SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Betim 10mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains timolol maleate 10 mg.

For a full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White, round, flat, with a score mark on one side and engraved with “V Bet” on the other side.

The tablet can be divided into equal doses.

4.    CLINICAL PARTICULARS

4.1 Therapeutic indications

Betim is indicated in angina pectoris due to ischaemic heart disease, for the treatment of hypertension and to reduce mortality and reinfarction in patients surviving acute myocardial infarction. Betim is also indicated in the prophylactic treatment of migraine in order to reduce the number of attacks.

4.2 Posology and method of administration

Posology

The lowest possible dosage should be given first in order to be able to identify cardiac decompensation or bronchial phenomena at an early stage; this is especially important in the elderly. Subsequent increases in dose should take place slowly, (e.g. once a week) under control or on the basis of clinical effect.

For angina:

The recommended dose range is 5 - 30 mg twice daily. The initial dose should be 5 mg twice daily, increasing the daily dose by 10 mg not more frequently than every 3 to 4 days to achieve optimum results.

Hypertension:

The recommended dose range is 10 - 60 mg daily. Most hypertensive patients will be controlled by 10 - 30 mg timolol which can be administered once daily or in two divided doses if preferred. Doses in excess of 30 mg daily should be given in two equally divided doses. The dose of Betim may need adjustment when used in conjunction with other antihypertensive drugs.

After myocardial infarction:

Start with 5 mg (U tablet) twice daily for two days. If there are no adverse effects, increase dosage to 10 mg twice daily and maintain at this dose.

For the prophylactic treatment of migraine:

10 to 20 mg once daily or in two divided doses.

Dosage in the elderly:

Initiate treatment with lowest adult dose and thereafter adjust according to response.

Paediatric population:

The safety and efficacy of Betim in children has not been established. No data are available.

Method of administration For oral use

4.3 Contraindications

Hypersensitivity to timolol or to any of the excipients.

Heart failure, unless adequately controlled, sinus bradycardia (<45 - 50 bpm) or heart block. Cardiogenic shock. History of bronchospasm and bronchial asthma. Chronic obstructive pulmonary disease. Patients receiving monoamine oxidase inhibitors. Pregnancy. Sick sinus syndrome (including sino-atrial block), severe peripheral vascular disease or Raynaud's disease. Prinzmetal's angina. Untreated phaeochromocytoma. Metabolic acidosis. Hypotension. Severe peripheral circulatory disturbances.

4.4 Special warnings and precautions for use

Cardiovascular

Although Betim has no direct myocardial depressant activity, the continued depression of sympathetic drive through beta blockade may lead to cardiac failure in patients with latent cardiac insufficiency. All patients should be observed for evidence of cardiac failure and, if it occurs, then treatment with beta blockers should be gradually withdrawn. If it is not possible to withdraw beta blocker treatment, then digitalisation and diuretic therapy should be considered.

Beta blockers should not be used in patients with untreated congestive heart failure. This condition should first be stabilised.

In patients with ischaemic heart disease, treatment should not be discontinued suddenly. The dosage should gradually be reduced, i.e. over 1-2 weeks. If necessary, replacement therapy should be initiated at the same time, to prevent exacerbation of angina pectoris.

Beta blockers may induce bradycardia. If the pulse rate decreases to less than 50-55 beats per minute at rest and the patient experiences symptoms related to the bradycardia, the dosage should be reduced.

In patients with peripheral circulatory disorders (Raynaud's disease or syndrome, intermittent claudication), beta blockers should be used with great caution as aggravation of these disorders may occur.

Metabolic/endocrine

Betim should be administered with caution to patients with impaired renal function or impaired hepatic function. Patients with liver or kidney insufficiency may need a lower dosage.

Betim may be used safely in diabetes. It may, however, interfere with the cardiovascular and possibly the metabolic responses to hypoglycaemia and, therefore, should be used with caution in diabetic patients treated with insulin or oral hypoglycaemic agents as well as patients subject to spontaneous hypoglycaemia.

Beta blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia.

Other warnings

Patients with a history of psoriasis should take beta blockers only after careful consideration.

Beta blockers may increase sensitivity to allergens and the seriousness of anaphylactic reactions.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs. The reported incidence is rare and in most cases the symptoms have cleared when treatment was withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable. Cessation of therapy with the beta blocker should be gradual although withdrawal symptoms with timolol are infrequent.

