Pharmacokinetics in children

Following a mean, single IV dose of 0.91-1 mg/kg to preterm (26-36 weeks GA, 1-69 days PNA) and a terme neonates, the following mean (range of means or ± SE) pharmacokinetic parameters were found (Peterson et al. 1980, Vert et al. 1982):

 

	Premature neonate (26-36 weken GA, 1-69 dagen PNA)	Term neonate
n=	22	7
Cmax (mg/l)	4,9 ± 0,5 (dose: 1 mg/kg)	-
t½ (hour)	19,9-26,8	13,4 ± 3,3
Cl (ml/kg/hour)	6,9-10,6	11,8 ± 3,5
Vd (l/kg)	0,20-0,24	0,52 ± 0,16

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

Overfilling and oedema

Oral Premature neonates Gestational age < 37 weeks [4] [25] [26] [29] 0.5 - 1 mg/kg/dose, as required. Max: 2 mg/kg/day. Term neonate [4] [25] [26] [29] 0.5 - 1 mg/kg/dose, as required. Max: 2 mg/kg/day. 1 month up to 18 years [1] [3] 1 - 4 mg/kg/day in 2 - 4 doses. Directions for administration: if you want to avoid nocturnal peaks in diuresis, give furosemide before 17:00 Maximum dose in chronic renal insufficiency or proteinuria: 12 mg/kg/day Intravenous Premature neonates Gestational age < 37 weeks [4] [20] [24] [26] [27] 0.05 - 2 mg/kg/day, continuous infusion. ALTERNATIVE: intermittent administration (as per the oral route): 0.5-1 mg/kg/dose, max. 2 mg/kg/day Intravenous dose <2 mg/kg: slow IV administration (5 minutes) Intravenous dose >2 mg/kg: administer over 30-60 minutes. Term neonate [4] [22] [24] [27] 0.05 - 2 mg/kg/day, continuous infusion. Max: 5 mg/kg/day. For severe therapy resistance: max 12 mg/kg/day. ALTERNATIVE: intermittent administration (as per the oral route): 0.5-1 mg/kg/dose, max. 2 mg/kg/day Intravenous dose <2 mg/kg: slow IV administration (5 minutes) Intravenous dose >2 mg/kg: administer over 30-60 minutes.  1 month up to 18 years [1] [5] [23] 1 - 2 mg/kg/dose, as required. Max single dose: 4 mg/kg/dose. ALTERNATIVE: Continuous intravenous administration: 2-4 mg/kg/day (maximum 12 mg/kg/day in cases of severe therapy resistance) Intravenous dose < 2 mg/kg: slow IV administration (5 minutes). Intravenous doseof > 2 mg/kg; administer over 30-60 minutes.

Hypertension
Oral 1 month up to 18 years [1] [2] [3] [18] 0.5 - 2 mg/kg/day in 1 - 2 doses. Max: 6 mg/kg/day.

Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2

Dose adjustment not needed

GFR 30-50 ml/min/1.73 m2

Dose adjustment not needed

GFR 10-30 ml/min/1.73 m2

Start at normal dose, increase dose as needed based on effect

GFR < 10 ml/min/1.73 m2

A general recommendation is not provided

Clinical consequences

Strong diuresis may cause reversible renal function impairment. Adequate fluid supply is necessary.

Patients on dialysis

Intermittent hemodialysis, continuous venovenous hemodialysis and hemo(dia)filtration, peritoneal dialysis: standard starting dose, increase dose as needed based on effect.

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

Hearing damage (in prolonged use), hypokalaemia, hypomagnesaemia. In children in particular, dehydration can result in thromboembolic processes or collapse.

Calcification of the kidneys and kidney stones have been reported in premature infants. 

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 children at the start of treatment, use low doses to prevent hypovolaemia with circulatory insufficiency caused by abrupt diuresis. Combine with spironolactone for hypokalaemia. Not for use as maintenance therapy in neonates (hypercalciuria) unless on cardiological indication. In newborns treated with furosemide for a long time, osteoclastic bone damage was found, presumably as a result of the increased calcium excretion with subsequent hyperparathyroidism.

Intravenous administration: The liquid for injection is strongly alkaline: administer continuously over a separate line, not together with standard IC medication.

Be careful in cases of arrhythmia, digoxin use or corticosteroids.

In premature infants with respiratory distress syndrome, furosemide increases the risk of the ductus Botalli remaining open if it is administered in the first weeks after birth.In premature infants nephrocalcinosis and the formation of renal stones may occur. Monitor renal functions and perform renal ultrasound.

