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

Interactions
PK
Renal impairment
References

Hydrocortisone

Generic name
Hydrocortisone
Brand name
ATC Code
H02AB09

Pharmacokinetics in children

The following pharmacokinetic data are available for preterm infants (<1000 g) [Watterberg et al. 1996]:

t½ (h) Cl (ml/kg/h) Vd (l/kg)
12.1 ± 5.8 (3.6-19) 120 ± 120 (47-357) 1.39 ± 0.33 (0.82-1.85)

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

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Available formulations

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Dosages

Supplementation in adrenal cortex insufficiency
  • Oral
    • 1 month up to 18 years
      • 8 - 10 mg/m²/day in 3 doses. 1-3 months: Because of the lack of a day/night rhythm until the age of 3 months a 1-1-1 pattern is chosen, instead of 2-1-1 pattern. In situations where it is needed, a glucocorticoid stress regimen should be used.
        ≥ 3 months: Dosage split in the ratio 2:1:1.

      • Titrate upon individual clinical response.

    • Term neonate
      [20]
      • 8 - 10 mg/m²/day in 3 doses.

      • Adjust dose based on individual respons.
        Spread over equal doses at 8 hours.
        Because of the lack of a day/night rhythm until the age of 3 months a 1-1-1 pattern is chosen, instead of 2-1-1 pattern. In situations where it is needed, a glucocorticoid stress regimen should be used.

  • Intravenous
Acute adrenal crisis
  • Rectal
    • Children including term neonates 0 years up to 18 years
      • hydrocortisone (base) in Witepsol 100 mg/m²/dose, once only.
        • Rectal hydrocortisone administration is known to have a considerable spread in the serum cortisol levels achieved after administration.
        • If the child does not improve after 15 minutes, change to intramuscular medication
        • If the child does improve, switching to the oral route as quickly as possible is indicated.
  • Intravenous
    • Children including term neonates 0 years up to 18 years
      • 2 mg/kg/dose, once only. Continue with high doses of hydrocortisone (oral or intravenous) according to the stress regimen (50 mg/m2/day in 4 doses), then gradually decrease to a three times daily regimen (according to phasing out indication).

      • Corresponding to
        0 to1 jaar : 25 mg/dosis, once. (Act-O-Vial)
        1 to 6 jaar : 50 mg/dosis, once. (Act-O-Vial)
        6 to18 jaar: 100 mg/dosis, once.(Act-O-Vial)

  • Intramuscular
    • Children including term neonates 0 years up to 18 years
      • 2 mg/kg/dose, once only. Continue with high doses of oral hydrocortisone according to the stress regimen, then gradually decrease to a three times daily regimen (according to phasing out indication).

      • Corresponding to
        0 to1 jaar : 25 mg/dosis, once. (Act-O-Vial)
        1 to 6 jaar : 50 mg/dosis, once. (Act-O-Vial)
        6 to18 jaar: 100 mg/dosis, once.(Act-O-Vial)

  • Oral
    • Children including term neonates 0 years up to 18 years
      [1]
      •   MILD STRESS MODERATE STRESS SEVERE STRESS
        DEFINITIE Mild stress: not feeling good, languid, temperature < 38.0°C, short physical effort only

        Slightly raised temperature between 38.0-39.0°C, mild flu infection, vaccination, anaesthesia (dentist).

        In exceptional cases, psychological stress (test, exam) or serious physical exertion can also be a reason to temporarily increase the substitution dose to a 2-3-fold dose. Temperature is not always a good parameter for assessing stress

        		 Temperature > 39°C, vomiting, diarrhoea, severely ill, accident, operation, narcosis (for perioperative policy, see the prednisolone monograph)
          No dose adjustment needed, normal substitution dose) 30 mg/m2/day in 3-4 divided doses 
        (= 3 x normal substitution dose)        		 50 mg/m2/day in 4 divided dose 
        (= 5 x normal substitution dose)
               

         
Phasing-out schedule
  • Route of administration not applicable
    • Children including term neonates 0 years up to 18 years
      [19]

      • PHASING-OUT SCHEDULE (when used for longer than 14 days) applies to the following patients

        • Patients who have a daily administration of a dose after 04.00 PM
        • Patients on daily use of corticosteroids (inhalation, cuteneous, rectal, nasal, intravenous, oral) and who experience an unexpected deflecting length growth or Cushingoid characteristics
        • Concomittant use of strong Cyp3A4 inhibitors that inhibit glucocorticoid breakdown

        Step 1: Down titrate the therapeutic (supraphysiological) dose to physiologic dose of 10 mg/m2/day (ratio 2:1:1)after consulation with paediatric endocrinologist.

