oma
(see section 4.4).
Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.
4.9 Overdose
The toxicity of beta-blockers is an extension of their therapeutic effects:
· Cardiac symptoms of mild to moderate poisoning are decreased heart rate and hypotension.
Atrioventricular blocks, intraventricular conduction delays, and congestive heart failure can occur with more severe poisoning.
· Bronchospasm may develop particularly in patients with asthma.
· Hypoglycemia may develop and manifestations of hypoglycemia (tremor, tachycardia) may be masked by other clinical effects of beta-blocker toxicity.
Propranolol is highly lipid-soluble and may cross the blood brain barrier and cause seizures.
Support and treatment:
The patient should be placed on a cardiac monitor, monitor vital signs, mental status and blood glucose. Intravenous fluids for hypotension and atropine for bradycardia should be given. Glucagon then catecholamines should be considered if the patient does not respond appropriately to intravenous fluid. Isoproterenol and aminophylline may be used for bronchospasm.
5 PHARMACOLOGICAL PROPERTIES
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Beta-Blocking agent, non-selective, ATC code: C07AA05
Mechanism of action
Potential mechanisms of action of propranolol in proliferating infantile haemangioma described in the literature could include various mechanisms all in close relationship:
· a local haemodynamic effect (vasoconstriction which is a classical consequence of beta- adrenergic blockade and a decrease of infantile haemangioma lesion perfusion);
· an antiangiogenic effect (decrease of vascular endothelial cells proliferation, reduction of the neovascularization and formation of vascular tubules, reduction of the secretion of Matrix
Metalloproteinase 9);
· an apoptosis-triggering effect on capillary endothelial cells;
· a reduction of both VEGF and bFGF signalling pathways and subsequent angiogenesis /
proliferation.
Pharmacodynamic effects
Propranolol is a beta-blocker that is characterised by three pharmacological properties:
· the absence of cardioselective beta-1 beta-blocking activity,
· an antiarrhythmic effect,
· lack of partial agonist activity (or intrinsic sympathomimetic activity).
Clinical efficacy and safety in the paediatric population
The efficacy of propranolol in infants (aged 5 weeks to 5 months at treatment initiation) with proliferating infantile haemangioma requiring systemic therapy has been demonstrated in a pivotal
randomised, controlled, multicentre, multidose, adaptive phase II/III study aimed to compare four regimens of propranolol (1 or 3 mg/kg/day for 3 or 6 months) to placebo (double blind).
Treatment was administered to 456 subjects (401 Propranolol at a dose of 1 or 3 mg/kg/day for 3 or
6 months; 55 Placebo), including a titration phase over 3 weeks. Patients (71.3% female; 37% aged
35-90 days old and 63% aged 91-150 days old) presented a target haemangioma on the head in 70%
a
