HEMANGIOL Oral solution Ref.[7053] Active ingredients: Propranolol

Initiation of treatment

Prior to initiating propranolol therapy, screening for risks associated with propranolol use must be performed. An analysis of the medical history and a full clinical examination must be performed including heart rate, cardiac and pulmonary auscultation.

In case of suspected cardiac abnormality, a specialist advice must be sought before treatment initiation to determine any subjacent contra-indication.

In case of acute broncho-pulmonary abnormality, the initiation of the treatment should be postponed.

Cardiovascular disorders

Propranolol, due to its pharmacological action, may cause or worsen bradycardia or blood pressure abnormalities. Bradycardia should be diagnosed if the heart rate declines by more than 30 bpm from baseline.

Bradycardia is defined below the following limits:

After the first intake and each dose increase, a clinical monitoring, including blood pressure and heart rate must be performed at least hourly for at least 2 hours. In case of symptomatic bradycardia or bradycardia under 80 bpm, immediate specialist advice must be sought. In case of severe and/or symptomatic bradycardia or hypotension occurring at any time during treatment, treatment must be discontinued and a specialist advice should be sought.

Hypoglycaemia

Propranolol prevents the response of endogenous catecholamines to correct hypoglycaemia. It masks the adrenergic warning signs of hypoglycaemia, particularly tachycardia, shakiness, anxiety and hunger. It can aggravate hypoglycaemia in children, especially in case of fasting, vomiting or overdose.

These hypoglycaemic episodes associated with the taking of propranolol may present exceptionally in the form of seizures and/or coma.

If clinical signs of hypoglycaemia occur, it is necessary to make the child drink a sugary liquid solution and to temporarily stop the treatment. Appropriate monitoring of the child is required until symptoms disappear.

In children with diabetes, blood glucose monitoring should be more frequent and followed by the endocrinologist.

Respiratory disorders

In the event of lower respiratory tract infection associated with dyspnoea and wheezing, treatment should be temporarily discontinued. The administration of beta2 agonists and inhaled corticosteroids is possible. The readministration of propranolol may be considered when the child has fully recovered; in case of reoccurrence, treatment should be permanently discontinued. In the event of isolated bronchospasm, treatment must be permanently discontinued.

Cardiac failure

Sympathetic stimulation may be a vital component supporting circulatory function in patients with congestive heart failure, and its inhibition by beta blockade may precipitate more severe failure. In children with cardiac failure, the treatment should be managed by the cardiologist.

PHACE syndrome

Very limited safety data of propranolol in PHACE syndrome patients are available.

Propranolol may increase the risk of stroke in PHACE syndrome patients with severe cerebrovascular anomalies by dropping blood pressure and attenuating flow through occluded, narrow, or stenotic vessels.

Infants with large facial infantile hemangioma should be thoroughly investigated for potential arteriopathy associated with PHACE syndrome, with magnetic resonance angiography of the head and neck and cardiac imaging to include the aortic arch, prior to considering propranolol therapy. Specialised advice should be sought.

Breast-feeding

Propranolol passes through breast milk, mothers being treated with propranolol who breastfeed their infant should inform their health care professional.

Liver or kidney failure

Propranolol is metabolised in the liver and excreted by the kidneys. In the absence of data in children, propranolol is not recommended in case of renal or hepatic impairment (see section 4.2).

Hypersensitivity

In patients likely to experience severe anaphylactic reaction, regardless of origin, particularly with iodinated contrast agents, beta-blocker treatment may lead to worsening of the reaction and resistance to its treatment with adrenaline at normal doses. In children who are at risk of anaphylaxis, the benefit risk of the medicinal product should be evaluated.

General anaesthesia

Beta-blockers will result in an attenuation of reflex tachycardia and an increased risk of hypotension.

It is necessary to alert the anaesthetist to the fact that the patient is being treated with beta-blockers.

When a patient is scheduled for surgery, beta-blocker therapy should be discontinued at least 48 hours prior to the procedure.

Hyperkaliemia

Hyperkaliemia cases have been reported in patients with large ulcerated hemangioma. A monitoring of electrolyte should be performed in these patients.

Psoriasis

Worsening of disease has been reported with beta-blockers in patients suffering from psoriasis.

Therefore the need for treatment should be carefully weighed up.

Excipients with known effects

This medicinal product contains less than 1 mmol sodium (23 mg) per dose, i.e. essentially ‘sodium-free’.