        Step 2: Decrease of physiological dose of 10 mg/m2/day every week with 1 mg/m2 increments:

          07.00 13.00 18.00
        Week 0 5 mg/m2 2,5 mg/m2 2,5 mg/m2
        Week 1 5 mg/m2 2,5 mg/m2 1,5 mg/m2
        Week 2 5 mg/m2 2 mg/m2 1 mg/m2
        Week 3 5 mg/m2 2 mg/m2 -
        Week 4 5 mg/m2 1mg/m2 -
        Week 5 5 mg/m2 - -
        Week 6 4 mg/m2 - -
        Week 7 3 mg/m2 - -
        Week 8 2 mg/m2 - -
        Week 9 1 mg/m2 - -
        Week 10 STOP    
        • A stress regimen still needs to be maintained during the phasing-out schedule.
        • Week 21: Low dose ACTH test: 
          • If Cortisol ≥ 0,55 µmol/L,(note the cut-off value for the particular assay), the stress schedule is no longer required
          • If cortisol< 0,55 µmol/L (note the cut-off value for the particular assay), repeat test after 3 to 6 months. Consider taking the metyrapone test after 2 abnormal ACTH tests and ≥ 6 years of age. Maintain the stress schedule.

         
Neonatale shock, hypotensie
Severe systemic allergic reactions
  • Intravenous
    • 1 month up to 18 years
      • 4 mg/kg/dose, once only. Max single dose: 100 mg/dose.

      • As supporting treatment in oncological conditions, in anaphylaxis: 10 mg/kg/dose
Treatment of chronic lungdisease (CLD)
  • Oral
    • Premature neonaten: Gestational age < 28 weeks
      [8] [10] [13] [15]
      • 5 mg/kg/day in 4 doses.
      • Duration of treatment:

        Gedurende 7 dagen.
        Afbouwen: vermindering met 1 dosis om de 5 dagen op geleide kliniek

    • Premature neonaten: Gestational age < 28 weeks
      [8] [10] [13] [15]
      • 5 mg/kg/day in 4 doses.
      • Duration of treatment:

        During 7 days, phasing-out stage: reduction by 1 dose every 5 days according to the clinical picture

    • Premature neonates: Gestational age < 28 weeks
      [8] [10] [13] [15]
      • 5 mg/kg/day in 4 doses.
      • Duration of treatment:

        For 7 days.
        Phasing out: reduction by 1 dose every 5 days according to the clinical picture

  • Intravenous
    • Premature neonates: Gestational age < 28 weeks
      [8] [10] [13] [15]
      • 5 mg/kg/day in 4 doses.
      • Duration of treatment:

        For 7 days,
        Phasing out: reduction by 1 dose every 5 days according to the clinical picture
Prophylaxis chronic lungdisease(CLD)
  • Intravenous
    • Premature neonates: Gestational age < 28 weeks
      [18]
      • 1 mg/kg/day in 2 doses. For 7 days. Then 3 days at 0.5 mg/kg/day in a single dose.
  • Oral
    • Premature neonates: Gestational age < 28 weeks
      [18]
      • 1 mg/kg/day in 2 doses. For 7 days. Then 3 days at 0.5 mg/kg/day in a single dose.
Adrenogenital syndrome (AGS) treatment in the non-acute phase
  • Oral
    • Children including term neonates 0 years up to 1 year
      [5] [20]

      • Initially: 5 mg/dose one-time.

        • Thereafter 9 mg/day in 3 doses for 2 days. 
        • Thereafter 3 mg/day in 3 doses, but not less than 8-10 mg/m²/day

      • Dosage must be adjusted based on the clinical picture and the individual’s biochemistry

        Treatment of children with AGS is the responsibility of the paediatric endocrinologist who has expertise in AGS. 

    • 1 year up to 18 years
      [5] [20]
      • 10 - 15 mg/m²/day in 3 doses.

      • Higher doses can be necessary. Dosage must be adjusted based on the clinical picture and the individual’s biochemistry.

        Treatment of children with AGS is the responsibility of the paediatric endocrinologist who has expertise in AGS. 

  • Intravenous
    • Children including term neonates 0 years up to 1 year
      [5]

      • Initially: 5 mg/dose one-time.

        • Thereafter 9 mg/day in 3 doses for 2 days. 
        • Thereafter 3 mg/day in 3 doses, but not less than 8-10 mg/m²/day

      • Dosage must be adjusted based on the clinical picture and the individual’s biochemistry.

