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

• MUSCULO-SKELETAL SYSTEM
• ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS

ANTIINFLAMMATORY AND ANTIRHEUMATIC PRODUCTS, NON-STEROIDS

This pages provides a list of drugs from the same ATC class for comparison. This does not necessarily mean that these drugs are interchangeable.

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

References

1. Rademaker C.M.A. et al, Geneesmiddelen-formularium voor Kinderen, 2007
2. Allegaert K et al, Impact of ibuprofen administration on renal drug clearance in the first weeks of life., B.J. Methods Find EXp Clin Pharmacol, 2006, Oct:28(8), 519-22
3. Reckitt Benckiser Healthcare B.V, SPC Nurofen zetpil 60-125 mg (RVG 33132/31759), www.cbg-meb.nl, Geraadpleegd 10 juli 2010, http://db.cbg-meb.nl/IB-teksten/h31759.pdf
4. Reckitt Benckiser Healthcare B.V. 17/11/2008, SPC Nurofen suspensie 100 mg/5 ml (RVG 19838) 01-07-2016, www.cbg-meb.nl
5. NVK, Richtlijn pijnmeting en behandeling pijn bij kinderen, www.nvk.nl, 2007, http://www.nvk.nl/Kwaliteit/Richtlijnenenindicatoren/Richtlijnen/Pijnmetingenbehandelingvan/tabid/348/language/nl-NL/Default.aspx
6. CBO, Richtlijn Postoperatieve Pijnbehandeling, www.cbo.nl, 2003, 127-156, http://www.cbo.nl/Downloads/108/postoppijn2003.pdf
7. Franssen MJAM et al, Werkboek Kinderreumatologie, VU Uitgeverij, 2008, 2e druk
8. Farmanco/KNMP, Geneesmiddeltekorten, www.farmanco.knmp.nl, http://www.farmanco.knmp.nl/tekortgeneesmiddelen/diversen/pedea
9. Bijl, D., Varicella zoster, herpes zoster en NSAID’s: ernstige dermatologische complicaties, Geneesmiddelbulletin, 2010, 44: 9 (Sept), 103-4
10. ABDA-Datenbank, Wirkstoffdossier Ibuprofen, accessed 11/07/2018
11. Compendium.ch, Compendium Interaktionen Ibuprofen Stand: V2017-10-19, 2017
12. UpToDate, Lexicomp® Drug Interactions Ibuprofen Version 309.0, Acessed 07/2017
13. Johnson & Johnson GmbH, SmPC Dolormin 400 mg Weichkapseln (89883.00.00), 09/2015
14. Merckle Recordati GmbH, SmPC Imbun Zäpfchen, 500 mg (15797.00.00), 02/2011
15. bene-Arzneimittel GmbH, SmPC ib-u-ron® 75 mg/150 mg Zäpfchen (61309.00.00 / 61310.00.00), 09/2015
16. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior 125 mg Zäpfchen (55141.00.00), 03/2015
17. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior 60 mg Zäpfchen (55141.01.00), 03/2015
18. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior Kaudragee Orange (95058.00.00), 02/2017
19. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen® 200 mg Schmelztabletten Lemon (50464.00.00), 03/2016
20. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Immedia 400 mg Filmtabletten (43917.01.00), 08/2015
21. Hexal AG, IbuHEXAL® akut 200 mg / 400 mg (2129.99.99 / 2129.97.99), 08/2015
22. 1 A Pharma GmbH, SmPC Ibu 1A Pharma 400/ 600 / 800 / 800 ret mg (14494.01.00 / 9574.01.00 / 17644.00.00 / 12142.00.00), 09/2015
23. PUREN Pharma, SmPC Ibuprofen PUREN Granulat 600 mg (23294.00.00), 11/2015
24. PUREN Pharma, SmPC Ibuprofen PUREN Granulat 400 mg (22155.00.00), 10/2015
