ACEBUTOLOL TEVA 200 mg Coated Tablet Blister/30

Film-coated tablet.

Acebutolol hydrochloride.....................................................................................................................221,70 mg

Quantity corresponding to acebutolol base........................................................................................200,00 mg

For a film-coated tablet.

Excipients with known effect: 10,53 mg of lactose.

Excipients:

• Arterial hypertension

• Prophylaxis of exertional angina attacks

• Long-term treatment after myocardial infarction (acebutolol reduces the risk of recurrent myocardial infarction and mortality, particularly sudden death).

• Treatment of certain rhythm disorders: supraventricular (tachycardia, atrial flutter and fibrillation, junctional tachycardia) or ventricular (ventricular extrasystole, ventricular tachycardia)

Dosage

• Arterial hypertension: the usual daily dose of acebutolol is 400 mg, to be administered preferably as a single dose each morning, or in two doses, one in the morning and one in the evening. This dose may be increased in cases of severe arterial hypertension.

• Prophylaxis of angina pectoris attacks on exertion, tachyarrhythmias: the daily dose may vary from 400 to 800 mg (600 mg on average), starting with the lowest dose and adjusting the dosage in progressive steps according to the clinical condition or the electrocardiogram.

• Long-term treatment after myocardial infarction: treatment with acebutolol should preferably be initiated between day 3th and the 21th after the acute episode of infarction: the dose is 2 tablets per day, in two doses.

Method of administration

Oral use.

This medicine must NEVER be used in the following cases:

• Hypersensitivity to the active substance or to other beta-blockers or to any of the excipients listed in section Composition,

• Asthma and chronic obstructive pulmonary disease, in their severe forms,

• Heart failure not controlled by treatment,

• Cardiogenic shock,

• Second- and third-degree atrioventricular blocks without a pacemaker,

• Prinzmetal angina (in pure forms and as monotherapy),

• Sinus node disease (including sinoatrial block),

• Bradycardia (< 45-50 beats per minute),

• Raynaud's phenomenon and peripheral arterial disorders, in their severe forms,

• Untreated pheochromocytoma,

• Hypotension (blood pressure ≤ 100/60 mmHg),

• History of anaphylactic reaction,

• Metabolic acidosis,

• Breastfeeding.

Special warnings

Never abruptly interrupt treatment in patients with angina: abrupt withdrawal may lead to serious rhythm disorders, myocardial infarction or sudden death.

Related to excipients:

This medicine contains lactose. Patients with galactose intolerance, total lactase deficiency or glucose-galactose malabsorption syndrome (rare hereditary diseases) must not take this medicine.

Precautions for use

Discontinuation of treatment :

Treatment must not be interrupted abruptly, particularly in patients with ischaemic heart disease. The dose must be reduced gradually, ideally over one to two weeks, starting at the same time, if necessary, with substitution therapy, to avoid worsening of angina.

Asthma and chronic obstructive pulmonary disease:

Beta-blockers may only be administered in mild forms, by choosing a selective beta-1 at a low initial dose. Respiratory function tests are recommended before starting treatment.

In the event of an attack occurring during treatment, beta-mimetic bronchodilators may be used.

Drug-induced bronchospasm is usually at least partially reversible with the use of an appropriate agonist.

Although cardioselective beta-blockers have less effect on pulmonary function than non-selective beta-blockers, as with all beta-blockers, they should be avoided in patients with chronic obstructive pulmonary disease unless there is a clinical reason justifying their use. When such reasons exist, cardioselective beta-blockers must be used with the greatest caution.

Heart failure:

In patients with heart failure controlled by treatment and where necessary, acebutolol will be administered at very low, gradually increasing doses and under strict medical supervision.

Bradycardia:

If the heart rate falls below 50-55 beats per minute at rest and the patient presents symptoms related to bradycardia, the dosage should be reduced.

First-degree atrioventricular block:

Given their negative dromotropic effect, beta-blockers must be administered with caution to patients with first-degree atrioventricular block.

Prinzmetal angina:

Beta-blockers may increase the number and duration of attacks in patients suffering from Prinzmetal angina. The use of a cardioselective beta-1 beta-blocker is possible, in minor and associated forms, provided that a vasodilator is administered concomitantly.

