotoxicity risk due to

therapeutic errors involving mixed formulation

Thank you.