        Treatment of children with AGS is the responsibility of the paediatric endocrinologist who has expertise in AGS. 
Stress dosing: PERIOPERATIVE SUBSTITUTION SCHEDULE
  • Oral
    • Children including term neonates 0 years up to 18 years

      • The following dosage recommendations are only guidelines. The dose should always be coordinated with the treating paediatric endocrinologist.

        • For older children, an extra dose of hydrocortisone may be needed the evening before surgery
        • The surgery should preferably be planned early in the morning. If it is only being done during the day, the morning dose of hydrocortisone must be given as a 3-fold dose. In the case of surgery later in the day, a glucose/NaCl infusion is recommended due to the risk of hypoglycaemia from the moment of fasting.
        • The glucocorticoid dosage after the first day post-op should be determined as guided
          by the clinical condition of the patient, and if necessary by the (expected) post-operative complications.
        • Intravenous: Prednisolone sodium succinate
           
        Severity of the surgery Time 0-1 year (0.3-0.5 m²) 1-3 years (0.5-0.7 m²) 3-12 years (0.7-1.2 m²) > 12 years (1.2-1.5 m²) Adults
        MINOR

        e.g. inspection under narcosis, place tympanostomy tubes        		 When inducing anaesthesia 2.5 mg intravenous prednisolone 5 mg intravenous prednisolone 7.5 mg intravenous prednisolone 10 mg intravenous prednisolone 20 mg intravenous prednisolone
        MINOR Rest of the surgery day 2-fold or 3-fold oral dose of hydrocortisone 2-fold or 3-fold oral dose of hydrocortisone 2-fold or 3-fold oral dose of hydrocortisone 2-fold or 3-fold oral dose of hydrocortisone 2-fold or 3-fold oral dose of hydrocortisone
        MINOR first post-op day Normal substitution dose of hydrocortisone Normal substitution dose of hydrocortisone Normal substitution dose of hydrocortisone Normal substitution dose of hydrocortisone Normal substitution dose of hydrocortisone
        MEDIUM

        e.g. inguinal hernia, tonsillectomy or adenotomy        		 When inducing anaesthesia 2.5 mg intravenous prednisolone 5 mg intravenous prednisolone 7.5 mg intravenous prednisolone 10 mg intravenous prednisolone 20 mg intravenous prednisolone
        MEDIUM Rest of the surgery day (spread over the remaining 24 hours) 2x 1.5 mg intravenous prednisolone 2x 2.5 mg intravenous prednisolone 2x5 mg intravenous prednisolone 2x5 mg intravenous prednisolone 2x 10 mg intravenous prednisolone
        MEDIUM first day post-op (spread over 24 hours) 3x 1.5 mg intravenously or 3-fold dose of hydrocortisone orally 3x 2.5 mg intravenously or 3-fold dose of hydrocortisone orally 3x 5 mg intravenously or 3-fold dose of hydrocortisone orally 3x 5 mg intravenously or 3-fold dose of hydrocortisone orally 3x 10 mg intravenously or 3-fold dose of hydrocortisone orally
        SEVERE

        e.g. genitoplasty, laparotomy, craniotomy        		 When inducing anaesthesia 5 mg intravenous prednisolone 7.5 mg intravenous prednisolone 10 mg intravenous prednisolone 12.5 mg intravenous prednisolone 25 mg intravenous prednisolone
        MAJOR Rest of the surgery day (spread over the remaining 24 hours) 2x 2.5 mg intravenous prednisolone 2x 3.5 mg intravenous prednisolone 2x5 mg intravenous prednisolone 2x 7.5 mg intravenous prednisolone 2x 12.5 mg intravenous prednisolone
        MAJOR first day post-op (spread over 24 hours) 3x 2.5 mg intravenous prednisolone 3x 3.5 mg intravenous prednisolone 3x5 mg intravenous prednisolone 3x 7.5 mg intravenous prednisolone 3x 12.5 mg intravenous prednisolone

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Renal impaiment in children > 3 months

No information available on dose adjustment in renal impairment.

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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

Hyperglycaemia, arrhythmias.
In prolonged use of supra-physiological doses: growth inhibition and osteoporosis, in addition to gastrointestinal ulcers, reduced resistance to infections, obesity and suppression of the hypothalamic-pituitary-adrenal axis.

Infants and children treated long-term with corticosteroids are at an additional risk of increased intracranial pressure.

High doses of corticosteroids can cause pancreatitis in children.

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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 in children

For the Act-O-Vial: Neonates, because of the presence of benzyl alcohol.

