BICARDOL

· Arterial hypertension.

· Prophylaxis of angina pectoris on exertion.

More particularly in patients with ischemic heart disease, treatment with DETENSIEL must not be stopped abruptly except in cases of absolute necessity, as this could lead to a transient aggravation of the cardiac condition (see section 4.2).

DETENSIEL must be used with caution in the following cases:

· hypertension or angina accompanied by heart failure,

· diabetes with significant fluctuations in blood glucose, as symptoms of hypoglycemia (for example tachycardia, palpitations or hyperhidrosis) may be masked,

· strict fasting,

· ongoing desensitization treatment. Like other beta-blockers, bisoprolol may increase sensitivity to allergens and the severity of anaphylactic reactions. Epinephrine treatment does not always produce the expected therapeutic effect,

· first-degree atrioventricular block,

· Prinzmetal angina. Cases of coronary vasospasms have been observed. Although bisoprolol is highly beta-1 selective, angina attacks cannot be completely excluded in the case of administration to patients suffering from Prinzmetal angina,

· occlusive peripheral arterial disorders. An aggravation of symptoms may occur, notably at the start of treatment.

In patients presenting with psoriasis or having a history of psoriasis, beta-blockers (bisoprolol for example) should only be administered after carefully evaluating the benefits and risks.

Symptoms of thyrotoxicosis may be masked during treatment with DETENSIEL.

In patients presenting with pheochromocytoma, DETENSIEL should only be administered after treatment with an alpha-blocker.

In patients under general anesthesia, the beta-blocker decreases the incidence of arrhythmias and myocardial ischemias during induction of anesthesia, intubation and the postoperative period. It is currently recommended to continue beta-blocker treatment during the peri-operative period.

The anesthesiologist must be informed of the beta-blocker treatment due to the potential for interactions with other drugs, leading to brady-arrhythmias, a decrease in reflex tachycardia and the reflex compensatory capacity in case of blood loss. If stopping the beta-blocker treatment is deemed necessary before the intervention, it must be done gradually and be completed approximately 48 hours before anesthesia.

Although cardio-selective beta-blockers (beta 1) may have less effect on pulmonary function than non-selective beta-blockers, it should be avoided, as with any beta-blocker, to use them in patients with obstructive airway disease unless imperative medical reasons justify it. If this is the case, DETENSIEL must be used with caution. In asthma or other chronic obstructive broncho-pneumopathies which may be symptomatic, concomitant administration of a bronchodilator treatment is recommended. An increase in airway resistance may sometimes occur in asthmatic patients and consequently require an increase in the dose of beta-2 stimulants.

The combination of bisoprolol with calcium antagonists of the vérapamil or diltiazem type, and with centrally acting antihypertensives is generally not recommended (see section 4.5).

Athletes

Athletes' attention is drawn to the fact that this specialty contains an active ingredient that can induce a positive reaction in tests carried out during anti-doping controls.

Bradycardic drugs

Many drugs can cause bradycardia. This is notably the case with class Ia antiarrhythmics, beta-blockers, certain class III antiarrhythmics, certain calcium antagonists, digitalis, pilocarpine, anticholinesterases etc.

Antiarrhythmics

Many antiarrhythmics are depressants of cardiac automaticity, conduction and contractility. The association of antiarrhythmics of different classes may provide a beneficial therapeutic effect, but is most often very delicate, requiring close clinical monitoring and ECG control. The association of antiarrhythmics causing torsades de pointes (amiodarone, disopyramide, quinidiniques, sotatol) is contraindicated.

The association of antiarrhythmics of the same class is not recommended, except in exceptional cases, due to the increased risk of cardiac adverse effects.

The association with drugs having negative inotropic and bradycardic properties and/or slowing atrioventricular conduction is delicate and requires clinical monitoring and ECG control.

Associations not recommended (see section 4.4)

+ Calcium channel blockers of the verapamil type and, to a lesser extent, of the diltiazem type

Negative effect on contractility and atrioventricular conduction. Intravenous administration of verapamil in patients treated with beta-blockers can induce severe hypotension and atrioventricular block.

+ Antihypertensives of central action (for example clonidine, méthyldopa, monoxidine, rilménidine)

Concomitant administration of antihypertensives of central action can lead to a decrease in heart rate and cardiac output and vasodilation. Abrupt withdrawal of treatment can increase the risk of "rebound hypertension".

+ Fingolimod

Potentiation of bradycardic effects which can have fatal consequences. Beta-blockers are at even greater risk as they prevent adrenergic compensatory mechanisms. Clinical monitoring and continuous ECG during the 24 hours following the first dose.

Associations subject to precautions for use

+ Class I antiarrhythmics (for example quinidine, disopyramide, lidocaïne, phénytoïne, flécaïnide, propafénone)

Risk of potentiation of the effect on atrioventricular conduction time and increase of the negative inotropic effect.

+ Dihydropyridine type calcium channel blockers (for example nifédipine)

The risk of hypotension may be increased in case of concomitant administration and an increased risk of more severe deterioration of ventricular function in patients presenting with heart failure cannot be excluded.

