Few cases of propranolol overdose were reported. For a single intake, the maximum dose was 20 mg/kg. Symptomatic cases featured hypotension, hypoglycemic seizure, and restlessness/euphory/insomnia; for most cases, propranolol was maintained or reintroduced.
The toxicity of beta-blockers is an extension of their therapeutic effects:
Place the patient on a cardiac monitor, and monitor vital signs, mental status and blood glucose. Give intravenous fluids for hypotension and atropine for bradycardia. Glucagon then catecholamines should be considered if the patient does not respond appropriately to IV fluid. Isoproterenol and aminophylline may be used for bronchospasm.
Propranolol is not dialyzable.
HEMANGEOL is contraindicated in the following conditions:
The following serious adverse reactions are discussed in greater detail in other sections of the labeling:
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 hemangiomaIn 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 | 5.90% | 17.50% | 16.10% |
| Bronchitis | 4.7 | 8 | 13.4 |
| Peripheral coldness | 0.4 | 8 | 6.7 |
| Agitation | 2.1 | 8.5 | 4.5 |
| Diarrhea | 1.3 | 4.5 | 6.3 |
| Somnolence | 0.4 | 5 | 0.9 |
| Nightmare | 1.7 | 2 | 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.
Skin and subcutaneous tissue disorders: Urticaria, alopecia
Investigations: Decreased blood glucose, decreased heart rate
Compassionate Use ProgramMore 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.
Postmarketing ExperienceThe 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
HEMANGEOL oral solution contains the beta-adrenergic blocker propranolol hydrochloride and is indicated for the treatment of proliferating infantile hemangioma requiring systemic therapy.
HEMANGEOL is not intended to be prescribed to pregnant women.
Pregnancy Category CIn 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.
Oral solution: 4.28 mg/mL propranolol hydrochloride
Alcohol, paraben and sugar free.
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
Storage And HandlingStore at 25°C (77°F); excursions permitted from 15° to 30°C (59° to 86°F).
Do not freeze.
Do not shake the bottle before use.
Dispense in original container with enclosed oral dosing syringe.
The product can be kept for 2 months after first opening.
See instructions for using enclosed oral dosing syringe.
Manufactured for: Pierre Fabre Pharmaceuticals, Inc. Parsippany, NJ 07054. Issued: March 2014
Included as part of the PRECAUTIONS section.
PRECAUTIONS HypoglycemiaHEMANGEOL 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.
Bradycardia And HypotensionHEMANGEOL 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.
BronchospasmHEMANGEOL 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.
Cardiac FailureSympathetic stimulation supports circulatory function in patients with congestive heart failure, beta blockade may precipitate more severe failure.
Increased Risk Of Stroke In PHACE SyndromeBy 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.
HypersensitivityBeta blockers will interfere with epinephrine used to treat serious anaphylaxis.
Patient Counseling InformationSee FDA-approved patient labeling (Medication Guide and Instructions for Use).
Patient adviceAdvise parents or caregivers to read the FDA-approved patient labeling (Medication Guide and Instructions for Use).
Instructions for using oral dosing syringeInstruct parents or caregivers on use of the oral dosing syringe.
Risk of hypoglycemiaInform parents or caregivers that there is a risk of hypoglycemia when HEMANGEOL is given to infants who are not feeding regularly or who are vomiting. Instruct them to skip dosing under such conditions.
Instruct parents or caregivers how to recognize the signs of hypoglycemia. Tell them to discontinue HEMANGEOL and call their health care provider immediately or take the child to the emergency room in case of suspected hypoglycemia.
Cardiovascularrisks Advise parents or caregivers that there is a potential risk for bradycardia, aggravation of pre-existing conduction disorders, and hypotension associated with the use of HEMANGEOL. Instruct them to contact their healthcare provider in case of fatigue, pallor, slow or uneven heart beats, peripheral coldness or fainting.
Respiratory risksInform parents or caregivers that HEMANGEOL carries risk of bronchospasm or exacerbation of lower respiratory tract infections. Instruct them to contact their healthcare provider or go to the nearest hospital emergency room if their child has breathing problems or wheezing during treatment with HEMANGEOL.
Other risksInform parents or caregivers that changes in sleep patterns may occur during HEMANGEOL therapy.
Ask parents or caregivers to tell you all the medications they are administering to their child including prescription and over the counter medicines, vitamins, and herbal supplements. Ask breastfeeding mothers to tell you all the medications they are currently taking, as these may pass into the milk.
Nonclinical Toxicology Carcinogenesis, Mutagenesis, Impairment Of FertilityIn 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 evaluated 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.
Use In Specific Populations PregnancyHEMANGEOL is not intended to be prescribed to pregnant women.
Pregnancy Category CIn 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.
Nursing MothersHEMANGEOL is not intended to be prescribed to breastfeeding women. Propranolol is excreted in human milk.
Pediatric UseOf 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.
Safety and effectiveness for infantile hemangioma have not been established in pediatric patients greater than 1 year of age.
Hepatic ImpairmentThere is no experience in infants with hepatic impairment.
Renal ImpairmentThere is no experience in infants with renal impairment.
Initiate treatment at age 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.
Monitor heart rate and blood pressure for 2 hours after HEMANGEOL initiation or dose increases.
If hemangiomas recur, treatment may be re-initiated.
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
| Weight (kg) | Week 1 | Week 2 | Week 3 (maintenance) |
| Volume administered twice a day | Volume administered twice a day | Volume administered 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 | 1.0 mL | 2.0 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 | 3.0 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 |
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 |
| Warfarin | Increase |
| Propafenone | Increase > 200 % |
| Nifedipine | Increase 80 % |
| Verapamil | No change |
| Pravastatin, lovastatin | Decrease 20% |
| Fluvastatin | No change |
| Zolmitriptan | Increase 60 % |
| Rizatriptan | Increase 80 % |
| Thioridazine | Increase 370 % |
| Diazepam | Increase |
| Oxazepam, triazolam, lorazepam, alprazolam | No change |
| Theophylline | Increase 70 % |
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) |
| Diazepam | No change |
| Verapamil | No change |
| Metoclopramide | No change |
| Ranitidine | No change |
| Lansoprazole | No change |
| Omeprazole | No change |
| Propafenone | Increase 200 % |
| Aluminum hydroxide | Decrease 50 % |