Peripheral arterial disorders:

In patients suffering from peripheral arterial disorders (Raynaud's disease or syndrome, arteritis or chronic obliterative arteriopathies of the lower limbs), beta-blockers may cause worsening of these disorders. In these situations, a cardioselective beta-blocker with partial agonist activity should be preferred, and administered with caution.

Pheochromocytoma:

The use of beta-blockers in the treatment of hypertension due to treated pheochromocytoma requires close monitoring of blood pressure.

They should only be used in patients with pheochromocytoma treated with an alpha-adrenoceptor blocker.

Elderly subject:

In elderly subjects, absolute respect of contraindications is imperative. Care should be taken to initiate treatment at a low dose and to ensure close monitoring.

Renal insufficiency:

Renal impairment is not a contraindication to the use of acebutolol, which has both renal and extra-renal elimination. Precautions must be taken when high doses are administered to patients with severe renal impairment, as accumulation of the product is possible in these circumstances.'acébutolol, which has both renal and extra-renal elimination.èPrecautions must be taken when high doses are administered to patients with severe renal impairment, as accumulation of the product is possible in these circumstances.

In cases of renal impairment, the dosage should be adjusted to the state of renal function: in practice, it is sufficient to monitor heart rate so as to reduce doses if excessive bradycardia occurs (< 50-55 beats/min at rest).

The frequency of intake must not exceed one administration per day in patients with renal insufficiency. It may be recommended to reduce the dose by 50% when the glomerular filtration rate is between 25 and 50 mL/min and by 75% when it is below 25 mL/min (see section Dosage and administration).

Diabetic subject:

Inform the patient and, at the start of treatment, reinforce blood glucose self-monitoring. Warning signs of hypoglycaemia may be masked, in particular tachycardia, palpitations and sweating.

Psoriasis:

Worsening of the disease has been reported under beta-blockers; the indication should be carefully weighed.

Allergic reactions:

In patients liable to have a severe anaphylactic reaction, whatever its origin, in particular with iodinated contrast media or floctafenine, or during desensitisation treatments, beta-blocker treatment may lead to an aggravation of the reaction and resistance to treatment with adrenaline at usual doses.

General anaesthesia:

Beta-blockers will lead to attenuation of reflex tachycardia and an increased risk of hypotension. Continuation of beta-blocker treatment reduces the risk of arrhythmia, myocardial ischaemia and hypertensive episodes. The anaesthetist should be informed that the patient is being treated with a beta-blocker.

• If discontinuation of treatment is deemed necessary, a suspension of at least 24 hours may be considered sufficient to allow the reappearance of sensitivity to catecholamines.

• In certain cases, beta-blocker treatment cannot be interrupted:

• in patients with coronary insufficiency, it is desirable to continue treatment until the intervention, given the risk associated with abrupt withdrawal of beta-blockers;
• in cases of emergency or impossibility of withdrawal, the patient must be protected against vagal predominance by sufficient premedication with atropine, repeated as needed. Anaesthesia should use agents that depress the myocardium as little as possible, and blood losses should be compensated.

• The risk of anaphylaxis should be taken into account.

Thyrotoxicosis:

Beta-blockers may mask its cardiovascular signs.

Bradycardic medicinal products

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

Sinus arrest may occur when beta-blockers, including acebutolol, are used in combination with other medicinal products known to induce sinus arrest (see section Adverse effects.).

Combinations not recommended

+ Diltiazem, verapamil

Disorders of automaticity (excessive bradycardia, sinus arrest), disorders of sino-atrial and atrioventricular conduction, and cardiac failure.

Such a combination should only be made under close clinical and ECG monitoring, particularly in elderly subjects or at the start of treatment.

Acebutolol must not be used with verapamil or within the days following verapamil intake (or vice versa). Great care must be taken when combining with any other calcium antagonist, in particular with diltiazem.

An increased risk of depression has been reported when beta-blockers are co-administered with diltiazem. (see section Adverse effects).

+ Fingolimod

Potentiation of bradycardic effects which may have fatal consequences. Beta-blockers are all the more at risk as they prevent adrenergic compensation mechanisms.

Clinical monitoring and continuous ECG for 24 hours following the first dose.