+ Class III antiarrhythmics (for example amiodarone)

The effect on atrioventricular conduction time may be potentiated.

+ Parasympathomimetic drugs

Atrioventricular conduction time and the risk of bradycardia may be increased in case of concomitant administration.

+ Topical beta-blockers (for example eye drops for the treatment of glaucoma)

Can potentiate the systemic effects of bisoprolol.

+ Insulin and oral antidiabetics

Increase in hypoglycemic effect. Inhibition of beta-adrenergic receptors may mask the symptoms of hypoglycemia.

+ Anesthetics

Decrease in reflex tachycardia and increase in the risk of hypotension (for more information on general anesthesia, see section 4.4).

+ Digitalis

Increase in atrioventricular conduction time and consequently decrease in heart rate

+ Non-steroidal anti-inflammatory drugs (NSAIDs)

NSAIDs may decrease the hypotensive effect of bisoprolol.

+ Beta-sympathomimetics (for example isoprénaline, dobutamine)

Association with bisoprolol may decrease the effect of both drugs.

+ Sympathomimetics that activate both beta and alpha-adrenergic receptors

Association with bisoprolol may lead to hypertension. These interactions are considered more likely to occur with non-selective beta-blockers.

The risk of hypotension may be increased in case of concomitant administration with antihypertensives or with other drugs likely to lower blood pressure (for example tricyclic antidepressants, barbiturates, phenothiazines).

Associations to be considered

+ Monoamine oxidase inhibitors (except for MAO-B)

Increase in the hypotensive effect of beta-blockers, but also risk of hypertensive crisis.

+ Méfloquine

Increase in the risk of bradycardia.

Pregnancy

Bisoprolol has pharmacological properties that may lead to harmful effects on pregnancy and/or the foetus/newborn. In general, beta-blockers decrease placental perfusion; this effect has been associated with growth retardation, intrauterine deaths, abortions or preterm labour. Adverse effects (for example hypoglycemia and bradycardia) may occur in the foetus and the newborn. If beta-blocker treatment is necessary, selective beta-1 agents should be preferred.

Bisoprolol should not be used during pregnancy except when necessary. If bisoprolol treatment proves necessary, uteroplacental blood flow and foetal growth should be monitored. In case of harmful effects on pregnancy or on the foetus, starting another treatment should be considered.

The newborn should be subject to close monitoring. Symptoms of hypoglycemia and bradycardia generally appear within the first 3 days of life.

Breastfeeding

There are no data on the excretion of bisoprolol in human breast milk or on the safety of exposure to bisoprolol in the infant. Consequently, breastfeeding is not recommended during administration of bisoprolol.

In a study conducted in patients with coronary heart disease, bisoprolol did not affect the ability to drive. However, due to inter-individual variability in reactions to the medicine, the ability to drive vehicles and use machines may be impaired. This effect should be taken into account, particularly at the start of treatment, in the event of a change in treatment, and in the event of combination with alcohol.

The frequency terms used below correspond to the following definitions.

Common (≥ 1% and < 10%), uncommon (≥ 0.1% and < 1%), rare (≥ 0.01% and < 0.1%), very rare (≤ 0.01%).

Cardiac disorders

Uncommon: atrioventricular conduction disorders, aggravation of pre-existing heart failure, bradycardia.

Investigations

Rare: increased triglycerides, increased liver enzymes (ALAT, ASAT).

Nervous system disorders

Common: dizziness*, headache*.

Rare: syncope.

Eye disorders

Rare: decreased lacrimation (to be taken into account if the patient wears contact lenses).

Very rare: conjunctivitis.

Ear and labyrinth disorders

Rare: hearing disorders.

Respiratory, thoracic and mediastinal disorders

Uncommon: bronchospasm in patients with a history of asthma or obstructive airway disorders.

Rare: allergic rhinitis.

Gastrointestinal disorders

Common: gastrointestinal disorders such as nausea, vomiting, diarrhoea, constipation.

Skin and subcutaneous tissue disorders

Rare: hypersensitivity reactions such as pruritus, flushing, rash and angioedema.

Very rare: alopecia, beta-blockers can trigger or aggravate psoriasis or induce a psoriasiform rash.

Musculoskeletal and systemic disorders

Uncommon: muscle weakness, cramps.

Vascular disorders

Common: sensation of cold or numbness in the extremities, hypotension particularly in patients with heart failure.

General disorders

Common: fatigue*

Uncommon: asthenia.

Hepatobiliary disorders

Rare: hepatitis.

Reproductive system and breast disorders

Rare: erectile dysfunction.

Psychiatric disorders

Uncommon: depression, sleep disorder.

Rare: nightmares, hallucinations.

* These symptoms appear in particular at the start of treatment. They are generally mild and usually disappear within one to two weeks.

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 report any suspected adverse reaction via the national reporting system: French National Agency for Medicines and Health Products Safety (ANSM) and network of Regional Pharmacovigilance Centres - Website: https://signalement.social-sante.gouv.fr .