This medicinal product contains 2.08 mg of propylene glycol/kg/day. Caution should be taken into account in babies less than 4 weeks old, in particular if the baby is given other medicines that contain propylene glycol or alcohol.

Co-administration with any substrate for alcohol dehydrogenase such as ethanol may induce serious adverse effects in neonates.

In the absence of specific studies in children, the drug interactions with propranolol are those known in adults. Combinations should consider the 2 following situations (not mutually exclusive):

• Infants given any other medicinal products, notably those mentioned below.
• Infants breastfed by mothers taking any other medicinal products, notably those mentioned below. In this case, the need of stopping breast-feeding should be discussed.

A close clinical surveillance of any impaired tolerance of propranolol is requested.

Concommitant use not recommended

Bradycardia–inducing calcium-channel blockers (diltiazem, verapamil, bepridil)

Co-administration with propranolol can cause altered automaticity (excessive bradycardia, sinus arrest), sino-atrial and atrio-ventricular conduction disorders, and increased risk of ventricular arrhythmias (torsades de pointes) along with heart failure.

This combination must only be administered under close clinical and ECG monitoring, particularly at the start of the treatment.

Interactions requiring precautions for use

Cardiovascular medicinal products

Antiarrhythmics:

• Propafenone has negative inotropic and beta-blocking properties that can be additive to those of propranolol.
• The metabolism of propranolol is reduced by co-administration of quinidine, leading to a two-three-fold increased blood concentration and greater degrees of clinical beta-blockade.
• Amiodarone is an antiarrhythmic agent with negative chronotropic properties that may be additive to those seen with β-blockers such as propranolol. Automatism and conduction disorders are expected because of the suppression of sympathetic compensative mechanisms.
• The metabolism of intravenous lidocaine is inhibited by co-administration of propranolol, resulting in a 25% increase in lidocaine concentrations. Lidocaine toxicity (neurological and cardiac adverse events) has been reported following co-administration with propranolol.

Digitalis glycosides:

Both digitalis glycosides and beta-blockers slow atrioventricular conduction and decrease heart rate. Concomitant use can increase the risk of bradycardia. The advice of a cardiologist should be sought.

Dihydropyridines:

Caution should be exercised when patients receiving a beta blocker are administered a dihydropyridine. Both agents may induce hypotension and/or heart failure in patients whose cardiac function is partially controlled because of additive inotropic effects. Concomitant use may reduce the reflex sympathetic response involved when excessive distal vasodilatation.

Antihypertensives (ACE Inhibitors, angiotensin II-receptors antagonists, diuretics, alpha-blockers whatever the indication, centrally-acting antihypertensives, reserpine, etc):

When combined with beta-blockers, medicinal products that decrease arterial pressure can cause or increase hypotension, notably orthostatic. With regard to centrally-acting antihypertensives, beta-blockers may exacerbate the rebound hypertension after clonidine abrupt withdrawal, and propranolol should be stopped several days before discontinuing clonidine.

Non-cardiovascular medicinal products

Corticosteroids:

Patients with infantile haemangioma may be at increased risk if they have received or are concomitantly receiving treatment with corticosteroids because adrenal suppression may result in loss of the counterregulatory cortisol response and increase the risk of hypoglycaemia. This also applies when children are breastfed by mothers treated with corticosteroids in case of high dosage or prolonged treatment (see section 4.4 concerning hypoglycaemia).

Medicinal products inducing orthostatic hypotension:

Medicinal products that induce postural hypotension (nitrates derivatives, type 5-phosphodiesterase inhibitors, tricyclic antidepressants, antipsychotics, dopaminergic agonists, levodopa, amifostine, baclofen...) may add their effects to that of beta-blockers. The advice of a cardiologist should be sought.

Enzyme inducers:

Blood levels of propranolol may be decreased by co-administration of enzyme inducers like rifampicin or phenobarbital.

Hypoglycaemic agents:

All beta-blocking agents can mask certain symptoms of hypoglycaemia: palpitations and tachycardia.

Use of propranolol alongside hypoglycaemic therapy in diabetic patients should be with caution since it may prolong the hypoglycaemic response to insulin. In this case, inform the caregiver, and increase monitoring of blood glucose levels, particularly at the start of treatment.

