Pharmacokinetics in children

There is only pharmacokinetic data available of children with an open ductus arteriosus. An open ductus arteriosus results in changes in the physiological parameters, liver values and kidney perfusion. this data is consequently not representative for children with a non-abnormal cardiovascular system.

The following pharmacolinetic parameters were reported in premature neonates with gestational age of 23-34 weeks (n=189) with open ductus arteriosus:

Parameter	Mean value	References
t1/2	16-36 hours	Thalji 1980, Yaffe 1980, Gal 1993, Sharma 2003, Al Za’abi 2007
Cl	8-19 (ml/kg/hour)	Thalji 1980, Gal 1993, Al Za’abi 2007
Vd before closure of the ductus arteriosus	220-530 (ml/kg)	Gal 1991, Gal 1993
Vd after closure of the ductus arteriosus	100-580 (ml/kg)	Gal 1991, Gal 1993

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
Oral 2 years up to 18 years 2 mg/kg/day in 2 - 4 doses. Max: 150 mg/day. Also in combination with other analgesics for pain resulting from bone metastases

Painmanagement (among which Juvenile Idiopathic Arthritis (JIA))
Oral Normal preparation (immediate release) 2 years up to 18 years [2] [10] 1 - 2 mg/kg/day in 2 - 3 doses. Max: 150 mg/day.

Pain, inflammatory activity and fever in juvenile idiopathic arthritis (JIA)
Oral Tablet with regulated release 2 years up to 18 years [2] 1 - 2 mg/kg/day in 1 - 2 doses. Max: 150 mg/day.

Closing a ductus arteriosus

Intravenous Postnatal age < 2 days [1] [9] Initial dose: 0.2 mg/kg/day, once only. Maintenance dose: 0.1 mg/kg/dose 2 doses with an interval of 12-24 hours. Postnatal age 2 days up to 7 days [1] [9] Initial dose: 0.2 mg/kg/dose, once only. Maintenance dose: 0.2 mg/kg/dose 2 doses with an interval of 12-24 hours. Postnatal age ≥ 7 days [1] [10] Initial dose: 0.2 mg/kg/dose, once only. Maintenance dose: 0.25 mg/kg/dose 2 doses with an interval of 12-24 hours.

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 indometacin 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 indometacin 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 indometacin 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

Cases of hepatotoxicity have been reported, including fatalities. Concentration disorders are sometimes seen in children.
In intravenous administration: After intravenous administration to infants, reversible deterioration of the renal function can occur, including acute kidney failure. Hyponatraemia can occur in neonates
The following side effects have also been reported in infants, although a causal relationship has not been established: bradycardia, apnoea, acidosis or alkalosis and retrolental fibroplasia.

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

Contra-indications in children

Contraindications for the ‘close the ductus arteriosus’ indication: sepsis, shock, necrotizing enterocolitis, cerebral hypoxic-ischemic damage, clotting disorders, pre-existing kidney disease (with oliguria and creatinine > 150 mcg/litre), thrombocytes < 75,000/mm³. Relative contraindication: unstable intraventricular bleeding and periventricular leukomalacia.

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

Regularly monitor hepatic function in children, as fatal cases of hepatotoxicity have been reported. Indometacin is used when other NSAIDs are insufficiently effective. The conditions under which the medicine can be used safely in children under 2 years of age are uncertain. Avoid use of NSAIDs when infected with Varicella.

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.

Propionic acid derivatives
	Ibuprofen Related Medicines Menu">	M01AE01

References

1. Lundbeck Pharmaceuticals Ireland Limited, SPC Indocid PDA (RVG 10776), www.cbg-meb.nl, Geraadpleegd 18 augustus 2010
2. Armbrust W et al, Werkboek Kinderreumatologie, VU Uitgeverij, 2014, 3e druk
3. Al Za'abi, M., et al, Orogastric and intravenous indomethacin administration to very premature neonates with patent ductus arteriosus: population pharmacokinetics, absolute bioavailability, and treatment outcome, Ther Drug Monit, 2007, 29(6), 807-14
4. Sharma, P. K., et al, A preliminary study on pharmacokinetics of oral indomethacin in premature infants in north India, Indian J Med Res, 2003, 117, 164-9
5. Gal, P. et al. , Indomethacin pharmacokinetics in neonates: the value of volume of distribution as a marker of permanent patent ductus arteriosus closure, Ther Drug Monit, 1991, 13(1), 42-5
6. Gal, P., et al, Drug disposition in neonates with patent ductus arteriosus, Ann Pharmacother, 1993, 27(11), 1383-8
7. Yaffe, S. J., et al, The disposition of indomethacin in preterm babies, J Pediatr, 1980, 97(6), 1001-6
8. Thalji, A. A., et al, Pharmacokinetics of intravenously administered indomethacin in premature infants, J Pediatr, 1980, 97(6), 995-1000
9. Lyophilization Services of New England (LSNE) for Navinta LLC, Product Information Indomethacin for injection, USP, www.fda.gov, December 2015
10. Apotex Europe BV, SmPC Indometacine capsules 25 mg, 50 mg (RVG 52225 en 57631) 30-06-2017, www.geneesmiddeleninformatiebank.nl

Changes

Therapeutic Drug Monitoring

Overdose