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

Interactions
PK
Renal impairment
References

Propranolol

Generic name
Propranolol
Brand name
ATC Code
C07AA05

Pharmacokinetics in children

Once corrected for bodyweight, the established primary pharmacokinetic parameters for propranolol (such as plasma clearance) in children less than 1 year of age are
the same as those reported in the literature for adults.

The study by Filippi et al. reports an average Cmax of 71.7 ng/ml and an average tmax of 2.6 hours for neonates treated with 0.5 mg/kg 4x daily. A longer elimination half-life (an average of 14.9 hours at 0.5 mg/kg 4x daily or an average of 15.9 hours at 0.25 mg/kg 4x daily) and a lower apparent total body clearance (an average of 27.2 ml/kg/min at 0.5 mg/kg 4x daily and 31.3 ml/kg/min at 0.25 mg/kg 4x daily) are reported for neonates.

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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

Hypertension
  • Oral
    • Term neonate
      [1]
      • 0.5 - 2 mg/kg/day in 2 - 3 doses.

      • No studies have been carried out in neonates.

    • 1 month up to 1 year
      [1]
      • 0.5 - 4 mg/kg/day in 2 - 3 doses.

      • No studies have been carried out in children aged from 1 month to 1 year.

    • 1 year up to 18 years
      [5] [19]
      • Starting dose 1 - 2 mg/kg/day in 2 - 3 doses. Max: 4mg/kg/day Increase dose if needed based on effect and side effects up to max 640 mg/day.
Migraine prophylaxis
Haemangioma: outpatient
  • Oral
    • 1 month up to 12 months
      [2] [3] [7] [8] [10] [11] [12] [13] [14] [15] [16] [17] [21] [22] [33]

      • Propranolol hydrochloride:
        Initial dose: 0.5 mg/kg/day in 3 doses
        Maintenance dose: Double the initial dose every week to 2-3 mg/kg/day in 3 doses
        Duration of treatment: Continue until no clinical improvement of the haemangioma is being achieved or until the age of 1 year. After that, gradually reduce in 2-4 weeks.

        Propranolol base (Hemangiol®):
        Initial dose: 0.5 mg/kg/day in 2 doses for 1 week
        Maintenance dose: Increase the initial dose to 2 mg/kg/day in 2 doses for 1 week; after that 3 mg/kg/day in 2 doses.
        Duration of treatment: 6 months. Discontinuation does not require gradual lowering of the dose. If the symptoms recur after stopping, the treatment may be restarted.
Haemangioma: clinical
  • Oral
    • 1 month up to 12 months
      [2] [3] [7] [8] [10] [11] [12] [13] [14] [15] [16] [17] [21] [22] [33]

      • Propranolol hydrochloride:
        Initial dose: 0.5-1 mg/kg/day in 3 doses
        Maintenance dose: Double the initial dose every 2-3 days to 2-3 mg/kg/day in 3 doses
        Duration of treatment: Continue until no clinical improvement of the haemangioma is being achieved or until the age of 1 year. After this gradually reduce in 2-4 weeks.


        Propranolol base (Hemangiol®):
        Initial dose: 1 mg/kg/day in 2 doses for 1 week
        Maintenance dose: Increase initial dose to 2 mg/kg/day in 2 doses for 1 week, after that 3 mg/kg/day in 2 doses.
        Duration of treatment: 6 months. Discontinuation does not require gradual lowering of the dose. If the symptoms recur after stopping, the treatment may be restarted
Tachyarrythmias; prevention cyanotic spell in Fallots tetralogy
  • Oral
    • Term neonate
      [1]
      • 1 - 2 mg/kg/day in 4 doses. Max: 4 mg/kg/day.

      • No studies have been carried out into the use of propranolol in neonates

    • 1 month up to 18 years
      [6] [32]
      • Initial dose: 0.5 - 1.5 mg/kg/day in 3 - 4 doses.
      • Maintenance dose: 2 - 4 mg/kg/day in 3 - 4 doses. Max: 4 mg/kg/day.
Superficial haemangiomas
  • Cutaneous
    • 1 month up to 12 months
      [18] [23]

      • Apply 1% cream 2-3 times daily

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Renal impaiment in children > 3 months

GFR ≥10 ml/min/1.73m2: Dose adjustment not required.

GFR <10 ml/min/1.73m2: A general recommendation on dose adjustment cannot be provided.

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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

Very common (> 10%): bronchitis, sleep disorders (around 17%: insomnia, poor quality sleep and hypersomnia). Diarrhea (approx. 17%), vomiting (approx. 12%).

Common (1-10%): nightmares, agitation, irritability, drowsiness. Lowered blood pressure. Cold hands and feet. Bronchospasm, bronchiolitis. Constipation, abdominal pain. Erythema, diaper dermatitis. Decreased appetite.