Associations requiring precautions for use

+ Halogenated volatile anaesthetics

Reduction of compensatory cardiovascular reactions by beta-blockers. Beta-adrenergic inhibition may be reversed during surgery by beta-mimetics.

As a general rule, do not stop beta-blocker treatment and, in any case, avoid abrupt withdrawal. Inform the anaesthetist of this treatment (see section Warnings and precautions).

+ Amiodarone

Disorders of automaticity and conduction (suppression of compensatory sympathetic mechanisms). Clinical monitoring and ECG.

Class I antiarrhythmics (such as disopyramide) and amiodarone may increase atrial conduction time and induce negative inotropic effects when used in combination with beta-blockers.

+ Central antihypertensives

Significant increase in blood pressure in case of abrupt withdrawal of the central antihypertensive treatment. Avoid abrupt withdrawal of central antihypertensive treatment. Clinical monitoring.

If a beta-blocker is used in combination with clonidine, gradual withdrawal of the beta-blocker should first be considered before withdrawal of clonidine.

+ Insulin, glinides, gliptins and hypoglycaemic sulfonylureas

All beta-blockers may mask certain symptoms of hypoglycaemia: palpitations and tachycardia.

Inform the patient and reinforce blood glucose self-monitoring, especially at the start of treatment (see section Warnings and precautions.)

In patients suffering from unstable diabetes or insulin-dependent diabetes, the dosage of the hypoglycaemic medicine (e.g. insulin or oral antidiabetic) may need to be reduced. In addition, beta-blockers are also known to reduce the effect of glibenclamide.

+ Lidocaine administered intravenously

Increased plasma concentrations of lidocaine with possible neurological and cardiac adverse effects (reduced hepatic clearance of lidocaine).

Clinical monitoring, ECG and possibly monitoring of plasma lidocaine concentrations during the combination and after withdrawal of the beta-blocker. Adjust the lidocaine dose if necessary.

+ Medicinal products liable to induce torsades de pointes

Increased risk of ventricular rhythm disorders, in particular torsades de pointes.

Clinical and electrocardiographic monitoring.

+ Class I antiarrhythmics such as propafenone (except lidocaine)

Disorders of contractility, automaticity and conduction (suppression of compensatory sympathetic mechanisms). Clinical monitoring and ECG.

Class I antiarrhythmics (such as disopyramide) and amiodarone may increase atrial conduction time and induce negative inotropic effects when used in combination with beta-blockers.

Associations to be taken into account

+ Non-steroidal anti-inflammatory drugs

Reduction of the antihypertensive effect (inhibition of vasodilatory prostaglandins by non-steroidal anti-inflammatory drugs and sodium and water retention with phenylbutazone).

+ Alpha-blockers for urological use

Increase of the hypotensive effect. Increased risk of orthostatic hypotension.

+ Alpha-blocking antihypertensives

Increased hypotensive effect. Increased risk of orthostatic hypotension.

+ Other bradycardic agents

Risk of excessive bradycardia (additive effects).

+ Dapoxetine

Risk of increased adverse effects, notably dizziness or syncope.

+ Dihydropyridines

Hypotension, heart failure in patients with latent or uncontrolled heart failure (additive negative inotropic effects). The beta-blocker may also minimise the reflex sympathetic reaction triggered by excessive haemodynamic repercussions.

+ Dipyridamole (IV route)

Increase in the antihypertensive effect.

+ Pilocarpine

Risk of excessive bradycardia (additive bradycardic effects).

+ Medicinal products causing orthostatic hypotension (notably antihypertensives, nitrates, phosphodiesterase type 5 inhibitors, alpha-blockers used for urological purposes, imipramine-type antidepressants, phenothiazine neuroleptics, dopamine agonists, levodopa)

Risk of increased hypotension, in particular orthostatic hypotension.

Pregnancy

Animal studies have not shown any teratogenic effect. In the absence of a teratogenic effect in animals, a malformative effect in humans is not expected. Indeed, to date, substances responsible for malformations in humans have been shown to be teratogenic in animals in well-conducted studies in two species.

In clinical practice, no teratogenic effect has been reported to date, and the results of prospective controlled studies with some beta-blockers have not reported birth malformations.

Acebutolol must not be administered to pregnant women during the 1er trimester of pregnancy unless the physician considers the treatment essential. In such cases, the lowest possible dose should be used.