25. Winthrop Arzneimittel GmbH, SmPC Ibuflam® Kindersaft 2 % 20 mg/ml Suspension zum Einnehmen (22292.00.00), 08/2015
26. ratiopharm GmbH, SmPC IBU-ratiopharm® Fiebersaft für Kinder 40 mg/ml (60523.00.00), 02/2017
27. ratiopharm GmbH, SmPC IBU-ratiopharm® Fiebersaft für Kinder 20 mg/ml (60522.00.00), 01/2017
28. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior Fieber- und Schmerzsaft Erdbeer 40 mg/ml Suspension zum Einnehmen (77581.00.00), 10/2015
29. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior Fiebersaft Orange 2 % Suspension zum Einnehmen (39181.00.00), 01/2015
30. Orphan Europe SARL, SmPC Pedea 5 mg/ml Injektionslösung (EU/1/04/284/001), 12/2013
31. Orphan, SmPC Pedea 5 mg/ml Injektionslösung (EU/1/04/284/001), 05/18
32. AbZ Pharma, SmPC Ibu-Lysin AbZ Migräne 684 mg Filmtabletten (79783.00.00), 05/13
33. AbZ Pharma, SmPC Ibuprofen AbZ 400/600/800 mg Filmtabletten (2129.98.99), 12/17
34. bene-Arzneimittel, SmPC ib-u-ron® 75 mg/150 mg Zäpfchen (61309.00.00/61310.00.00), 03/18
35. ratiopharm, SmPC IBU-ratiopharm® Fiebersaft für Kinder 20 mg/ml (60522.00.00), 01/18
36. UpToDate, Lexicomp® Drug Interactions Ibuprofen Version 309.0, Acessed 07/2017
37. PUREN Pharma, SmPC Ibuprofen PUREN Granulat 600 mg (23294.00.00), 11/2015
38. 1 A Pharma GmbH, SmPC Ibu 1A Pharma 400/ 600 / 800 / 800 ret mg (14494.01.00 / 9574.01.00 / 17644.00.00 / 12142.00.00), 09/2015
39. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen® 200 mg Schmelztabletten Lemon (50464.00.00), 03/2016
40. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior Kaudragee Orange (95058.00.00), 02/2017
41. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior 60 mg Zäpfchen (55141.01.00), 03/2015
42. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior 125 mg Zäpfchen (55141.00.00), 03/2015
43. Compendium.ch, Compendium Interaktionen Ibuprofen Stand: V2017-10-19, 2017
44. ABDA-Datenbank, Wirkstoffdossier Ibuprofen, accessed 11/07/2018
45. Orphan Europe SARL, SmPC Pedea 5 mg/ml Injektionslösung (EU/1/04/284/001), 12/2013
46. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior Fiebersaft Orange 2 % Suspension zum Einnehmen (39181.00.00), 01/2015
47. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Junior Fieber- und Schmerzsaft Erdbeer 40 mg/ml Suspension zum Einnehmen (77581.00.00), 10/2015
48. ratiopharm GmbH, SmPC IBU-ratiopharm® Fiebersaft für Kinder 20 mg/ml (60522.00.00), 01/2017
49. ratiopharm GmbH, SmPC IBU-ratiopharm® Fiebersaft für Kinder 40 mg/ml (60523.00.00), 02/2017
50. Winthrop Arzneimittel GmbH, SmPC Ibuflam® Kindersaft 2 % 20 mg/ml Suspension zum Einnehmen (22292.00.00), 08/2015
51. PUREN Pharma, SmPC Ibuprofen PUREN Granulat 400 mg (22155.00.00), 10/2015
52. Hexal AG, IbuHEXAL® akut 200 mg / 400 mg (2129.99.99 / 2129.97.99), 08/2015
53. Reckitt Benckiser Deutschland GmbH, SmPC Nurofen Immedia 400 mg Filmtabletten (43917.01.00), 08/2015
54. bene-Arzneimittel GmbH, SmPC ib-u-ron® 75 mg/150 mg Zäpfchen (61309.00.00 / 61310.00.00), 09/2015
55. Merckle Recordati GmbH, SmPC Imbun Zäpfchen, 500 mg (15797.00.00), 02/2011
