5.1 Hypoglycemia

HEMANGEOL prevents the response of endogenous catecholamines to correct hypoglycemia and masks the adrenergic warning signs of hypoglycemia, particularly tachycardia, palpitations and sweating. HEMANGEOL can cause hypoglycemia in children, especially when they are not feeding regularly or are vomiting; withhold the dose under these conditions. Hypoglycemia may present in the form of seizures, lethargy, or coma. If a child has clinical signs of hypoglycemia, discontinue HEMANGEOL and call their health care provider immediately or take the child to the emergency room.

Concomitant treatment with corticosteroids may increase the risk of hypoglycemia [see Drug Interactions (7)].

5.2 Bradycardia and Hypotension

HEMANGEOL may cause or worsen bradycardia or hypotension. In the studies of HEMANGEOL for infantile hemangioma the mean decrease in heart rate was about 7 bpm with little effect on blood pressure. Monitor heart rate and blood pressure after treatment initiation or increase in dose. Discontinue treatment if severe (<80 beats per minute) or symptomatic bradycardia or hypotension (systolic blood pressure <50 mmHg) occurs.

5.3 Bronchospasm

HEMANGEOL can cause bronchospasm; do not use in patients with asthma or a history of bronchospasm. Interrupt treatment in the event of a lower respiratory tract infection associated with dyspnea and wheezing.

5.4 Cardiac Failure

Sympathetic stimulation supports circulatory function in patients with congestive heart failure, beta blockade may precipitate more severe failure.

5.5 Increased Risk of Stroke in PHACE Syndrome

By dropping blood pressure, HEMANGEOL may increase the risk of stroke in PHACE syndrome patients with severe cerebrovascular anomalies.

Investigate infants with large facial infantile hemangioma for potential arteriopathy associated with PHACE syndrome prior to HEMANGEOL therapy. 

5.6 Hypersensitivity

Beta-blockers will interfere with epinephrine used to treat serious anaphylaxis.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical
trials of a drug may not reflect the rates observed in clinical practice.

Clinical Trials Experience with HEMANGEOL in Infants with proliferating infantile hemangioma
In clinical trials for proliferating infantile hemangioma, the most frequently reported adverse reactions (>10%) in infants treated with HEMANGEOL were sleep disorders, aggravated respiratory tract infections such as bronchitis and bronchiolitis associated with cough and fever, diarrhea, and vomiting.  Adverse reactions led to treatment discontinuation in fewer than 2% of treated patients.

Overall, 479 patients in the pooled safety population were exposed to study drug in the clinical study program (456 in placebo-controlled trials). A total of 424 patients were treated with HEMANGEOL at doses 1.2 mg/kg/day or 3.4 mg/kg/day for 3 or 6 months. Of these, 63% of patients were aged 91-150 days and 37% were aged 35-90 days at randomization.

The following table lists according to the dosage the most common adverse reactions (treatment-emergent adverse events with an incidence at least 3% greater on one of the two doses than on placebo).

Table 2. Treatment-emergent adverse events occurring at least 3% more often on HEMANGEOL than on placebo

The following adverse events have been observed during clinical studies, with an incidence of less than 1%:

Cardiac disorders: Second degree atrioventricular heart block, in a patient with underlying conduction disorder, required definitive treatment discontinuation [see Warnings and Precautions(5.4)].

Skin and subcutaneous tissue disorders: Urticaria, alopecia

Investigations: Decreased blood glucose, decreased heart rate

Compassionate Use Program

More than 600 infants received HEMANGEOL in a compassionate use program (CUP). Mean age at treatment initiation was 3.6 months. Mean dose of HEMANGEOL was 2.2 mg/kg/day and mean treatment duration was 7.1 months.

The adverse reactions reported in the CUP were similar to the ADRs observed during clinical trials but some were more severe.

6.2 Postmarketing Experience

The following adverse reactions have been identified during post-approval use of propranolol. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

These adverse reactions are as follows:

Blood and lymphatic system disorders: Agranulocytosis

Psychiatric disorders: Hallucination

Skin and subcutaneous tissues disorders: Purpura

8.1 Pregnancy

HEMANGEOL is not intended to be prescribed to pregnant women [see Indications and Usage (1)].

Pregnancy Category C.