Uncommon (0.1-1%): AV block, reduced heart rate. Urticaria, alopecia. Hypoglycaemia. Neutropenia.

The following were also reported: hypoglycaemic seizure. Bradycardia, hypotension, vasoconstriction, Raynaud's phenomenon. Psoriaform dermatitis. Agranulocytosis, hyperkalaemia.

Be aware of the possibility of hypoglycaemia in formerly premature infants, children younger than 3 months, long-term use of corticosteroids or during a period of reduced intake or increased energy use (illness). Recommendation: feed every 3 to 4 hours.

Patients with cardiac failure caused by high liver flow in liver haemangiomas are at risk of cardiac decompensation due to the negative chronotropic and inotropic function of propranolol.

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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

Sinus bradycardia, AV block, hypotension, asthma and congestive heart failure.

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

Great caution is needed in concomitant use of verapamil (Isoptin) because of the risk of severe arrhythmia. For children younger than 3 months and for children with an increased risk of developing side effects, consider setting up the medication in the clinic. Because propranolol makes children more susceptible to hypoglycaemia, it should be given with nutrition. Extra attention should also be given in case of propranolol use at a young age, a low birthweight, illness, a reduced intake of nutrition and combined use with glucocorticosteroids, because propranolol can mask the adrenergic symptoms of hypoglycaemia.

Assess the medical history and perform a general physical examination before beginning treatment. If there is a suspicion of a heart defect, exclude an underlying contra-indication.

Heart failure may be exacerbated by treatment with propranolol; refer to a cardiologist. Untreated heart failure is a contraindication to treatment with this medicine.

Children with a large facial hemangioma should be examined by a specialist doctor for PHACE syndrome prior to start of treatment; Severe cerebrovascular anomalies are more common in these children and therefore there is a greater risk of having a stroke.

Be careful in case of severe hypersensitivity reactions in the anamnesis, as propranolol may increase the severity of anaphylactoid reactions.

Postpone treatment in case of acute bronchopulmonary anomaly.

After the first intake and after each dose increase, clinically monitor the child every hour for at least 2 hours, including blood pressure and heart rate. In the event of severe and / or symptomatic bradycardia or hypotension, discontinue treatment and seek the advice of a specialist doctor.

Propranolol can mask the adrenergic symptoms of hypoglycaemia (in particular tachycardia, trembling, anxiety and hunger), while recovery of glucose levels after hypoglycaemia can be delayed. It may exacerbate hypoglycaemia in children, in particular with fasting, vomiting or (relative) overdose. In the case of clinical symptoms of hypoglycaemia, the child should drink a liquid containing sugar and temporarily stop treatment. In the case of diabetes, check blood glucose levels more frequently and, if necessary, refer them to the endocrinologist.

Hyperkalaemia has been reported in patients with a large ulcerated hemangioma.

In case of infection of the lower respiratory tract in combination with dyspnea and wheezing, interrupt treatment; treatment can be resumed when fully recovered. In the event of a recurrence or with isolated bronchospasm, discontinue treatment permanently.

In the case of general anesthesia, inform the anesthesist about the use of propranolol; if it is necessary to stop propranolol before the operation, stop taking propranolol at least 48 hours before the operation.

In the event of recurrence of hemangioma symptoms after treatment cessation, treatment can be restarted.

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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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References

