Pharmacokinetics in children

The bioavailability is greater in rectal administration than oral administration (relative bioavailability = 1.26) (ages 2-8 years, N=26) [Van de Maarel 2004]

Two studies (n=21, ages 4 -15 jyears) reported the following pharmocokinetic parameters: [Romsing 2001; Korpela 1990]

Cmax after oral administration	0.5-4.5 µg/ml
Tmax  after oral administration	1.5-3 hour
t1/2	± 0.5-2 hour
Cl/F	5.6-18.4 ml/min/kg
Vd/F	443-1089 ml/kg

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))

Oral Regulated release ≥ 25 kg 1 - 3 mg/kg/day in 1 - 2 doses. Max: 200 mg/day. Available formulations limit the use of the regulated release tablet in children < 25 kg Normal preparation (immediate release) 3 months up to 18 years 1 - 3 mg/kg/day in 2 - 4 doses. Max: 200 mg/day. Rectal 3 months up to 18 years 1 - 3 mg/kg/day in 2 - 4 doses. Max: 200 mg/day. Intravenous Normal preparation (immediate release) 3 months up to 18 years 0.3 - 0.5 mg/kg/dose, as required, max. 4 times daily. Max: 37.5 mg/dose. Intraoperatively, a single dose of 1 mg/kg/dose (max. 75 mg/dose) can be started.[Nze 2006] Do not use longer than 1 week in children less than 3 years of age as the IV fluid contains benzyl alcohol.

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 diclofenac 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 diclofenac 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 diclofenac 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

Diclofenac slows the thrombocyte aggregation. This process is reversible. Gastritis

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

When used post-operatively, be aware of the elevated risk of further bleeding.  Liquids for injection may contain benzyl alcohol.
Be aware of the possibility of exacerbation of asthma (do not use in children with acute or active asthma). Caution is needed in impaired liver function and elevated risk of renal impairment and concomitant use of nephrotoxic drugs.

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 ibuprofen in cases of varicella(Prescrire Internat 2010).

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

Oxicams
	Piroxicam Related Medicines Menu">	M01AC01

Propionic acid derivatives
	Dexibuprofen Related Medicines Menu">	M01AE14
	Ibuprofen Related Medicines Menu">	M01AE01
	Naproxen Related Medicines Menu">	M01AE02

Fenamates
	Mefenaminsäure Related Medicines Menu">	M01AG01

Coxibs
	Celecoxib Related Medicines Menu">	M01AH01

References

1. Korpela R, et al, Pharmacokinetics of intravenous diclofenac sodium in children, Eur J Clin Pharmacol, 1990, 38, 293-5
2. Littlejohn IH, et al., Post-operative pain relief in children following extraction of carious deciduous teeth under general anaesthesia: a comparison of nalbuphine and diclofenac, Eur J Anaesthesiol, 1996, 13, 359-63
3. Mendham JE, et al, Comparison of diclofenac and tenoxicam for postoperative analgesia with and without fentanyl in children undergoing adenotonsillectomy or tonsillectomy, Paediatr Anaesth, 1996, 6, 467-73
4. Nishina K, et al., Diclofenac and flurbiprofen with or without clonidine for postoperative analgesia in children undergoing elective ophthalmological surgery, Paediatr Anaesth, 2000, 10, 645-51
5. Nze PU, et al, Intraoperative diclofenac for post-adenoidectomy analgesia in small children., J Clin Pract, 2006, 9, 102-4
6. Romsing J, et al, Diclofenac or acetaminophen for analgesia in paediatric tonsillectomy outpatients., Acta Anaesthesiol Scand, 2000, 44, 291-5
7. Romsing J, et al, Pharmacokinetics of oral diclofenac and acetaminophen in children after surgery, Paediatr Anaesth, 2001, 11, 205-13
8. Ryhanen P, et al, Postoperative pain relief in children: A comparison between caudal bupivacaine and intramuscular diclofenac sodium, Anaesthesia, 1994, 49, 57-61
9. Tawalbeh MI, et al, Comparative study of diclofenac sodium and paracetamol for treatment of pain after adenotonsillectomy in children, Saudi Med J, 2001, 22, 121-3
10. Thiagarajan J, et al, Blood loss following tonsillectomy in children. A blind comparison of diclofenac and papaveretum, Anaesthesia, 1993, 48, 132-5
11. Nederlandse Vereniging voor KNO-heelkunde en Heelkunde van het Hoofd-Halsgebied, Richtlijn Ziekten van Adenoïd en Tonsillen in de Tweede lijn, 2007, 52-55
12. Armbrust W et al, Werkboek Kinderreumatologie, VU Uitgeverij, 2014, 3e druk
13. CBO, Richtlijn postoperatieve pijn, www.diliguide.nl, 2012, 176-178, http://www.diliguide.nl/document/2995/postoperatieve-pijnstilling.html
14. Ratiopharm, SmPC Diclofenac-ratiopharm® Gel (32385.00.00), 04/2015
15. Standing, J. F., et al, Diclofenac for acute pain in children, Cochrane Database Syst Rev, 2009, (4), Cd00553
16. Standing, J. F., et al, Diclofenac pharmacokinetic meta-analysis and dose recommendations for surgical pain in children aged 1-12 years, Paediatr Anaesth, 2011, 21 (3), 316-2
17. Standing, J. F., et al, Population pharmacokinetics of oral diclofenac for acute pain in children, Br J Clin Pharmacol, 2008, 66(6), 846-53
18. Strengell, T., et al, Antipyretic agents for preventing recurrences of febrile seizures: randomized controlled trial, Arch Pediatr Adolesc Med, 2009, 163 (9), 799-804
19. Mireskandari, S. M. et al, Effect of rectal diclofenac and acetaminophen alone and in combination on postoperative pain after cleft palate repair in children, J Craniofac Surg, 2011, 22(5), 1955-9
20. Nnaji, C. T., et al, The analgesic effects of rectal diclofenac versus rectal paracetamol following caudal-bupivacaine for pediatric day-case inguinal herniotomies: a randomized controlled prospective trial., J Pediatr Surg, 2017, 52(9), 1384-88
21. van der Marel, C. D., et al, Diclofenac and metabolite pharmacokinetics in children., Paediatr Anaesth, 2004, 14(6), 443-51
22. Littlejohn IH, et al., Post-operative pain relief in children following extraction of carious deciduous teeth under general anaesthesia: a comparison of nalbuphine and diclofenac, Eur J Anaesthesiol, 1996, 13, 359-63
23. Nze PU, et al, Intraoperative diclofenac for post-adenoidectomy analgesia in small children., J Clin Pract, 2006, 9, 102-4
24. Romsing J, et al, Pharmacokinetics of oral diclofenac and acetaminophen in children after surgery, Paediatr Anaesth, 2001, 11, 205-13
25. Ryhanen P, et al, Postoperative pain relief in children: A comparison between caudal bupivacaine and intramuscular diclofenac sodium, Anaesthesia, 1994, 49, 57-61
26. <No author listed>, Varicella, herpes zoster and nonsteroidal anti-inflammatory drugs: serious cutaneous complications., Prescrire Internat, 2010, 19, 72-73

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