Beta-blockers administered at the end of pregnancy may increase the risk of bradycardia, hypoglycaemia and cardiac or pulmonary complications in the foetus and newborn.

In newborns of treated mothers, the beta-blocking action persists for several days after birth and may result in bradycardia, respiratory distress, hypoglycaemia; however, most often this persistence is without clinical consequence. Nevertheless, due to reduction of compensatory cardiovascular reactions, cardiac failure requiring hospitalisation in intensive care may occur (see section Overdose), while avoiding plasma-expanding solutions (risk of pulmonary oedema).

Beta-blockers may reduce placental perfusion, which may lead to intrauterine foetal death, miscarriage, premature births and newborns small for their gestational age.

Consequently, this medicine, under normal conditions of use, may be prescribed during pregnancy if necessary. In the case of treatment up to delivery, careful monitoring of the newborn (heart rate and blood glucose during the 3 to 5 first days of life) is recommended.

Breast-feeding

In case of treatment with acebutolol, breastfeeding is contraindicated due to significant passage into milk and the risks of hypoglycaemia and bradycardia to which the newborn is exposed (see section Pharmacokinetics).

No study on the effects of acebutolol on the ability to drive vehicles and use machines has been performed. As with all beta-blockers, dizziness or fatigue may occasionally occur. This should be taken into account when driving vehicles or using machines.

The adverse effects associated with acebutolol during controlled clinical trials in patients suffering from hypertension, angina pectoris or arrhythmia (1002 patients exposed to acebutolol) are presented by system organ class and in order of decreasing frequency.

The frequency of the adverse reactions "anti-nuclear antibodies" and "lupus-like syndrome" was determined from 1440 patients suffering from hypertension, angina pectoris or arrhythmia and exposed to acebutolol in open or double-blind studies conducted in the United States.

Frequencies are defined as: 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 (< 10 000), not known (cannot be estimated from the available data).

Adverse reactions reported during post-marketing experience have also been listed. These adverse reactions come from spontaneously reported cases and therefore, the frequency of these reactions is unknown (cannot be estimated from the available data).

The most frequent and most severe adverse effects of acebutolol are related to the adrenergic beta-blocking activity. The most frequently reported clinical adverse effects are fatigue and gastrointestinal disorders. The most severe adverse effects are heart failure, atrioventricular block and bronchospasm. Abrupt withdrawal, as with all beta-blockers, may exacerbate angina pectoris and precautions are particularly necessary in patients with ischaemic heart disease (see section Warnings and precautions).

Table 1: Undesirable effects

System organ class	Frequency	Undesirable effect(s)
Immune system disorders	Very common	Antinuclear antibody*
	Uncommon	Lupus-like syndrome*
Psychiatric disorders	Common	Depression, nightmare
	Unknown	Psychoses, hallucinations, confusion, loss of libido, sleep disorder
Nervous system disorders	Very common	Fatigue
	Common	Malaise, headache
	Unknown	Paresthesia, central nervous system disorder
Eye disorders	Common	Visual disturbance
	Unknown	Dryness of the eyes
Cardiac disorders	Unknown	Heart failure, first-degree atrioventricular block of 1, worsening of pre-existing atrioventricular block, bradycardia, sinus arrest in predisposed patients (for example, elderly patients or patients with pre-existing bradycardia, sinus node dysfunction or atrioventricular block).
Vascular disorders	Unknown	Intermittent claudication, Raynaud's syndrome, cyanosis and coldness of the extremities, hypotension
Respiratory, thoracic and mediastinal disorders	Common	Dyspnoea
	Unknown	Pneumonia, pulmonary infiltration, bronchospasm
Gastrointestinal disorders	Very common	Gastrointestinal disorders
	Common	Nausea, diarrhoea
	Unknown	Vomiting
Skin and subcutaneous tissue disorders	Common	Rash
	Unknown	Alopecia*
General disorders and administration site conditions	Unknown	Withdrawal syndrome (see section Warnings and precautions)
Hepatobiliary disorders	Unknown	Increase in blood levels of liver enzymes, liver damage mainly hepatocellular

* Upon discontinuation of treatment 

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

In cases of bradycardia or excessive hypotension, 1 mg of atropine sulfate administered intravenously will be given without delay. If this is insufficient, this injection should be followed by a slow intravenous injection of isoprenaline (5 µg per minute) with continuous monitoring until the response occurs. In severe cases of overdose with circulatory collapse not responding to atropine or catecholamines, intravenous injection of 10 to 20 mg of glucagon could result in significant improvement. Cardiac pacing should be used if the bradycardia becomes severe.

