SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Sectral 400mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 443.40mg of the active substance Acebutolol hydrochloride (equivalent to 400mg of base).

Also contains 21.20mg of lactose monohydrate.

For a full list of excipients, see section 6.1.

3 PHARMACEUTICAL FORM

Tablet

White to off-white, circular, biconvex, film-coated tablets with bevel edges, one face impressed ‘SECTRAL 400 or ACB 400. Plain reverse.

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

The management of hypertension, angina pectoris and the control of tachyarrhythmias.

4.2 Posology and method of administration

Hypertension: Initial dosage of 400 mg orally once daily at breakfast or 200 mg orally twice daily. If response is not adequate within two weeks, dosage may be increased up to 400 mg orally twice daily; in some patients 1200 mg orally daily, given as 800 mg at breakfast and 400 mg in the evening may be required. A further reduction in blood pressure may be obtained by concurrent administration of a thiazide diuretic or other anti-hypertensive agent (except Rauwolfia and its alkaloids).

Angina pectoris: Initial dosage of 400 mg orally once daily at breakfast or 200 mg twice daily. In severe forms up to 300 mg three times daily may be required. Up to 1200 mg daily has been used.

Cardiac arrhythmias: When given orally, an initial dose of 200 mg is recommended. The daily dose requirement for long term antiarrhythmic activity should lie between 400 and 1200 mg daily. The dose can be gauged by response, and better control may be achieved by divided doses rather than a single doses. It may take up to three hours for maximal antiarrhythmic effect to become apparent.

Elderly: There are no specific dosage recommendations for the elderly with normal glomerular filtration rate. Dose reduction is necessary if moderate to severe renal impairment is present (see Section 4.4).

Children: Paediatric dose has not been established.

For all indications, it is advised that the lowest recommended dosage be used initially.

4.3    Contraindications

Cardiogenic shock is an absolute contraindication. Extreme caution is required in patients with blood pressures of the order of 100/60 mmHg or below.

Sectral/Acebutolol is also contraindicated in patients with second and third degree heart block, sick sinus syndrome, marked bradycardia (< 45 - 50 bpm) and uncontrolled heart failure, metabolic acidosis, severe peripheral circulatory disorders, hypersensitivity to Acebutolol, any of the excipients or to beta blockers, and untreated phaeochromocytoma.

4.4    Special warnings and precautions for use

Renal impairment is not contraindicated to the use of Sectral /Acebutolol which has both renal and non-renal excretory pathways. Some caution should be exercised when administering high doses to patients with severe renal failure as accumulation could possibly occur in these circumstances.

The dosage frequency should not exceed once daily in patients with renal impairment. As a guide, the dosage should be reduced by 50% when glomerular filtration rates are between 25-50ml/min and by 75% when they are below 25ml/min (see section 4.2). Drug-induced bronchospasm is usually at least partially reversible by the use of a suitable agonist.

Although cardio-selective beta blockers may have less effect on lung function than non-selective beta blockers as with all beta blockers these should be avoided in patients with obstructive airways disease unless there are compelling clinical reasons for their use. Where such reasons exist, cardio-selective P-blockers should be used with the utmost care (see section 4.3).

Beta-blockers may induce bradycardia. In such cases, the dosage should be reduced. They may be used with patients with controlled heart failure (see Section 4.3).

Use with caution in patients with Prinzmetal’s angina.

Beta-blockers may aggravate peripheral circulatory disorders. They may mask signs of thyrotoxicosis and hypoglycaemia. They should only be used in patients with phaeochromocytoma with concomitant alpha-adrenoreceptor therapy.

Patients with known psoriasis should take beta-blockers only after careful consideration.

Beta-blockers may increase both the sensitivity towards allergens and the seriousness of anaphylactic reactions.

Withdrawal of treatment by beta-blockers should be achieved by gradual dosage reduction: this is especially important in patients with ischaemic heart disease.

When it has been decided to interrupt beta-blockade prior to surgery, therapy should be discontinued for at least 24 hours. Continuation of the therapy reduces the risk of arrhythmias but the risk of hypotension may be increased. If treatment is continued, caution should be observed with certain anaesthetic drugs. The patient may be protected against vagal reactions by intravenous administration of atropine.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Sectral /Acebutolol should not be used with Verapamil or within several days of Verapamil therapy (and vice versa). Use with great care with any other calcium antagonists, particularly Diltiazem.

