Pharmacokinetics in children

Rectal administration
After a single rectal administration of 20 mg/kg after induction of anesthesia to 24 infants 1 to 52 weeks, tmax was reached after 1-2 hours. No differences were found in Cmax and t½ between these infants and adults (Kyllönen et al. 2005).

Oral administration
The following pharmacokinetic parameters were found in children 3 months to 17 years of age administered ibuprofen orally (Brown et al. 1992, Rey et al. 1994, Kelley et al. 1992, Nahata et al. 1991, Gelotte et al. 2010, Tarabar et al. 2020, Kauffman and Nelson 1992, Playne et al. 2018):

Tmax (hour)	0,5-6,1
T½ (hour)	1,3-2
Cl (ml/min/kg)	1-1,8
Vd (ml/kg)	147-217

In addition, (Playne et al. 2018, Gelotte et al. 2010, Kauffman and Nelson 1992, Brown et al. 1992, Nahata et al. 1991) found a Cmax ranging from 25 to 53 mg/L with single oral administration of 7-10 mg/kg/dose in children 3 months to 12 years of age.

Intravenous administration
The following pharmacokinetic parameters were found after intravenous administration of 10 mg/kg in children 0 months-16 years of age (Khalil et al. 2017):

Age	N	AUC0-t (mg*hr/ml) (min;max)	AUC0-4 (mg*hr/ml)(min;max)	Cmax (mg/ml)(min;max)	Tmax (hr)(min;max)	T1/2el (hr)(min;max)	Cl (ml/hr)(min;max)	Vz (ml)(min;max)
0-6 months	1	51,18	69,14	49,83	0,167	1,8	620	1054
6 months-2 years	5	71,15 (34,67; 95,20)	70,92 (34,67; 95,20)	59,24 (38,37; 92,02)	0,234 (0,167; 0,500)	1,78 (1,06; 2,35)	1173 (845; 1956)	2806 (2036; 3569)
2-6 years	12	79,19 (19; 110)	80,25 (22,96; 124)	64.18 (15,91; 96.31)	0,309 (0,167; 0,767)	1,48 (0,79; 2,87)	1967 (1099; 4745)	3696 (1851; 5411)
6-16 years	25	80,67 (40, 161)	85,73 (39,62; 162)	61,89 (31,03; 93,32)	0,212 (0,167; 667)	1,55 (0,79; 2,54)	4878 (999; 12537)	10314 (2640; 23964)

AUC0-t: Area under the concentration-time curve from time zero to the last measurable concentration using linear-log trapezoidal rule
AUC0–4: Area under the concentration-time curve from time zero to 4 h
Cmax: Maximum observed concentration
Tmax: Time of observed Cmax
T½ el: Elimination half-life, calculated as ln(2)/Kel
Cl: Total body clearance, calculated as Dose/AUC0-inf
Vz: Volume of distribution, calculated as Dose/(Kel x AUC0-inf)

dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

Available formulations

No information is present at this moment.

Dosages

Pain relief and anti-inflammation (including in Juvenile Idiopathic Arthritis (JIA)); Fever

Oral 3 months up to 12 years [4] 7 - 10 mg/kg/dose, as required up to 3-4 times daily. Max: 30mg/kg/day, but not exceeding 1.600 mg/day. Max single dose: 400 mg/dose. Young children tend to need doses at the upper end of the dosing range 12 years up to 18 years [4] 200 - 400 mg/dose, as required, max. 6 times daily. Max: 30mg/kg/day, but not exceeding 1.600 mg/day. Max single dose: 400 mg/dose. Maximum in short term use: 2400 mg/day. Maximum in short term use: 600 mg/dose, PRN 4 times per day, maximum 2400 mg/day.  Rectal 3 months up to 12 years [3] 7 - 10 mg/kg/dose, as required up to 3-4 times daily. Max: 30 mg/kg/day. Intravenous 3 months up to 12 years [63] [72] [73] [75] 10 mg/kg/dose, as required up to 4 times a day. Max: 40mg/kg/day Max single dose: 400 mg/dose. There are almost no data available on i.v. ibuprofen use for indications pain or fever in children < 6 months of age. 12 years up to 18 years [72] 400 mg/dose, as required, max. 6 times daily. Max: 30mg/kg/day, but not exceeding 2.400 mg/day. Max single dose: 400 mg/dose.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Consider whether use of an NSAID is justified
If the use of ibuprofen is considered to be appropriate and the patient belongs to a risk group: check the renal function before and within 1 week after starting ibuprofen