Cases of sinus arrest have been reported during overdose.

The use of vasopressors, diazepam, phenytoin, lidocaine, digoxin and bronchodilators should be considered depending on the patient's condition.

Acebutolol can be removed from the blood by haemodialysis. Other symptoms and signs of overdose include cardiogenic shock, atrioventricular block, conduction problems, pulmonary oedema, depression of the level of consciousness, bronchospasm and rarely hyperkalaemia.

In case of cardiac decompensation in the newborn of a mother treated with beta-blockers:

• glucagon on the basis of 0,3 mg/kg;

• hospitalisation in intensive care;

• isoprenaline and dobutamine: the generally high dosages and prolonged treatment require specialised monitoring.

Pharmacotherapeutic class: Beta-blocker, selective, ATC code: C07AB04.

Acebutolol is characterised by three pharmacological properties:

• selective beta-1 beta-blocking activity;

• anti-arrhythmic effect;

• partial agonist activity (moderate intrinsic sympathomimetic activity).

Absorption

Administered orally, acebutolol is rapidly and almost completely absorbed; however, the hepatic first-pass effect is significant and the bioavailability is 40 %; the peak plasma concentration is reached after approximately 2 to 4 hours.

Distribution

Binding to plasma proteins:

Protein binding is low: 9 to 11 % for acebutolol, 6 to 9 % for diacetolol.

Elimination half-life :

The plasma elimination half-life of acebutolol is approximately 4 hours and 10 hours for diacetolol.

Biotransformation

The majority of acebutolol is metabolised in the liver into an N-acetylated derivative, diacetolol, which is an active metabolite; the peak plasma concentration of this metabolite is reached after approximately 4 hours, and plasma concentrations of diacetolol are double those of acebutolol.

Elimination

Circulating acebutolol and diacetolol are excreted predominantly by the kidney.

At-risk populations

Renal impairment

Urinary elimination is reduced and the half-lives of acebutolol, and even more so of diacetolol, increase. There is a very significant correlation between creatinine clearance and renal clearance of diacetolol.

Risks of accumulation exist in renal insufficiency, particularly in cases of twice-daily dosing. Reduce doses where appropriate, with careful clinical monitoring of the bradycardic effect, for example (see section Warnings and precautions).

Elderly subject

The physiological decline in renal function may lead to an increase in the half-lives of acebutolol and diacetolol.

Pregnancy

Acebutolol crosses the placenta. The mean cord blood/maternal blood concentration ratios of acebutolol and its active metabolite, diacetolol, are approximately 1,6 for doses of 200 and 400 mg. Maximum concentrations are observed, for acebutolol, 4 to 5 hours after the last dose, and for diacetolol, 5 to 7 hours later.

Breast-feeding

Acebutolol is excreted into breast milk; the concentration of acebutolol in milk is maximal between 4 h 30 and 6 hours after intake. The mean milk/maternal blood concentration ratios vary within a ratio of 4 to 5,5 for doses of 200 and 400 mg respectively. For diacetolol, these ratios vary between 3 and 4, the maximum concentration being observed 7 hours after a 200 mg dose and 12 hours after a 400 mg dose.

30 months.

Store protected from light and moisture.

No special requirements.

List I

Marketing authorisation (AMM)

CIP 3400936146365 (Plq/30). CIP 3400937311069 (Plq/90).

Price:

3,69 euros (Plq/30). 10,12 euros (Plq/90).

Social Security reimbursement at 65% (Plq/30).
Social security reimbursement at 65% (Plq/90) in the indications:

• Arterial hypertension (Plq/90)
• Ventricular tachycardia (Plq/90)
• Angina, preventive treatment (of) (Plq/90)
• Atrial flutter (Plq/90)
• Ventricular extrasystole (Plq/90)
• Atrial fibrillation (Plq/90)
• Paroxysmal supraventricular tachycardia (Plq/90)
• Supraventricular tachycardia (Plq/90)

Collection.