Mechanism Of Action
The mechanism of HEMANGEOL’s effects on infantile hemangiomas is not well understood.
Propranolol is a nonselective beta-adrenergic receptor blocking agent possessing no other autonomic nervous system activity. It specifically competes with beta-adrenergic receptor stimulating agents for available receptor sites. When access to beta-receptor sites is blocked by propranolol, chronotropic, inotropic, and vasodilator responses to betaadrenergic stimulation are decreased proportionately.
Propranolol selectively blocks beta-adrenergic receptors, leaving alpha-adrenergic responses intact. There are two well-characterized subtypes of beta receptors (beta1 and beta2); propranolol interacts with both subtypes equally.
Beta1-adrenergic receptors are found primarily in the heart. Blockade of cardiac beta1-adrenergic receptors leads to a decrease in the activity of both normal and ectopic pacemaker cells and a decrease in A-V nodal conduction velocity. Blockade of cardiac beta1-adrenergic receptors also decreases the myocardial force of contraction and may provoke cardiac decompensation in patients with minimal cardiac reserve.
Beta2-adrenergic receptors are found predominantly in smooth muscle-vascular, bronchial, gastrointestinal and genitourinary. Blockade of these receptors results in constriction. Propranolol’s beta-blocking effects are attributable to its S(-) enantiomer.
Pharmacodynamic Drug Interactions
Co-administration of beta-blockers with alpha blockers (prazosin) has been associated with prolongation of first dose hypotension and syncope.
The hypotensive effect of MAO inhibitors and tricyclic antidepressants is exacerbated when administered with beta-blockers.
Nonsteroidal anti-inflammatory drugs
Nonsteroidal anti-inflammatory drugs (NSAIDs) may attenuate the antihypertensive effect of beta-adrenoreceptor blocking agents. Monitor blood pressure.
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 Pgp 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.
Propranolol is extensively metabolized with most metabolites appearing in the urine.
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 (EMs) and poor metabolizers (PMs) 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.
The pharmacokinetics of propranolol and 4-OH-propranolol were evaluated in a multiple dose 12 week study conducted in 23 male and female infants 35 to 150 days of age with hemangioma. The infants were stratified by age (35 to 90 days and 91 to 150 days). The starting dose was 1.2 mg/kg/day which was titrated to the target dose of 3.4 mg/kg/day in 1.1 mg/kg/day increments at weekly intervals. At steady state, following administration of 3.4 mg/kg/day twice daily, peak plasma propranolol concentrations were observed within 2 hours of oral administration. Clearance of propranolol in infants was similar across the age range studied (2.7 (SD=0.03) L/h/kg in infants <90 days of age and 3.3 (SD=0.35) L/h/kg in infants >90 days of age) and to that in adults when adjusted by body weight. The median elimination half-life of propranolol was about 3.5 hours. Plasma propranolol concentrations approximate a dose proportional increase in the dose range of 1.2 mg/kg/day to 3.4 mg/kg/day.
Plasma concentration of 4-OH-propranolol, the main metabolite, was about 5% of total plasma exposure of propranolol.
There is no known dependence of pharmacokinetics of propranolol by sex in infants.
There is little information on dependence of pharmacokinetics of propranolol by race in infants.
A study conducted in 12 Caucasian and 13 African-American adult male subjects taking propranolol, showed that at steady state, the clearance of R(+)- and S(-)-propranolol were about 76% and 53% higher in African-Americans than in Caucasians, respectively.
Chinese adult subjects had a greater proportion (18% to 45% higher) of unbound propranolol in plasma compared to Caucasians, which was associated with a lower plasma concentration of alpha1 acid glycoprotein.
Impact Of Propranolol On Co-Administered Drugs
The effect of propranolol on plasma concentration of coadministered drug is presented in the table below.