The following statement will appear on the label of this product: Do not take this medicine if you have a history of wheezing or asthma'.

4.5 Interactions with other medicinal products and other forms of interaction

The depressant effect of beta-blocking drugs on myocardial contractility and on intracardiac conduction may be increased by concomitant use with other drugs having similar effects. Serious effects have been reported with verapamil, disopyramide, lignocaine and tocainide and may be anticipated with diltiazem, quinidine, amiodarone and any of the class 1 antiarrhythmic agents. Special care is necessary when any of these agents are given intravenously in patients who are beta blocked.

Concurrent administration of digitalis glycosides may increase the atrioventricular conduction time.

Beta-blockers increase the risk of ‘rebound hypertension’ when taken with clonidine. When clonidine is used in conjunction with non-selective beta-blockers such as timolol, treatment with clonidine should be continued for some time after treatment with the beta-blocker has been discontinued.

Concomitant administration of tricyclic antidepressants, barbiturates and phenothiazines, dihydropyridine derivatives such as nifedipine or antihypertensive agents may increase the blood pressure lowering effect.

Beta-blockers may intensify the blood sugar lowering effect of insulin and oral antidiabetic drugs.

Anaesthesia

The anaesthesiologist should be informed when the patient is receiving a betablocking agent. Concomitant use of beta blockers and anaesthetics may attenuate reflex tachycardia and increase the risk of hypotension.

The withdrawal of beta blocking drugs prior to surgery is not necessary in the majority of patients. If beta-blockade is interrupted in preparation for surgery, therapy should be discontinued at least 24 hours beforehand.

Continuation of beta-blockade reduces the risk of arrhythmias during induction and intubation, however the risk of hypertension may be increased. Anaesthetic agents such as ether, cyclopropane and trichloroethylene should not be used whereas halothane, isoflurane, nitrous oxide, intravenous induction agents, muscle relaxants, narcotic analgesics and local anaesthetic agents are all compatible with beta-adrenergic blockade. Local anaesthetics with added vasoconstrictors, e.g. adrenaline, should be avoided. The patient may be protected against vagal reactions by intravenous administration of atropine.

The bioavailability of Betim will be increased by co-administration with cimetidine or hydralazine and reduced with rifampicin.

Betim may be prescribed with vasodilation, but increased gastro-intestinal blood flow may affect absorption and metabolism of timolol.

Alcohol induces increased plasma levels of hepatically metabolised beta-blockers such as timolol.

Some prostaglandin synthetase inhibiting drugs have been shown to impair the antihypertensive effect of beta-blocking drugs.

The effect of sympathomimetic agents, e.g. isoprenaline, salbutamol, will be reduced by concomitant use of beta blockers. In addition, sympathomimetics may counteract the effect of beta-blocking agents.

The adverse vasoconstrictor effects of ergot preparations may be potentiated during the treatment of migraine with beta blocking drugs.

Caution is recommended when Betim is administered to patients on catecholamine depleting drugs such as reserpine or guanethidine.

4.6    Fertility, pregnancy and lactation

Betim is contraindicated during pregnancy (see section 4.3).

Timolol maleate appears in breast milk (milk: plasma ratio 0.8). Breast feeding is therefore not recommended during administration of this product.

4.7    Effects on ability to drive and use machines

None known. When driving vehicles or operating machines it should be taken into account that occasionally dizziness or fatigue may occur.

4.8    Undesirable effects

Psychiatric disorders		Psychotic disorder; hallucination; depression; disorientation; confusional state; nightmare; insomnia; sleep disorder
Nervous system disorders		Paraesthesia; dizziness; headache; somnolence
Eye disorders	Dry eye	Visual impairment
Ear and labyrinth disorders		Vertigo
Cardiac disorders		Atrioventricular block; bradycardia; cardiac failure; cyanosis
Vascular disorders		Hypotension; Raynaud's phenomenon; increase of an existing intermittent claudication; peripheral coldness
Respiratory, thoracic and mediastinal disorders		Dyspnoea; bronchospasm (in patients with bronchial asthma or a history of asthmatic complaints)
Gastrointestinal disorders	Retroperitoneal fibrosis	Dyspepsia; vomiting; nausea; diarrhoea
Skin and subcutaneous tissue disorders	Dermatitis allergic; dermatitis psoriasiform; rash erythematous
Musculoskeletal and connective tissue disorders	Arthralgia
Reproductive system and breast disorders		Erectile dysfunction
General disorders and administration site conditions		Fatigue; weakness
Investigations		Antinuclear antibody increased