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

Monitor the growth and development of infants and children closely during prolonged use of corticosteroids; to prevent growth inhibition, aim for an alternating dose. The progression of chickenpox and measles can be more severe and even fatal in non-immune patients who are using corticosteroids; exposed patients should be given medical treatment immediately.

Infants and children treated with corticosteroids for a long time are at an additional risk of increased intracranial pressure.

High doses of corticosteroids can cause pancreatitis in children.

Benzyl alcohol (present in Act-O-Vial) can cause toxic reactions and anaphylactoid reactions in infants and children aged under 3. 

Caution is needed when switching patients from conventional formulations to Alkindi. Acute adrenal insufficiency may occur. Children should be observed carefully during teh first weekvfor signs of adrenal insufficiency. [DHPC Alkindi]

Hypertrophic cardiomyopathy has been reported following administration of hydrocortisone to preterm infants. Therefore, appropriate diagnostic assessment and monitoring of cardiac function and structure should be performed.

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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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Mineralocorticoids
H02AA02
Glucocorticoids
H02AB02
H02AB04
H02AB06
H02AB07
H02AB08

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References

  1. Noordam C et al, Werkboek Kinderendocrinologie, digitale publicatie op www.nvk.nl (alleen leden), 2010
  2. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2007
  3. Kamps WA et al, Werkboek ondersteundende behandeling kinderoncologie, VU Uitgeverij, 2005
  4. Turner N, et al. , Advanced Pediatric Life Support - de Nederlandse editie., Reed Business , 2011, 407-17
  5. Werkboek Androgenitaal Syndroom, NVK, 2009
  6. Werkgroep Neonatale Farmacologie NVK sectie Neonatologie, Expert opinie, 13 november 2019
  7. Clyman, R.I. et al, Hypotension following patent ductus arteriosus ligation: the role of adrenal hormones., J Pediatr , 2014, 164 (6), 1449-55
  8. Doyle, L. W. et al, Late (> 7 days) systemic postnatal corticosteroids for prevention of bronchopulmonary dysplasia in preterm infants., Cochrane Database Syst Rev , 2017, 10
  9. Hochwald, O. et al, Adding hydrocortisone as 1st line of inotropic treatment for hypotension in very low birth weight infants., Indian J Pediatr , 2014, 81(8), 808-10
  10. Lodygensky, G. A. et al. , Structural and functional brain development after hydrocortisone treatment for neonatal chronic lung disease, Pediatrics, 2005, 116 (1), 1-7
  11. Ng, P. C. et al, A double-blind, randomized, controlled study of a "stress dose" of hydrocortisone for rescue treatment of refractory hypotension in preterm infants." , Pediatrics, 2006, 117(2), 367-75
  12. Noori, S. et al, Hemodynamic changes after low-dosage hydrocortisone administration in vasopressor-treated preterm and term neonates." , Pediatrics, 2006, 118(4), 1456-66
  13. Onland, W. et al, Systemic Hydrocortisone To Prevent Bronchopulmonary Dysplasia in preterm infants (the SToP-BPD study): a randomized controlled trial." , Not yet published., 2018
  14. Peeples, E. S. , An evaluation of hydrocortisone dosing for neonatal refractory hypotension, J Perinatol, 2017, 37 (8), 943-46
  15. Rademaker, K. J. et al, Neonatal hydrocortisone treatment: neurodevelopmental outcome and MRI at school age in preterm-born children, J Pediatr, 2007, 150(4), 351-7
  16. Salas, G. et al, Hydrocortisone for the treatment of refractory hypotension: a randomized controlled trial, An Pediatr (Barc), 2014, 80 (6), 387-93
  17. Watterberg, K. L. et al, Pharmacokinetics of hydrocortisone (HC) in extremely low birthweight (ELBW) infants in the first week of life, Pediatric Research, 1996, 39, 251
  18. Baud O. et al., Effect of early low-dose hydrocortisone on survival without bronchopulmonary dysplasia in extremely preterm infants (PREMILOC): a double-blind, placebo-controlled, multicentre, randomised trial, Lancet, 2016, 387(10030), 1827-36
  19. Nederlandse Vereniging voor Kindergeneeskunde, Guideline Down titration of glucocorticosteroids in children, 2019
  20. Diurnal Europe B.V., SmPC Alkindi granulaat in capsules (EU/1/17/1260/001-004) 08-11-2019, www.geneesmiddeleninformatiebank.nl
  21. Diurnal Europe BV, DHPC: Risk of acute adrenal insufficiency when switching from crushed or compounded oral hydrocortisone formulations to Alkindi, 04 feb 2021

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Changes

Changes