Dosages
Side effects in children
Warnings & precautions in children
Contra-indications in children

Interactions
PK
Renal impairment
References

Milrinone

Generic name
Milrinone
Brand name
ATC Code
C01CE02

Pharmacokinetics in children

The following pharmacokinetic parameters were observed after intravenous infusion  (SmPC Corotrope):

Age Dose
(mcg/kg/min)		 t½
(hour)		 Cl
(ml/kg/min)		 Vd
(l/kg)
Extreme prematue neonate 0,5 - - 0,5
Premature neonate - 10 0,64 -
Neonate 0,5-0,75 - 1,64 0,35-0,9
Infant 0,5-0,75 2-4 3,4-3,8 0,35-0,9
Child 0,5-0,75 2-4 5,9-6,7 0,35-0,9

Pellicer et al. 2013 reported the following tmax and Cmax after intravenous infusion of 0,5-1 mcg/kg/minin 9 neonates of 6-30 days PNA:

Tmax = 11,9 – 54 hours
Cmax = 635 – 1189 ng/ml

Lindsay et al. 1998 reported a clearance of 10,6 ± 5,3 ml/kg/min in 11 children  0,67-15 years of age with septic shock

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dose recommendation of formulary compared to licensed use (on-label versus off-label)

No information is present at this moment.

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Available formulations

No information is present at this moment.

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Dosages

Prevention and treatment of circulatory insufficiency and pulmonary hypertension
  • Intravenous
    • Premature neonate Gestational age < 37 weeks
      • Initial dose: 0.75 microg./kg/minute During 3 hours..
      • Maintenance dose: 0.15 - 0.2 microg./kg/minute, continuous infusion.
        • Note: hypotension can occur as result of the initial dose
        • Dose depending on the haemodynamic response and any side-effects that may occur
        • Treatment by or after consultation with a pediatric specialist (pediatric cardiologist) who has experience with the use of milrinone for this indication.
    • 1 month up to 18 years
      • Initial dose: 1.25 microg./kg/minute During 1 hour..
      • Maintenance dose: 0.25 - 0.75 microg./kg/minute, continuous infusion.
        • Hoffman et al. 2003 found a better preventive effect with a maintenance dose of 0.75 microg./kg/min than with a maintenance dose of 0.25 microg./kg/min in children 2 days to 7 years.
        • Note: Dose depending on the haemodynamic response and any side-effects that may occur.
        • Treatment by or after consultation with a pediatric specialist (pediatric cardiologist) who has experience with the use of milrinone for this indication.
Vasospasm/ischemia of the limbs
  • Intravenous
    • Term neonate
      • Initial dose: 1.25 microg./kg/minute over 1 hour..
      • Maintenance dose: 0.25 - 0.75 microg./kg/minute, continuous infusion.
        • Note:hypotension can occur as a result of the loading dose. Dose depending on the haemodynamic response and any side-effects that may occur.
        • Treatment by or after consultation with paediatric specialist (pediatric cardiologist) who has experience in using milrone in this indication.
        • There is very little evidence in children for this indication.
    • Term neonate
      [13] [19]
      • Initial dose: 1.25 microg./kg/minute over 1 hour..
      • Maintenance dose: 0.25 - 0.75 microg./kg/minute, continuous infusion.
        • Note:hypotension can occur as a result of the loading dose. Dose depending on the haemodynamic response and any side-effects that may occur.
        • Treatment by or after consultation with paediatric specialist (pediatric cardiologist) who has experience in using milrone in this indication.
        • There is very little evidence in children for this indication.

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Renal impaiment in children > 3 months

Adjustment in renal impairment as specified:

GFR 50-80 ml/min/1.73 m2
Adjustment not necessary.
GFR 30-50 ml/min/1.73 m2
0.22-0.43 mcg/kg/min; Do not adjust initial dose
If it is decided to give a loading dose: do not adjust
GFR 10-30 ml/min/1.73 m2
0.15-0.33 mcg/kg/min; Do not adjust initial dose
GFR < 10 ml/min/1.73 m2
No generalized dose recommendations are given
Clinical consequences

The half-life of milrinone is prolonged in cases of reduced renal function. The risk of side effects is elevated as a result. Dose-dependent side-effects are hypotension and arrhythmia.

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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

Headaches, hypotension, arrhythmia, thrombocytopenia. The risk of thrombocytopenia increases significantly with the infusion time. 