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

Poisoning due to an overdose of Betim may lead to severe hypotension, sinus bradycardia, atrioventricular block, heart failure, cardiogenic shock, cardiac arrest, bronchospasm, impairment of consciousness, coma, occasionally hyperkalaemia. The first manifestations usually appear 20 minutes to 2 hours after drug ingestion.

Treatment should include close monitoring of cardiovascular, respiratory and renal function and blood glucose and electrolytes. Further absorption may be prevented by induction of vomiting, gastric lavage or administration of activated charcoal if ingestion is recent.

Cardiovascular complications should be treated symptomatically, which may require the use of sympathomimetic agents, (e.g. noradrenaline, metariminol), atropine or inotropic agents, (e.g. dopamine, dobutamine). Temporary pacing may be required for AV block. Glucagon can reverse the effects of excessive beta blockade, given in a dose of 1-10 mg intravenously. Intravenous B₂-stimulants, e.g. terbutaline, may be required to relieve bronchospasm.

Timolol cannot be effectively removed by haemodialysis.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Cardiovascular system, Beta blocking agents, non-selective, timolol , ATC code: C07AA06

Betim is a beta adrenergic receptor blocking agent. The competitive antagonism of adrenergic transmitters at beta receptors blocks beta sympathomimetic activity particularly in the heart, the bronchi and blood vessels.

Betim has been shown to be a highly specific beta adrenergic blocking drug and it does not block the chronotropic or inotropic effects of calcium, glucagon, theophylline or digitalis. It does not have significant local anaesthetic or direct myocardial depressant activity nor any significant intrinsic beta adrenergic stimulant effect.

Betim reduces heart rate and force of myocardial contraction and, therefore, myocardial oxygen consumption. Modification of the cardiovascular responses to stress or exercise is therapeutically useful in the treatment of angina pectoris.

The beta blocking action of Betim is also of therapeutic value in hypertension, although the exact mechanism of action is unclear.

5.2. Pharmacokinetic properties

Timolol maleate is rapidly and nearly completely absorbed following oral administration. Beta blocking activity is apparent within 30 minutes of administration and the duration of action, though dependent on dose, has been shown to last for up to 24 hours. Dose proportionality has been established. Plasma half-life is approximately 2.7-5.0 hours with a peak plasma concentration occurring approximately 2 hours post dose. Timolol undergoes significant hepatic metabolism, but "first pass metabolism" is low.

5% of timolol is excreted unchanged by the kidneys.

These pharmacokinetic parameters are unchanged in hypertensive patients and following multiple dosages.

The rate of timolol metabolism varies between individuals. Poor metabolisers (approximately 10%) show higher plasma levels and slower elimination of timolol than extensive metabolisers. Within individuals, however, plasma concentrations and half-life are reproducible. As the therapeutic response and some adverse effects are related to plasma concentrations of timolol, poor metabolisers may require lower than normal doses.

5.3. Preclinical safety data

Timolol has low toxicity and mutagenicity and reproduction and fertility studies have not demonstrated evidence of changes relevant to the dosage used in man.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Microcrystalline cellulose

Pregelatinised starch

Magnesium stearate 6.2. Incompatibilities

None known.

Shelf life

5 years.

6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

6.5 Nature and contents of container

Aluminium blister packs or amber glass bottles with high density polyethylene screw cap and desiccant, containing 30 or 100 tablets.

Not all pack sizes may be marketed

6.6 Special precautions for disposal

No special requirements.

7 MARKETING AUTHORISATION HOLDER

Meda Pharmaceuticals Ltd Skyway House Parsonage Road Takeley

Bishop’s Stortford CM22 6PU

8. MARKETING AUTHORISATION NUMBER

PL 15142/0024

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE

AUTHORISATION

19/09/2005

10 DATE OF REVISION OF THE TEXT

26/02/2014