HEMANGEOL

HEMANGEOL is an oral solution of propranolol that is alcohol free, paraben free and sugar free. Each mL of HEMANGEOL contains 4.28 mg of propranolol hydrochloride, USP equivalent to 3.75 mg of propranolol. Propranolol hydrochloride is a synthetic beta-adrenergic receptor blocking agent chemically described as (2RS)1-[(1-methylethyl)amino]-3-(naphthalene-1-yloxy)-propan-2-ol hydrochloride. Its structural formula is shown in Figure 1: Figure 1. Propranolol HCl Structure Molecular formula: C 16 H 21 NO 2 -HCl Propranolol hydrochloride is a stable, white, crystalline solid with a molecular weight of 295.8. It is readily soluble in water and ethanol. HEMANGEOL contains the following inactive ingredients: strawberry/vanilla flavorings, hydroxyethylcellulose, saccharin sodium, citric acid monohydrate, and water. Figure 1. Propranolol HCl structure

HEMANGEOL oral solution contains the beta-adrenergic blocker propranolol hydrochloride and is indicated for the treatment of proliferating infantile hemangioma requiring systemic therapy. HEMANGEOL oral solution is a beta-adrenergic blocker indicated for the treatment of proliferating infantile hemangioma requiring systemic therapy. ( 1 )

Initiate treatment at ages 5 weeks to 5 months. The recommended starting dose of HEMANGEOL is 0.15 mL/kg (0.6 mg/kg) (see Table 1) twice daily, taken at least 9 hours apart. After 1 week, increase the daily dose to 0.3 mL/kg (1.1 mg/kg) twice daily. After 2 weeks of treatment, increase the dose to 0.4 mL/kg (1.7 mg/kg) twice daily and maintain this for 6 months. Readjust the dose periodically as the child’s weight increases. To reduce the risk of hypoglycemia, administer HEMANGEOL orally during or right after a feeding. Skip the dose if the child is not eating or is vomiting [see Warnings and Precautions (5.1) ] . Monitor heart rate and blood pressure for 2 hours after HEMANGEOL initiation or dose increases [see Warnings and Precautions (5.2) ]. If hemangiomas recur, treatment may be re-initiated [see Clinical Studies (14) ] . HEMANGEOL is supplied with an oral dosing syringe for administration. Administration directly into the child’s mouth is recommended. Nevertheless, if necessary, the product may be diluted in a small quantity of milk or fruit juice, given in a baby’s bottle. Table 1. Dose Titration According to Weight Week 1 Week 2 Week 3 (maintenance) Weight (kg) Volume administered Volume administered Volume administered twice a day twice a day twice a day 2 to <2.5 0.3 mL 0.6 mL 0.8 mL 2.5 to <3 0.4 mL 0.8 mL 1 mL 3 to <3.5 0.5 mL 0.9 mL 1.2 mL 3.5 to <4 0.5 mL 1.1 mL 1.4 mL 4 to <4.5 0.6 mL 1.2 mL 1.6 mL 4.5 to <5 0.7 mL 1.4 mL 1.8 mL 5 to <5.5 0.8 mL 1.5 mL 2 mL 5.5 to <6 0.8 mL 1.7 mL 2.2 mL 6 to <6.5 0.9 mL 1.8 mL 2.4 mL 6.5 to <7 1 mL 2 mL 2.6 mL 7 to <7.5 1.1 mL 2.1 mL 2.8 mL 7.5 to <8 1.1 mL 2.3 mL 3 mL 8 to <8.5 1.2 mL 2.4 mL 3.2 mL 8.5 to <9 1.3 mL 2.6 mL 3.4 mL 9 to <9.5 1.4 mL 2.7 mL 3.6 mL 9.5 to <10 1.4 mL 2.9 mL 3.8 mL 10 to <10.5 1.5 mL 3 mL 4 mL 10.5 to <11 1.6 mL 3.2 mL 4.2 mL 11 to <11.5 1.7 mL 3.3 mL 4.4 mL 11.5 to <12 1.7 mL 3.5 mL 4.6 mL 12 to <12.5 1.8 mL 3.6 mL 4.8 mL Initiate treatment at ages 5 weeks to 5 months. ( 2 ) Starting dose is 0.15 mL/kg (0.6 mg/kg) twice daily. After 1 week, increase dose to 0.3 mL/kg (1.1 mg/kg) twice daily. After 2 weeks, increase to a maintenance dose of 0.4 mL/kg (1.7 mg/kg) twice daily. ( 2 ) Administer doses at least 9 hours apart during or after feeding. ( 2 ) Readjust dose for changes in the child’s weight. ( 2 ) Monitor heart rate and blood pressure for 2 hours after the first dose or increasing dose. ( 2 )

HEMANGEOL is contraindicated in the following conditions: Premature infants with corrected age < 5 weeks Infants weighing less than 2 kg Known hypersensitivity to propranolol or any of the excipients [see Description (11) ] Asthma or history of bronchospasm Heart rate <80 beats per minute, greater than first degree heart block, or decompensated heart failure Blood pressure <50/30 mmHg Pheochromocytoma Premature infants with corrected age <5 weeks ( 4 ) Infants weighing less than 2 kg ( 4 ) Known hypersensitivity to propranolol or excipients ( 4 ) Asthma or history of bronchospasm ( 4 , 5.3 , 6 , 10 , 17 ) Bradycardia (<80 beats per minute), greater than first degree heart block, decompensated heart failure ( 4 , 5.2 , 5.4 , 10 , 17 ) Blood pressure <50/30 mmHg ( 4 , 5.2 , 10 , 17 ) Pheochromocytoma ( 4 )

The following serious adverse reactions are discussed in greater detail in other sections of the labeling: Hypoglycemia and related events, like hypoglycemic seizure [see Warnings and Precautions (5.1) ]. Bronchospasm [see Warnings and Precautions (5.3) ]. The most common adverse reactions to HEMANGEOL (occurring ≥ 10% of patients) were sleep disorders, aggravated respiratory tract infections, diarrhea, and vomiting. ( 6 ) To report SUSPECTED ADVERSE REACTIONS, contact Pierre Fabre Pharmaceuticals, Inc. at 1-855-PFPHARM (737-4276) or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . See 17 for PATIENT COUNSELING INFORMATION and Medication Guide 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 Reaction Placebo N=236 HEMANGEOL 1.2 mg/kg/day N=200 HEMANGEOL 3.4 mg/kg/day N=224 Sleep disorder 5.9% 17.5% 16.1% Bronchitis 4.7 8.0 13.4 Peripheral coldness 0.4 8.0 6.7 Agitation 2.1 8.5 4.5 Diarrhea 1.3 4.5 6.3 Somnolence 0.4 5.0 0.9 Nightmare 1.7 2.0 6.3 Irritability 1.3 5.5 1.3 Decreased appetite 0.4 2.5 3.6 Abdominal pain 0.4 3.5 0.4 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, dermatitis psoriasform

In the absence of specific studies in children, the drug interactions with propranolol are those known in adults. Consider both the infant’s medications and those of a nursing mother. Pharmacokinetic drug interactions Impact of co-administered drugs on propranolol: CYP2D6, CYP1A2 or CYP2C19 inhibitors increase propranolol plasma concentration. CYP1A2 inducers (phenytoin, phenobarbital) or CYP2C19 inducers (rifampin) decrease propranolol plasma concentration when co-administered. Pharmacodynamic drug interactions Corticosteroids: Patients on corticosteroids may be at increased risk of hypoglycemia because of loss of the counter-regulatory cortisol response; monitor patients for signs of hypoglycemia.