Table 3. Effect of propranolol on co-administered drugs
|Co-administered drug||Effect on plasma concentration of co-administered drug|
|Amide anesthetics (lidocaine, bupivacaine, mepivacaine)||Increase|
|Propafenone||Increase > 200 %|
|Nifedipine||Increase 80 %|
|Pravastatin, lovastatin||Decrease 20%|
|Zolmitriptan||Increase 60 %|
|Rizatriptan||Increase 80 %|
|Thioridazine||Increase 370 %|
|Oxazepam, triazolam, lorazepam, alprazolam||No change|
|Theophylline||Increase 70 %|
Impact Of Co-Administered Drugs On Propranolol
The effect of co-administered drugs on propranolol plasma concentration is presented in the table below.
Table 4. Effect of co-administered drugs on propranolol
|Co-administered drug||Effect on propranolol plasma concentration|
|CYP2D6, CYP1A2 or CYP2C19 inhibitors||Increase|
|CYP1A2 or CYP2C19 inducers||Decrease|
|Quinidine||Increase > 200 %|
|Nisoldipine||Increase 50 %|
|Nicardipine||Increase 80 %|
|Chlorpromazine||Increase 70 %|
|Cimetidine||Increase 50 %|
|Cholestyramine, colestipol||Decrease 50 %|
|Alcohol||Increase (acute use), decrease (chronic use)|
|Propafenone||Increase 200 %|
|Aluminum hydroxide||Decrease 50 %|
Animal Toxicology And/Or Pharmacology
This study in juvenile rats with propranolol hydrochloride described above was intended to cover the period of development corresponding to infancy, childhood and adolescence. Neurologic effects including hypoactivity and delayed air righting reflex, increased germinal centers of lymph nodes, and increased white blood cells and lymphocytes were seen at a propranolol hydrochloride dose 45.6 mg/kg/day that represents a systemic exposure of 3 times that seen in children at the MRHD. Body weights were transiently decreased, and transient decreases in urine volume were associated with higher incidences of minimal renal cysts and dilation of kidney tubules at doses about equal to the MRHD in children.
A randomized, double-blind study in 460 infants, aged 35 days to 5 months at inclusion, with proliferating infantile hemangiomas (IH) requiring systemic therapy (excluding life-threatening IH, function-threatening IH, and ulcerated IH with pain and lack of response to simple wound care measures) compared four regimens of HEMANGEOL (1.2 or 3.4 mg/kg/day in twice daily divided doses for 3 or 6 months; N=99-103 per group) to placebo (N=55). Clinical efficacy was evaluated by counting complete or nearly complete resolution of the target hemangioma, which was evaluated by blinded centralized independent assessments of photographs at Week 24 compared to baseline.
Demographic patient characteristics and hemangioma characteristics were similar among the five regimens. For the whole population, 29% were male, 37% were in the lower age group (35-90 days), and 72% were Caucasian. Overall, 70% had a target hemangioma on the head, most commonly cheek (13%) and forehead (11%).
The main reason for treatment discontinuation was the treatment inefficacy, which happened in 58% of patients randomized to placebo, 25-30% of patients randomized to HEMANGEOL for 3 months (mainly after the switch to placebo), and 7-9% of patients randomized to HEMANGEOL for 6 months.
Overall, 2 out of 55 patients (4%) in the placebo arm and 61 out of 101 patients (60%) on HEMANGEOL 3.4 mg/kg/day for 6 months had complete or nearly complete resolution of their hemangioma at Week 24 (p <0.0001).
There were no significant differences in response by age (35-90 days / 91-150 days), sex, or hemangioma site. There were too few non-Caucasians to assess differences in effects by race.
Of patients on HEMANGEOL 3.4 mg/kg/day for 6 months who were considered successes, 10% required retreatment for recurrence of hemangiomas.
A second uncontrolled study in 23 patients with proliferating IH included function-threatening IH, IH in certain anatomic locations that often leave permanent scars or deformity, large facial IH, smaller IH in exposed areas, severe ulcerated IH, pedunculated IH. Target lesions resolved in 36% of patients by 3 months.