56. Johnson & Johnson GmbH, SmPC Dolormin 400 mg Weichkapseln (89883.00.00), 09/2015
57. ratiopharm, SmPC IBU-ratiopharm® Fiebersaft für Kinder 20 mg/ml (60522.00.00), 01/18
58. bene-Arzneimittel, SmPC ib-u-ron® 75 mg/150 mg Zäpfchen (61309.00.00/61310.00.00), 03/18
59. AbZ Pharma, SmPC Ibuprofen AbZ 400/600/800 mg Filmtabletten (2129.98.99), 12/17
60. AbZ Pharma, SmPC Ibu-Lysin AbZ Migräne 684 mg Filmtabletten (79783.00.00), 05/13
61. Orphan, SmPC Pedea 5 mg/ml Injektionslösung (EU/1/04/284/001), 05/18
62. Nahata, M. C., et al, Pharmacokinetics of ibuprofen in febrile children, Eur J Clin Pharmacol, 1991, 40 (4), 427-8
63. Anderson, B. J., et al., A target concentration strategy to determine ibuprofen dosing in children., Paediatr Anaesth, 2019, 29 (11), 1107-1113
64. Gelotte, C. K., et al, Multiple-dose pharmacokinetics and safety of an ibuprofen-pseudoephedrine cold suspension in children, Clin Pediatr (Phila), 2010, 49 (7), 678-85
65. Brown, R. D., et al , Single-dose pharmacokinetics of ibuprofen and acetaminophen in febrile children, J Clin Pharmacol, 1992, 32 (3), 231-41
66. Kauffman, R. E., et al, Effect of age on ibuprofen pharmacokinetics and antipyretic response, J Pediatr, 1992, 121 (6), 969-73
67. Kelley, M. T., et al , Pharmacokinetics and pharmacodynamics of ibuprofen isomers and acetaminophen in febrile children, Clin Pharmacol Ther, 1992, 52 (2), 181-9
68. Kyllönen, M., et al, Perioperative pharmacokinetics of ibuprofen enantiomers after rectal administration, Paediatr Anaesth, 2005, 15 (7), 566-73
69. Playne, R., et al, Analgesic effectiveness, pharmacokinetics, and safety of a paracetamol/ibuprofen fixed-dose combination in children undergoing adenotonsillectomy: A randomized, single-blind, parallel group trial, Paediatr Anaesth, 2018, 28 (12), 1087-1095
70. Rey, E., et al. , Stereoselective disposition of ibuprofen enantiomers in infants, Br J Clin Pharmacol, 1994, 38 (4), 373-5
71. Tarabar, S., et al, Phase I Pharmacokinetic Study of Fixed-Dose Combinations of Ibuprofen and Acetaminophen in Healthy Adult and Adolescent Populations., Drugs R D, 2020, 20 (1), 23-37
72. Cumberland Pharmaceuticals Inc. , Drug Label Caldolor (NDC 66220-287-08) 4/2021, https://dailymed.nlm.nih.gov/
73. B. Braun Melsungen AG, SmPC Ibuprofen 200 mg infusjonsvæske, oppløsning (18-12653) 24-09-2021
74. Kokki H, et al., Cerebrospinal fluid distribution of ibuprofen after intravenous administration in children., Pediatrics, 2007, 120(4), e1002-8
75. Khalil SN,et al., A multicenter, randomized, open-label, active-comparator trial to determine the efficacy, safety, and pharmacokinetics of intravenous ibuprofen for treatment of fever in hospitalized pediatric patients., BMC Pediatr., 2017, 17(1), 42.
76. Tan E, et al., Comparison of Acetaminophen (Paracetamol) With Ibuprofen for Treatment of Fever or Pain in Children Younger Than 2 Years: A Systematic Review and Meta-analysis., JAMA Netw Open, 2020, 3(10), e2022398.

Changes

Therapeutic Drug Monitoring

Overdose