Interactions

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

References

1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
2. Heijden, van der AJ, Werkboek Kindernefrologie, VU Uitgeverij, 2010, 2e druk
3. Centrafarm BV, SmPC Furosemide (RVG 57091) 14-05-2020, www.geneesmiddeleninformatiebank.nl
4. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie, Expert opinie, 28 maart 2018
5. Fresenius Kabi, SmPC Furosemide (RVG 34774) 18-12-2019, www.geneesmiddeleninformatiebank.nl
6. Uptodate: UpToDate®, Pediatric Drug information: Topic 13329 Version 302.0, 05/19
7. ratiopharm GmbH, SmPC, Furosemid-ratiopharm® 125/250 mg Tabletten (45266.01.00/45266.02.00), 10/15
8. ratiopharm GmbH, SmPC, Furosemid-ratiopharm® 20/40 mg Tabletten (45266.00.00), 05/16
9. gelbe-liste.de, www.gelbe-liste.de, 05/19
10. HEUMANN PHARMA, SmPC, Furosemid 40 mg/ 500 mg Heumann (8327.00.02/37859.00.00), 01/18
11. ratiopharm GmbH, SmPC, Furosemid-ratiopharm® 30 mg Retardkapseln (6306302.00.00), 10/16
12. mibe GmbH Arzneimittel, SmPC, Diurapid® 40 mg Tabletten (39275.00.00), 12/15
13. medphano Arzneimittel GmbH, SmPC, Furanthril® 40 mg Tabletten (37182.00.00), 01/16
14. Sanofi-Aventis Deutschland GmbH, SmPC, Lasix® liquidum 10 mg/ml Lösung zum Einnehmen (12043.00.00), 05/18
15. Sanofi-Aventis Deutschland GmbH, SmPC, Lasix® long 30 mg Retardkapseln/Lasix® 40 mg Tabletten/Lasix® 500 mg Tabs (22343.00.00/6132196.00.00/6132227.00.00), 09/17
16. ratiopharm GmbH, SmPC, Furosemid-ratiopharm® 20 mg/2 ml; 40 mg/4 ml Injektionslösung; Furosemid-ratiopharm® 250 mg/25 ml Infusionslösung (234.00.01/36544.00.00/5941.00.00), 01/16
17. Sanofi-Aventis Deutschland GmbH, SmPC, Lasix® 20 mg/- 40 mg Injektionslösung, Lasix® 250 mg Infusionslösung (6132084.00.00/35018.00.00/6132115.00.00), 05/18
18. Lurbe, E. et al, European Society ofHypertension guidelines for the management of high blood pressure in children and adolescents, J Hypertens, 2016, 34 (1) , 1-34
19. Sanofi-Aventis, SmPC Lasix 40 mg Tbl. (12585), 10/2017
20. Yeh, T. F., et al, Early furosemide therapy in premature infants (less than or equal to 2000 gm) with respiratory distress syndrome: a randomized controlled trial, J Pediat, 1984, 105 (4), 603-9
21. Peterson, R. G., et al, Pharmacology of furosemide in the premature newborn infant, J Pediatr, 1980, 97 (1), 139-43
22. Karabayir, N., et al, Intravenous frusemide for transient tachypnoea of the newborn: a randomised controlled trial., J Paediatr Child Health, 2006, 42 (10), 640-2
23. Klinge, J. M., et al, Intermittent administration of furosemide versus continuous infusion in the postoperative management of children following open heart surgery., Intensive Care Med, 1997, 23 (6), 693-7
24. van der Vorst, M. M., et al, An exploratory study with an adaptive continuous intravenous furosemide regimen in neonates treated with extracorporeal membrane oxygenation, Crit Care, 2007, 11 (5), R111
25. Mirochnick, M. H., et al, Furosemide pharmacokinetics in very low birth weight infants., J Pediatr, 1988, 112 (4), 653-7
26. Stewart, A., et al, Intravenous or enteral loop diuretics for preterm infants with (or developing) chronic lung disease, Cochrane Database Syst Rev, 2011, (9), Cd001453
27. van der Vorst, M. M., et al, Evaluation of furosemide regimens in neonates treated with extracorporeal membrane oxygenation, Crit Care, 2006, 10 (6), R168
28. Vert, P., et al, Pharmacokinetics of furosemide in neonates., Eur J Clin Pharmacol , 1982, 22(1), 39-45
29. Wiswell, T. E., et al, Effect of furosemide on the clinical course of transient tachypnea of the newborn, Pediatrics , 1985, 75 (5), 908-10

Changes