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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

Milrinone should be administered under continuous haemodynamic and heart rhythm monitoring. In children, only start the treatment if the patient is haemodynamically stable.    Prolonged use is not recommended because it results in exacerbation of cardiac failure and increased mortality.

Caution is needed when administering a loading dose (risk of severe hypotension). Stop the treatment if there is a clear drop in blood pressure; it may potentially be resumed at a lower infusion rate after the blood pressure has normalized.

Additional checks are needed in neonates and the blood platelets, potassium level, hepatic function and renal function must be measured. Milrinone can delay the closure of the ductus arteriosus.

Milrinone has been linked to occurrences of acute kidney damage.

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Interactions

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

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Adrenergic and dopaminergic agents
C01CA24
C01CA07
C01CA04
C01CA26
C01CA02
C01CA17
C01CA24
C01CA03
C01CA06
Other cardiac stimulants
C01CX08

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References

  1. Bailey JM, et al., A population pharmacokinetic analysis of milrinone in pediatric patients after cardiac surgery., J Pharmacokinet Pharmacodyn, 2004, 31, 43-59
  2. Barton P, et al, Hemodynamic effects of IV Milrinone lactate in pediatric patients with septic shock. A prospective double blinded, randomized, placebo controlled interventional study., Chest, 1996, 109, 1302–12
  3. Chang AC, et al, Milrinone: systemic and pulmonary hemodynamic effects in neonates after cardiac surgery, Crit Care Med, 1995, 23, 1907–14
  4. Duggal B, et al., Milrinone and low cardiac output following cardiac surgery in infants: is there a direct myocardial effect?, Pediatr Cardioll, 2005, 26, 642-5
  5. Hoffman TM, et al., Efficacy and safety of milrinone in preventing low cardiac output syndrome in infants and children after corrective surgery for congenital heart disease., Circulation, 2003, 107, 996-1002
  6. Lindsay CA, et al., Pharmacokinetics and pharmacodynamics of milrinone lactate in pediatric patients with septic shock., J Pediatr, 1998, 132, 329–34
  7. Paradisis M, et al., Population pharmacokinetics and dosing regimen design of milrinone in preterm infants., Arch Dis Child Fetal Neonatal Ed., 2007, 92, 204-9
  8. Ramamoorthy C, et al, Pharmacokinetics and side effects of milrinone in infants and children after open heart surgery., Anesth Analg, 1998, 86, 283-9
  9. Zuppa AF,, Population pharmacokinetics of milrinone in neonates with hypoplastic left heart syndrome undergoing stage I reconstruction., Anesth Analg, 2006, 102, 1062-9
  10. Meyer S. et al, The role of milrinone in children with cardiovascular compromise: review of the literature, Wien Med Wochenschr, 2011, 161, 184-91
  11. Pellicer A, et al, Phase 1 study of two inodilators in neonates undergoing cardiovascular surgery, Pediatr Res, 2013, 73, 95-103
  12. Sanofi-Aventis Netherlands BV, SmPC Corotrope (RVG 12820) 28-09-11, www.cbg-meb.nl
  13. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie, Expert opinie, 28 maart 2018
  14. Vogt, W et al, Evaluation and optimisation of current milrinone prescribing for the treatment and prevention of low cardiac output syndrome in paediatric patients after open heart surgery using a physiology-based pharmacokinetic drug-disease model, Clin Pharmacokinet, 2014, 53(1), 51-72
  15. Hallik, M., et al, Population Pharmacokinetics and Dosing of Milrinone After Patent Ductus Arteriosus Ligation in Preterm Infants, Pediatr Crit Care Med, 2019, 20(7), 621-629
  16. Hallik, M., et al, Dosing of Milrinone in Preterm Neonates to Prevent Postligation Cardiac Syndrome: Simulation Study Suggests Need for Bolus Infusion., Neonatology, 2017, 111(1), 8-11
  17. Mizuno, T., et al, Developmental Pharmacokinetics and Age-Appropriate Dosing Design of Milrinone in Neonates and Infants with Acute Kidney Injury Following Cardiac Surgery., Clin Pharmacokinet, 2019, 58(6), 793-803
  18. Paradisis, M., et al., Randomized trial of milrinone versus placebo for prevention of low systemic blood flow in very preterm infants., J Pediatr, 2009, 154(2), 189-95
  19. Boyd, S., et al, A novel role for milrinone in neonatal acute limb ischaemia: successful conservative treatment of thrombotic arterial occlusion without thrombolysis., BMJ Case Rep, 2019, 12(12)

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Changes

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