Lipid lowering medicinal products:

Co-administration of cholestyramine or colestipol with propranolol resulted in up to 50% decrease in propranolol concentrations.

Halogenated Anesthetic Agents:

They may depress myocardial contractility and vascular compensating response when administered with propranolol. Beta stimulating agents may be used to counteract the beta-blockade.

Pregnancy

Not relevant.

Breast-feeding

Breastfeeding mothers: see section 4.4 and section 4.5.

Fertility

Although some reversible effects on male and female fertilities were reported in adult rats receiving high doses of propranolol in the literature, the study performed in juvenile animals did not show any effect on fertility (see section 5.3).

Not relevant.

Summary of the safety profile

In clinical trials for proliferating infantile haemangioma, the most frequently reported adverse reactions in infant treated with HEMANGIOL were sleep disorders (16.7%), aggravated respiratory tract infections such as bronchitis and bronchiolitis associated with cough and fever, diarrhoea (16.5%), and vomiting (11.5%). Globally, the adverse reactions reported in the compassionate use program and in literature concerned hypoglycemia (and related event like hypoglycaemic seizure) and aggravated respiratory tract infections with respiratory distress.

Tabulated list of adverse reactions

The following table gives the adverse reactions, reported whatever dose and treatment duration, in three clinical studies, including 435 patients treated by HEMANGIOL at 1 mg/kg/day or 3 mg/kg/day for a maximum treatment duration of 6 months.

Their frequency is defined using the following conventions: very common (≥1/10), common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Due to the clinical trial database size rare and very rare categories are not represented. Within each system organ class, adverse reactions are presented in order of decreasing seriousness.

Infections and infestations

Very common: Bronchitis

Common: Bronchiolitis

Metabolism and nutrition disorders

Common: Decreased appetite

Psychiatric disorders

Very common: Sleep disorder

Common: Agitation, Nightmares, Irritability

Nervous system disorders

Common: Somnolence

Not known: Hypoglycemic seizure

Cardiac disorders

Uncommon: AV block

Not known: Bradycardia

Vascular disorders

Common: Peripheral coldness

Not known: Hypotension, Vasoconstriction, Raynaud’s phenomenon

Respiratory, thoracic and mediastinal disorders

Common: Bronchospasm

Gastrointestinal disorders

Very common: Diarrhea, Vomiting

Common: Constipation, Abdominal pain

Skin and subcutaneous tissue disorders

Common: Erythema, Dermatitis diaper

Uncommon: Urticaria, Alopecia

Not known: Dermatitis psoriasiform

Investigations

Common: Decreased blood pressure

Uncommon: Decreased blood glucose, Decreased heart rate, Neutropenia

Not known: Agranulocytosis, Hyperkaliemia

Description of selected adverse reactions

Concerning the lower respiratory tract infections like bronchitis or bronchiolitis, an aggravation of symptoms (including bronchospasm) has been observed in patients treated with HEMANGIOL due to the bronchoconstrictive effect of propranolol. These effects rarely led to definitive treatment discontinuation (see section 4.4).

Sleep disorders corresponded to insomnia, poor quality of sleep and hypersomnia. Other Central Nervous System disorders were principally observed during the early periods of treatment.

Diarrhea was frequently reported and was not always associated with an infectious gastrointestinal disease. The occurrence of diarrhea seems to be dose-dependent between 1 and 3 mg/kg/day. None of cases was of severe intensity and led to treatment discontinuation.

Cardiovascular events reported during clinical studies were asymptomatic. In the context of the 4 hours cardiovascular monitoring during the titration days, it was observed a decrease of heart rate (about 7 bpm) and of systolic blood pressure (less than 3 mmHg) following drug administration. One case of second degree atrioventricular heart block in a patient with underlying conduction disorder led to definitive treatment discontinuation. Isolated cases of symptomatic bradycardia and hypotension have been reported in literature.

Blood sugar decreases observed during clinical studies were asymptomatic. However, several reports of hypoglycaemia with related hypoglycaemic seizure were reported during the compassionate use program and in literature, especially in case of fasting period during intercurrent illness (see section 4.4).

Concomitant treatment with systemic corticosteroids may increase the risk of hypoglycemia (see section 4.5).

Hyperkalaemia has been reported in the literature in few patients with large ulcerated haemangioma (see section 4.4).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

In the absence of compatibility studies, this medicinal product must not be mixed with other medicinal products.