Pharmacokinetics in children

The following pharmacokinteic parameters were reported in three studies in children aged 3 months-14 years aftre oral administration  (Valitalo et al. 2012, Wells et al. 1994, Ansell et al 1975):

Parameter	value	Age	n=	References
Cmax	47-95 mg/L (in a dose of 3.7-7.6 mg/kg)	8-14 year	22	(Wells et al. 1994)
	Mean  72±29 mg/L (in a dose of 10 mg/kg)	3 months-12 years	53	(Valitalo et al. 2012)
Tmax	1-8 hour Mean  2.2±2.1 hour for the suspension (n=10) and 2.7 ±2.0 hour for the tablet (n=12)	3 months-14 years	84	(Ansell et al 1975, Wells et al. 1994, Valitalo et al. 2012)
t1/2	5-18 hours	5-14 years	31	(Ansell et al1975, Wells et al. 1994)
Cl/F	0.1-0.2 ml/min/kg	8-14 years	22	(Wells et al. 1994)
Vd/F in steady state	90-200 ml/kg	8-14 years	22	(Wells et al. 1994)

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

Painmanagement (among which Juvenile Idiopathic Arthritis (JIA))
Rectal 3 months up to 18 years 10 - 15 mg/kg/day in 2 - 3 doses. Max: 1.000 mg/day. Oral 3 months up to 18 years 10 - 15 mg/kg/day in 2 - 3 doses. Max: 1.000 mg/day. Directions for administration: Take during or shortly after a meal due to stomach problems.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Consider whether the use of an NSAID is justified.
When naproxen is prescribed to children at risk: verify renal function prior to the start and within the first week after starting.

GFR 30-50 ml/min/1.73 m2

Consider whether the use of an NSAID is justified.
When naproxen is prescribed to children at risk: verify renal function prior to the start and within the first week after starting.

GFR 10-30 ml/min/1.73 m2

Consider whether the use of an NSAID is justified.
When naproxen is prescribed to children at risk: verify renal function prior to the start and within the first week after starting.

GFR < 10 ml/min/1.73 m2

A general recommendation is not given.

Clinical consequences

Risk-factors are: heart failure, liver cirrhosis, nephrotic syndrome, chronic kidney disease, causes leading to dehydration (e.g. summer heat), use of other drugs decreasing renal function, like diuretics or RAAS inhibitors.

NSAIDs (including COX-2 inhibitors) can cause acute renal failure by decreasing renal perfusion (by hypovolaemia). Normally, an increased prostaglandin synthesis in the kidneys prevents a rapid decrease in renal perfusion; however, NSAIDs disturb this compensating mechanism. Decreased renal perfusion also leads to water and salt retention, resulting in the occurrence or worsening of hypertension and heart failure.

Patients on dialysis

Haemodialysis / continuous venovenous haemodialysis or haemo(dia)filtration:

• residual kidney function (urine production) PRESENT: avoid use to save residual kidney function
• residual kidney function (urine production) NOT PRESENT: avoidance is not necessary

Patients undergoing dialysis have a higher bleeding risk, probably related to an abnormal platelet function. The bleeding risk can be increased by the use of low molecular weight heparines at the start of haemodialysis 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 in children

Pseudoporphyria may ocurr in children with juvenile idiopathic athritis using naproxen. Pseudoporphyria is characterized by increased fragility of the skin, blistering and scarring. [Lang et al 1994]

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

Contra-indications

No information available on specific 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

In exceptional cases, varicella can lead to serious infectious complications of the skin and soft tissues. To date, it cannot be ruled out that NSAIDs contribute to the worsening of these infections. It is therefore recommended not to use naproxen in cases of varicella (Prescrire Internat. 2020)

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
	Diclofenac Related Medicines Menu">	M01AB05
	Indomethacin Related Medicines Menu">	M01AB01

Oxicams
	Piroxicam Related Medicines Menu">	M01AC01

Propionic acid derivatives
	Dexibuprofen Related Medicines Menu">	M01AE14
	Ibuprofen Related Medicines Menu">	M01AE01

Fenamates
	Mefenaminsäure Related Medicines Menu">	M01AG01

Coxibs
	Celecoxib Related Medicines Menu">	M01AH01

References

1. Armbrust W et al, Werkboek Kinderreumatologie, VU Uitgeverij, 2014, 3e druk
2. Kamps WA et al, Werkboek ondersteundende behandeling kinderoncologie, VU Uitgeverij, 2005
3. MMI, Gelbe Liste I Online, 21/03/2018
4. Johnson & Johnson, SmPC Dolormin® GS mit Naproxen (35876.00.00), 09/2015
5. Hormosan, SmPC Naproxen-Hormosan 500 mg magensaftresistente Tabletten (91391.00.00), 02/2016
6. HWI, SmPC Togal Naproxen 200 mg Filmtabletten (52018.00.00), 01/2017
7. STADA, SmPC Naproxen STADA® 250 mg/ 500 mg/ 750 mg Tabletten (30570.00.00, 30570.01.00, 40323.00.00), 04/2015
8. Bayer, SmPC Aleve® (38457.00.00), 03/2017
9. Hormosan, SmPC Naproxen-Hormosan 250 mg magensaftresistente Tabletten (91390.00.00), 02/2016
10. Infectopharm, SmPC Naproxen Infectopharm 50 mg/ml Suspension zum Einnehmen (94696.00.00), 06/2017
11. UpToDate, Naproxen: Drug Information, Version 299.0
12. Lang et al., Naproxen-induced pseudoporphyria in patients with juvenile rheumatoid arthritis, J Pediatr, 1994, April, 124(4), 639-42
13. Wells, T. G., et al, Comparison of the pharmacokinetics of naproxen tablets and suspension in children, J Clin Pharmacol, 1994, 34(1), 30-3
14. Valitalo, P., et al, Plasma and cerebrospinal fluid pharmacokinetics of naproxen in children, E J Clin Pharmacol, 2012, 52(10), 1516-26
15. Ruperto, N., et al, A randomized, double-blind clinical trial of two doses of meloxicam compared with naproxen in children with juvenile idiopathic arthritis: short- and long-term efficacy and safety results, Arthritis Rheum, 2005, 52(2), 563-72
16. Reiff, A., et al, Evaluation of the comparative efficacy and tolerability of rofecoxib and naproxen in children and adolescents with juvenile rheumatoid arthritis: a 12-week randomized controlled clinical trial with a 52-week open-label extension, J Rheumatol, 2006, 33(5), 985-95
17. Kvien, T. K., et al, Naproxen and acetylsalicylic acid in the treatment of pauciarticular and polyarticular juvenile rheumatoid arthritis. Assessment of tolerance and efficacy in a single-centre 24-week double-blind parallel study, Scand J Rheumatol, 1984, 13(4), 342-50
18. Foeldvari, I.et al, A prospective study comparing celecoxib with naproxen in children with juvenile rheumatoid arthritis, J Rheumatol, 2009, 36(1), 174-82
19. Ansell, B. M., et al, Naproxen absorption in children, Curr Med Res Opin, 1975, 3(10, 46-50
20. <No author listed>, Varicella, herpes zoster and nonsteroidal anti-inflammatory drugs: serious cutaneous complications., Prescrire Internat., 2010, 19, 72-73

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