Class 1 anti-arrthythmic drugs (such as disopyramide) and amiodarone may increase atrial conduction time and induce negative inotropic effects when used concomitantly with beta-blockers.

In patients with labile and insulin-dependent diabetes, the dosage of the hypoglycaemic agent may need to be reduced. However beta-blockers have also been known to blunt the effect of glibenclamide. Beta-adrenergic blockade may also prevent the appearance of signs of hypoglycaemia (tachycardia, see section 4.4).

Cross reactions due to displacement of other drugs from plasma protein binding sites are unlikely due to the low degree of plasma protein binding exhibited by Acebutolol and Diacetolol.

If a beta-blocker is used concurrently with clonidine the latter should not be withdrawn until several days after the former is discontinued.

Acebutolol may antagonize the effect of sympathomimetic and xanthine bronchodilators.

Concurrent use of digoxin and beta-blockers may occasionally induce serious bradycardia. The anti-hypertensive effects of beta-blockers may be attenuated by non-steroidal anti-inflammatory agents.

Concomitant administration of tricyclic antidepressants, barbiturates and phenothiazines as well as other anti-hypertensive agents may increase the blood pressure lowering effects of beta-blockers.

There is a theoretical risk that concurrent administration of monoamine oxidase inhibitors and high doses of beta-blockers, even if they are cardio-selective can produce hypertension. Sectral /Acebutolol therapy should be brought to the attention of the anaesthetist prior to general anaesthesia (see Section 4.4). If treatment is continued, special care should be taken when using anaesthetic agents such as ether, cyclopropane and trichlorethylene.

Concomitant use of fingolimod with beta blockers may potentiate bradycardic effects and is not recommended. Where such co-administration is considered necessary, appropriate monitoring at treatment initiation, i.e. at least overnight monitoring, is recommended.

4.6 Fertility, pregnancy and lactation

Pregnancy: Acebutolol should not be administered to female patients during the first trimester of pregnancy unless the physician considers it essential. In such cases the lowest possible dose should be used.

Beta blockers administered in late pregnancy may give rise to bradycardia, hypoglycaemia and cardiac or pulmonary complications in the foetus/neonate.

Beta-blockers can reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries.

Animal studies have shown no teratogenic hazard.

Lactation: Acebutolol and its active metabolites are excreted in human milk and effects have been shown in breastfed newborns/infants of treated mothers. Acebutolol should not be used during breast-feeding.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. As with all beta-blockers, dizziness or fatigue may occur occasionally. This should be taken into account when driving or operating machinery.

4.8 Undesirable effects

Adverse reactions associated with acebutolol during controlled clinical trials in patients with hypertension, angina pectoris or arrhythmia (1002 patients exposed to acebutolol) are presented by system organ class and by decreasing order of frequency. The frequency of the events “anti-nuclear antibody” and “lupus like syndrome” was found from 1440 patients suffering from hypertension, angina pectoris or arrhythmia and exposed to acebutolol in open or double blind studies performed 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 (<1/10,000). When the exact frequency of the event was not reported, the frequency category assigned is “not known” (ADRs with *).

Adverse reactions reported from post-marketing experience are also listed. These adverse reactions are derived from spontaneous reports and therefore, the frequency of these adverse reactions is “not known” (cannot be estimated from the available data).

The most frequent and serious adverse reactions of acebutolol are related to the beta-adrenergic blocking activity. The most frequent reported clinical adverse reactions are fatigue and gastrointestinal disorders. Among the most serious adverse reactions are cardiac failure, atrioventricular block and bronchospasm. Abrupt withdrawal as for all beta-blockers may exacerbate angina pectoris and precaution is especially required in patients with ischaemic heart disease (see Section 4.4).

