nd majority of the infantile haemangiomas were localized (89%).
Treatment success was defined as a complete or nearly complete resolution of the target haemangioma, which was eva luated by blinded centralized independent assessments made on photographs at Week 24, in the absence of premature treatment discontinuation.
The regimen 3 mg/kg/day during 6 months (selected at the end of the phase II part of the study)
presented 60.4% of success versus 3.6% in the placebo arm (p value < 0.0001). Age (35-90 days / 91-
150 days), gender and haemangioma location (head / body) subgroups did not identify differences in response to propranolol. Improvement of haemangioma was observed at 5 weeks of treatment by propranolol in 88% of patients. 11.4% of patients needed to be re-treated after treatment discontinuation.
For ethical reasons related to the use of placebo, the demonstration of the efficacy was not established
in patients with high-risk haemangioma. Evidence of the efficacy of propranolol in patients with high- risk haemangioma is available both in literature and in a specific compassionate use program performed with Hemangiol.
Based on a retrospective study, a minority of patients (12%) required a re-initiation of systemic treatment. When treatment was re-initiated, a satisfactory response was observed in a large majority of patients.
5.2 Pharmacokinetic properties
Adults
Absorption and distribution:
Propranolol is almost completely absorbed after oral administration. However, it undergoes an extensive first-pass metabolism by the liver and on average only about 25% of propranolol reaches the systemic circulation. Peak plasma concentrations occur about 1 to 4 hours after an oral dose. Administration of protein-rich foods increases the bioavailability of propranolol by about 50% with no change in time to peak concentration.
Propranolol is a substrate for the intestinal efflux transporter, P-glycoprotein (P-gp). However, studies suggest that P-gp is not dose-limiting for intestinal absorption of propranolol in the usual therapeutic dose range.
Approximately 90% of circulating propranolol is bound to plasma proteins (albumin and alpha1 acid glycoprotein). The volume of distribution of propranolol is approximately 4 L/kg. Propranolol crosses the blood-brain barrier and the placenta, and is distributed into breast milk.
Biotransformation and elimination:
Propranolol is metabolized through three primary routes: aromatic hydroxylation (mainly 4- hydroxylation), N-dealkylation followed by further side-chain oxidation, and direct glucuronidation. The percentage contributions of these routes to total metabolism are 42%, 41% and 17%, respectively, but with considerable variability between individuals. The four major final metabolites are propranolol glucuronide, naphthyloxylactic acid and glucuronic acid, and sulfate conjugates of 4-hydroxy propranolol. In vitro studies indicated that CYP2D6 (aromatic hydroxylation), CYP1A2 (chain oxidation) and to a less extent CYP2C19 were involved in propranolol metabolism.
In healthy subjects, no difference was observed between CYP2D6 extensive metabolizers and poor metabolizers with respect to oral clearance or elimination half-life.
The plasma half-life of propranolol ranges from 3 to 6 hours. Less than 1% of a dose is excreted as
unchanged drug in the urine.
Paediatric population
The pharmacokinetics of repeated administrations of HEMANG |