GFR 30-50 ml/min/1.73 m2

Consider whether use of an NSAID is justified
If the use of ibuprofen is considered to be appropriate and the patient belongs to a risk group: check the renal function before and within 1 week after starting ibuprofen

GFR 10-30 ml/min/1.73 m2

Consider whether use of an NSAID is justified
If the use of ibuprofen is considered to be appropriate and the patient belongs to a risk group: check the renal function before and within 1 week after starting ibuprofen

GFR < 10 ml/min/1.73 m2

A general recommendation is not provided

Clinical consequences

Risk factors for use of ibuprofen in renal impairment: heart failure, cirrhosis of the liver, nephrotic syndrome, chronic kidney disease, conditions that lead to dehydration (for example, summer heat), use of drugs that can reduce kidney function, such as diuretics or RAAS inhibitors.

NSAIDs (including COX-2 inhibitors) can cause acute renal failure due to reduced renal perfusion (due to hypovolaemia). Normally, an excessive decrease in renal perfusion is prevented by increased prostaglandin synthesis in the kidneys; NSAIDs disrupt this compensation mechanism. Reduced renal perfusion also leads to water and salt retention, resulting in worsening or the development of hypertension and heart failure.

 

Patients on dialysis

Hemodialysis / continuous venovenous hemodialysis / hemo (dia) filtration:

• residual function kidneys (urine production) DO present: avoid use to save residual function kidneys
• residual function kidneys (urine production) NOT present: avoid use is not necessary

Patients undergoing dialysis have a higher risk of bleeding, probably related to abnormal platelet function. The risk of bleeding can be additionally increased by using an LMWH at the start of hemodialysis to prevent coagulation in the extracorporeal circulation.

 

The complete list of all undesirable drug reactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Side effects

No information is present at this moment.

The complete list of all contra-indications can be found in the national Summary of Product Characteristics (SmPC) – click here

Contra-indications in children

 

 

The complete list of all warnings and precautions can be found in the national Summary of Product Characteristics (SmPC) – click here

Warnings & precautions in children

Administering ibuprofen to young neonates reduces the glomerular filtration, resulting in slower excretion of medicines where this depends on the renal clearance.

There is a risk of renal function disorders in dehydrated children and adolescents.

When children of > 5 months in the home situation need ibuprofen for longer than 3 days or if the symptoms worsen, a doctor should be consulted. For children aged 3-5 months, medical advice should be
obtained if the symptoms worsen or within 24 hours if the symptoms continue.

In exceptional cases, varicella can result in severe infectious complications of the skin and soft tissues. As yet, it is not possible to exclude the possibility that NSAIDs play a role in exacerbating these infections. It is therefore recommended that ibuprofen should not be used in cases of varicella (source: SmPC)

In obese children, based on limited data, dosing based on adjusted body weight (ABW) is recommended (Ross et al. 2015). This can be calculated as follows:
ABW = ideal body weight + 0.4 x (total body weight-ideal body weight)
Indeed, distribution of ibuprofen in body weight above ideal body weight appears to be about 0.44 times more extensive than distribution in ideal body weight.

 

 

Interactions

The complete list of all interactions can be found in the national Summary of Product Characteristics (SmPC) – click here

Acetic acid derivatives and related substances
	Indomethacin Related Medicines Menu">	M01AB01

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