Immune system disorders	Very common	Antinuclear antibody
	Uncommon	Lupus like syndrome
Psychiatric disorders	Common	Depression, nightmare
	Not known	Psychoses, hallucinations, confusion, loss of libido*, sleep disorder
Nervous system disorders	Very common	Fatigue
	Common	Dizziness, headache
	Not known	Paraesthesia*, central nervous system disorder
Eye disorders	Common	Visual impairment
	Not known	Dry eye*
Cardiac disorders	Not known	Cardiac failure*, atrioventricular block first degree, increase of an existing atrioventricular block, bradycardia*
Vascular disorders	Not known	Intermittent claudication, Raynaud’s syndrome, cyanosis peripheral and peripheral coldness, hypotension*
Respiratory, thoracic and mediastinal disorders	Common	Dyspnoea
	Not known	Pneumonitis, lung infiltration, bronchospasm
Gastrointestinal disorders	Very common	Gastrointestinal disorders
	Common	Nausea, diarrhoea
	Not known	Vomiting*
Skin and subcutaneous tissue	Common	Rash

disorders
General disorders and administration site condition	Not known	Withdrawal syndrome (see Section 4.4)
Hepatobiliary disorders	Not known	Hepatic enzymes increased, liver injury mainly hepatocellular

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 Yellow Card Scheme at: www.mhra.gov .uk/yellowcard

4.9 Overdose

In the event of excessive bradycardia or hypotension, 1 mg atropine sulphate administered intravenously should be given without delay. If this is insufficient it should be followed by a slow intravenous injection of isoprenaline (5 mcg per minute) with constant monitoring until a response occurs. In severe cases of selfpoisoning with circulatory collapse unresponsive to atropine and catecholamines the intravenous injection of glucagon 10-20 mg may produce a dramatic improvement. Cardiac pacing may be employed if bradycardia becomes severe.

Judicious use of vasopressors, diazepam, phenytoin, lidocaine, digoxin and bronchodilators should be considered depending on the presentation of the patient. Acebutolol can be removed from blood by haemodialysis. Other symptoms and signs of overdosage include cardiogenic shock, AV block, conduction defects, pulmonary oedema, depressed level of consciousness, bronchospasm, hypoglycaemia and rarely hyperkalaemia.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Beta Blocker agents; Beta blocker agents, selective,

ATC code: C07AB04.

Mode of action: Sectral /Acebutolol is a beta adrenoceptor antagonist which is cardio selective, i.e. acts preferentially on beta-1 adrenergic receptors in the heart. Its principal effects are to reduce heart rate especially on exercise and to lower blood pressure in hypertensive subjects. Sectral /Acebutolol and its active metabolite, diacetolol have anti-arrhythmic activity, the combined plasma half-life of the active drug and metabolite being 7-10 hours. Both have partial agonist activity (PAA) also known as intrinsic sympathomimetic activity (ISA). This property ensures that some degree of stimulation of beta-receptors is maintained. Under conditions of rest, this

tends to balance the negative chronotropic and negative inotropic effects. Sectral /Acebutolol blocks the effects of excessive catecholamine stimulation resulting from stress.

5.2    Pharmacokinetic properties

After oral administration, Acebutolol is rapidly and almost completely absorbed. Absorption appears to be unaffected by the presence of food in the gut. There is rapid formation of a major equiactive metabolite, diacetolol, which possesses a similar pharmacological profile to Acebutolol. Peak plasma concentrations of active material (i.e. Acebutolol plus diacetolol) are achieved within 2-4 hours and the terminal plasma elimination half-life is around 8-10 hours. Because of biliary excretion and direct transfer across the gut wall from the systemic circulation to the gut lumen, more than 50% of an oral dose of Sectral /Acebutolol is recovered in the faeces with Acebutolol and diacetolol in equal proportions; the rest of the dose is recovered in the urine, mainly as diacetolol. Both Acebutolol and diacetolol are hydrophilic and exhibit poor penetration of the CNS.

5.3    Preclinical safety data

No particulars.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate Starch Maize Talc (E553b)

Silica colloidal anhydrous (E551)

Povidone K30 Magnesium Stearate (E572)

Tablet coat:

Opadry OY-L-28900 containing Titanium dioxide (E171)

Lactose monohydrate Hypromellose (E464)

Macrogol

6.2    Incompatibilities

Not applicable.

6.3    Shelf life

3 years

6.4    Special precautions for storage

None.

6.5    Nature and contents of container

Sectral is packed in securitainers or HDPE bottles of 100 tablets and in aluminium foil/PVC blister strip packs of 28 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements

7    MARKETING AUTHORISATION HOLDER

Aventis Pharma Limited

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

Trading as:-

Sanofi-aventis or Sanofi

One Onslow Street

Guildford

Surrey

GU1 4YS

UK

8    MARKETING AUTHORISATION NUMBER(S)

PL 04425/0264

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

07/12/2010

10 DATE OF REVISION OF THE TEXT

31/12/2014