IOL at 3 mg/kg/day given in 2 intakes has been investigated in 19 infants aged 35 to 150 days at the beginning of treatment. The pharmacokinetic eva luation was performed at steady-state, after 1 or 3 months of treatment.
Propranolol was rapidly absorbed, the maximum plasma concentration generally occurring 2 hours after administration with a corresponding mean value around 79 ng/mL whatever the infant age. Mean apparent oral clearance was 2.71 L/h/kg in infants aged 65- 120 days and 3.27 L/h/kg in infant aged 181- 240 days. Once corrected by the body weight, primary pharmacokinetic parameters for propranolol (such as plasma clearance) determined in infants were similar to those reported in the literature for adults.
The 4-hydroxy-propranolol metabolite was quantified, its plasma exposure accounting for less than
7% of the parent drug exposure.
During this pharmacokinetic study including infants with function-threatening haemangioma, haemangioma in certain anatomic locations that often leave permanent scars or deformity, large facial haemangioma, smaller haemangioma in exposed areas, severe ulcerated haemangioma, pedunculated haemangioma, efficacy was also studied as a secondary eva luation criteria. Treatment with propranolol resulted in a rapid improvement (within 7-14 days) in all patients and resolution of the target haemangioma was observed in 36.4% of patients by 3 months.
5.3 Preclinical safety data
In animals, after an acute dosing, propranolol is considered as a moderately toxic drug with an oral LD50 of about 600 mg/kg. The main effects reported after repeated administration of propranolol in adult and juvenile rats were a transient decrease in body weight and body weight gain associated with a transient decrease in organ weight. These effects were completely reversible when treatment was discontinued.
In dietary administration studies in which mice and rats were treated with propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis.
Although some data were equivocal, based on the overall available in vitro and in vivo data, it can be
concluded that propranolol is devoid of genotoxic potential.
In adult female rats, propranolol given into the uterus or by intravaginal administration is a powerful anti-implantation agent at dose ≥4 mg per animal, the effects being reversible. In adult male rats, repeated administration of propranolol at high dose levels (≥7.5 mg/kg) induced histopathological lesions of the testes, epididymis, and seminal vesicles, decrease in sperm motility, sperm cell concentration, plasma testosterone levels and significant increase in sperm head and tail abnormalities. The effects generally totally reversed after treatment cessation. Similar results were obtained
following intra-testicular administration of propranolol and using in vitro models. However, in the
study conducted in juvenile animals treated all over the development period corresponding to infancy, childhood and adolescence, no effect on male and female fertilities was observed (See section 4.6).
The potential effects of propranolol on the development of juvenile rats were eva luated following daily oral administration from post-natal Day 4 (PND 4) to PND 21 at dose-levels of 0, 10, 20 or
40 mg/kg/day.
Mortality with unknown although unlikely relationship to treatment was observed at 40 mg/kg/day, leading to a NOAEL of 20 mg/kg/day for juv |