  1. Rademaker C.M.A. et al, Geneesmiddelen-Formularium voor Kinderen, 2008
  2. Bayliss SJ, et al , Propranolol treatment for hemangioma of infancy: risks and recommendations, Pediatr Dermatol, 2010, May;27(3), 319-20
  3. Léauté-Labrèze C, et al , Propranolol for severe hemangiomas of infancy, N Engl J Med, 2008, Jun 12;358(24), 2649-51
  4. Victor S, et al, Drugs for preventing migraine headaches in children, Cochrane Database Syst Rev, 2003, (4), CD002761
  5. National High Blood Pressure Education Program Working Group on High Blood Pressure in Children and Adolescents. , The fourth report on the diagnosis, evaluation, and treatment of high blood pressure in children and adolescents, Pediatrics, 2004, Aug;114(2 Suppl 4th Report), 555-76
  6. Garson A Jr, et al, Propranolol: the preferred palliation for tetralogy of Fallot, Am J Cardiol, 1981, May;47(5), 1098-104
  7. Rosbe KW et al, Propranolol in the management of airway infantile hemangiomas, Arch Otolaryngol Head Neck Surg. , 2010, Jul;136(7), 658-65
  8. PIERRE FABRE DERMATOLOGIE, SmPC Hemangiol (EU/1/14/919/001) 6-4-2018, www.ema.europa.eu
  9. Filippi L, et al, Propranolol concentrations after oral administration in term and preterm neonates, J Matern Fetal Neonatal Med, 2013, May;26(8), 833-40
  10. Léauté-Labrèze C, et al, A randomized, controlled trial of oral propranolol in infantile hemangioma, N Engl J Med, 2015, Feb;372(8), 735-46
  11. Peridis S, et al,, A meta-analysis on the effectiveness of propranolol for the treatment of infantile airway haemangiomas, Int J Pediatr Otorhinolaryngol,, 2011, Apr;75(4), 455-60
  12. Patel NJ, et al, How should propranolol be initiated for infantile hemangiomas: inpatients versus outpatient?, Laryngoscope, 2014, Jun;124(6), 1279-81
  13. Xu S, et al, Treatment of periorbital infantile haemangiomas: a systematic literature review on propranolol or steroids, J Paediatr Child Health, 2014, Apr;50(4), 271-9
  14. Marqueling AL, et al, Propranolol and infantile hemangiomas four years later: a systematic review, Pediatr Dermatol, 2013, Mar-Apr;30(2), 182-91
  15. Menezes MD, et al, Status of propranolol for treatment of infantile hemangioma and description of a randomized clinical trial, Ann Otol Rhinol Laryngol, 2011, Oct;120(10), 686-95
  16. Vlastarakos PV, et al, Propranolol is an effective treatment for airway haemangiomas: a critical analysis and meta-analysis of published interventional studies, Acta Otorhinolaryngol Ital, 2012, Aug;32(4), 213-21
  17. Hermans DJ, et al, Behandeling van infantiele hemangiomen met propranolol; goede resultaten en weinig bijwerkingen, Ned Tijdschr Geneeskd, 2011, 155(40), A3482
  18. Ovadia SA, et al, Local administration of ?-blockers for infantile hemangiomas: a systematic review and meta-analysis, Ann Plast Surg, 2015, 74(2), 256-62
  19. Lurbe E, et al, Management of high blood pressure in children and adolescents: recommendations of the European Society of Hypertension, J Hypertens, 2009, Sep;27(9), 1719-42
  20. Raphael MF et al., Treatment of infantile hemangiomas: therapeutic options in regard to side effects and adverse events - a review of the literature, Expert Opin Drug Saf., 2016, 15(2), 199-214
  21. Kim KH, et al. , Comparison of efficacy and safety between propranolol and steroid for infantile hemangioma: a randomized clinical trial, JAMA Dermatol , 2017, 153, 529-536
  22. Tiwari P, et al, Role of propranolol in ulcerated haemangioma of head and neck: a prospective comparative study, Oral Maxillofac Surg, 2016, 20, 73-77
  23. Neri I, et al. , Topical 1% propranolol ointment with occlusion in treatment of pyogenic granulomas: An open-label study in 22 children, Pediatr Dermatol. , 2018, 35 , 117-20
  24. Bakalli, I. et al, Deep coma in a child treated with propranolol for infantile hemangioma , BMC Pediatrics, 2019, 19, 2016
  25. Togha, M., et al, Efficacy and safety of cinnarizine in the prophylaxis of migraine headaches in children: an open, randomized comparative trial with propranolol, Acta Neurol Belg, 2012, 112(1), 51-5
  26. Lütschg, J., et al, The treatment of juvenile migraine using flunarizine or propranolol, Schweiz Med Wochenschr, 1990, 120(46), 1731-6
  27. Ludvigsson, J. , Propranolol used in prophylaxis of migraine in children., Acta Neurol Scand, 1974, 50(1), 109-15
  28. Locher, C., et al, Efficacy, Safety, and Acceptability of Pharmacologic Treatments for Pediatric Migraine Prophylaxis: A Systematic Review and Network Meta-analysis., JAMA Pediatr, 2020, 174(4), 341-9
  29. Fallah, R., et al, Topiramate and propranolol for prophylaxis of migraine., Indian J Pediatr, 2013, 80(11), 920-4
  30. Bidabadi, E., et al, A randomized trial of propranolol versus sodium valproate for the prophylaxis of migraine in pediatric patients, Paediatr Drugs , 2010, (12(4), 269-75
  31. Ashrafi, M. R., et al , Sodium Valproate versus Propranolol in paediatric migraine prophylaxis., Eur J Paediatr Neurol, 2005, 99(5), 333-8
  32. Teva Nederland BV, SmPC Propranolol (RVG 10216) 02-11-2020, www.geneesmiddeleninformatiebank.nl
  33. Yang H, et al. , Efficacy and adverse effects of oral propranolol in infantile hemangioma: a meta-analysis of comparative studies., World J Pediatr, 2019, 15, 546-58

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