In a series of reproductive and developmental toxicology studies, propranolol hydrochloride was given to rats by gavage or in the diet throughout pregnancy and lactation. At a dose of 150 mg/kg/day [which is about 2 times the maximum recommended human oral daily dose (MRHD) of 640 mg propranolol hydrochloride in adults on a body surface area basis], treatment was associated with embryotoxicity (reduced litter size and increased resorption rates) as well as neonatal toxicity (deaths). Propranolol hydrochloride also was administered in the feed to rabbits throughout pregnancy and lactation at doses up to 150 mg/kg/day (about 5 times the maximum recommended human oral daily dose in adults). No evidence of embryo or neonatal toxicity was noted.

There are no adequate and well-controlled studies in pregnant women. Intrauterine growth retardation, small placentas, and congenital abnormalities have been reported in neonates whose mothers received propranolol during pregnancy. Neonates whose mothers received propranolol at parturition have exhibited bradycardia, hypoglycemia, and respiratory depression. Adequate facilities for monitoring such infants at birth should be available.

8.3 Nursing Mothers

HEMANGEOL is not intended to be prescribed to breastfeeding women [see Indications and Usage (1)].

Propranolol is excreted in human milk.

8.4 Pediatric Use

Of 460 infants with proliferating infantile hemangioma requiring systemic therapy who were treated with HEMANGEOL starting at 5 weeks to 5 months of age, 60% had complete or nearly complete resolution of their hemangioma at Week 24 [see Clinical Studies (14)].

Safety and effectiveness for infantile hemangioma have not been established in pediatric patients greater than 1 year of age.

8.6 Hepatic Impairment

There is no experience in infants with hepatic impairment.

8.7 Renal Impairment

There is no experience in infants with renal impairment.

12.1 Mechanism of Action

The mechanism of HEMANGEOL’s effects on infantile hemangiomas is not well understood.

12.2 Pharmacodynamics

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 beta-adrenergic 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

Alpha blockers: Co-administration of beta-blockers with alpha blockers (prazosin) has been associated with prolongation of first dose hypotension and syncope.

Antidepressants: 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.

12.3 Pharmacokinetics

Adults

Absorption: 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.

Distribution: 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.

Metabolism: 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.

Elimination: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.

Infants

The pharmacokinetics of propranolol and 4-OH-propranolol were eva luated 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.

Sex

There is no known dependence of pharmacokinetics of propranolol by sex in infants.

Race

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.

12.6 Drug Interactions

Impact of propranolol on co-administered drugs: The effect of propranolol on plasma concentration of co-administered drug is presented in the table below.

Table 3. Effect of propranolol on co-administered drugs

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

13.1 Carcinogenesis and Mutagenesis and Impairment of Fertility

In studies of mice and rats fed propranolol hydrochloride for up to 18 months at doses of up to 150 mg/kg/day, there was no evidence of drug-related tumorigenesis. On a body surface area basis, this dose in the mouse and rat is about 3 and 7 times, respectively, the MRHD of 3.4 mg/kg/day propranolol hydrochloride in children.

Based on differing results from bacterial reverse mutation (Ames) tests performed by different laboratories, there is equivocal evidence for mutagenicity in one strain (S. typhimurium strain TA 1538).

In a study in which both male and female rats were exposed to propranolol hydrochloride via diet at concentrations of up to 0.05% (about 50 mg/kg or less than the MRHD of 640 mg propranolol hydrochloride in adults) started from 60 days prior to mating and throughout pregnancy and lactation for two generations, there were no effects on fertility. The potential effects of propranolol hydrochloride on fertility 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, 11.4, 22.8 or 45.6  mg/kg/day. No propranolol related effects on reproductive parameters or reproductive development were observed up to the highest dose level of 45.6 mg/kg/day, a dose that represents a systemic exposure of 3 times that seen in children at the MRHD.

13.2 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.

16.1 How Supplied

HEMANGEOL is supplied as an oral solution. Each 1 mL contains 4.28 mg propranolol hydrochloride (equivalent to 3.75 mg propranolol). HEMANGEOL is supplied in a carton containing one 120 mL bottle with syringe adapter and one 5 mL oral dosing syringe.

NDC 64370-375-01                 Bottle 120 mL

16.2 Storage and Handling

Store at 25ºC (77ºF); excursions permitted from 15º to 30ºC (59º to 86ºF). [See USP Controlled Room Temperature.]