Prestim Tablets

Each tablet contains timolol maleate 10 mg and bendroflumethiazide 2.5 mg

For a full list of excipients, see section 6.1.

Tablet.

White, flat, oval-shaped tablets with a score mark on one side, and engraved on the other side with “V PRE”

Prestim tablets are indicated for the treatment of mild to moderate hypertension.

Posology

The recommended dosage range is 1 to 4 tablets daily. The dosage can be taken in the morning or in two divided doses, morning and evening.

If blood pressure control is not achieved on 4 tablets daily, consideration should be given to titrating timolol and bendroflumethiazide separately or adding another agent with hypotensive activity.

Dosage in the elderly

Initiate treatment with 1 tablet daily and thereafter adjust according to response.

Paediatric population

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

Method of administration

Prestim tablets are for oral use

Hypersensitivity to timolol maleate and/or bendroflumethiazide or to any of the excipients

Anuria. Prestim should not be used in patients with renal failure.

Uncontrolled heart failure, bradycardia, cardiogenic shock, history of bronchospasm, bronchial asthma, chronic obstructive pulmonary disease, patients receiving adrenergic augmenting drugs (monoamine oxidase inhibitors and tricyclic antidepressants), sick sinus syndrome (including sino-atrial block), Prinzmetals angina, untreated phaeochromocytoma, second to 3rd degree heart block, metabolic acidosis, hypotension, and severe peripheral circulatory disturbances.

Anaesthesia with agents that produce myocardial depression, such as chloroform and ether.

Prestim is contraindicated in pregnancy.

Cardiovascular

The continued depression of sympathetic drive through beta-blockade may lead to cardiac failure. All patients should be observed for evidence of cardiac failure, and if it occurs, digitalisation 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

Caution should be exercised in patients with diabetes mellitus, spontaneous hypoglycaemia, impaired renal or hepatic function

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.

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'.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenergic blocking drugs. The reported incidence is small 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.

As with other diuretics, Prestim should not be administered concurrently with lithium salts. Diuretics can reduce lithium clearance resulting in high serum levels of lithium.

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 receiving beta-blockers.

Concurrent administration of digitalis glycosides may increase the atrio-ventricular 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 beta blocking 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 beta-blockers will be increased by co-administration with cimetidine or hydralazine and reduced with rifampicin.

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.

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

Prestim is contraindicated during pregnancy. (See section 4.3).Both constituents cross the placenta and appear in breast milk therefore breastfeeding is not recommended.

Beta-blockers reduce placental perfusion, which may result in intrauterine foetal death, immature and premature deliveries. In addition, adverse effects (especially hypoglycaemia and bradycardia) may occur in foetus and neonate. There is an increased risk of cardiac and pulmonary complications in the neonate in the postnatal period.

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

Thiazide diuretics may cause excessive depletion of fluid and electrolytes during prolonged or intense use. Symptoms are muscle pain or fatigue, thirst and oliguria. With thiazide diuretics hypokalaemia is more severe in patients already depleted of potassium, as in renal or hepatic insufficiency.

The most common signs of overdosage are bradycardia, hypotension, bronchospasm and acute cardiac failure. Suggested treatments are as follows:

General measures should be taken to restore blood volume, maintain blood pressure and correct electrolyte imbalance.

Pharmacotherapeutic group: Cardiovascular system, Beta blocking agents, non-selective and thiazides ATC code: C07BA06

Timolol maleate is a non-selective Beta-adrenoceptor antagonist with marked hypotensive activity.

Bendroflumethiazide is a thiazide diuretic, which has a moderate duration of activity.

It has been shown that beta-blocking agents used in combination with a thiazide diuretic potentiates the effects of this diuretic giving an enhanced antihypertensive effect. This may be due to the inhibition of renin release or concomitant regional haemodynamic changes. This means that a relatively lower dose of the beta-blocker is required.

Timolol maleate is well absorbed, extensively metabolised in the liver and eliminated through the kidney with a half-life of 2.5 to 5 hours (the biological half-life is somewhat longer). The beta-blocking effect of timolol is apparent within 30 minutes of administration and has been shown to last for up to 24 hours. It has low to moderate lipid solubility. Protein binding is reported to be low. It crosses the placenta and appears in breast milk.

Bendroflumethiazide has been reported to be completely absorbed from the gastro-intestinal tract and to have a plasma half-life of about 3 or 4 hours. It is highly bound to plasma protein. There is evidence that bendroflumethiazide is fairly extensively metabolised; about 30% is excreted unchanged in the urine. The diuretic effect of bendroflumethiazide is usually complete in 12-18 hours.

There are no pre-clinical data of relevance to the prescriber, which are additional to that already included in other sections of the SPC.

Microcrystalline cellulose, starch, magnesium stearate.

None known.

The shelf life of Prestim tablets is three years.

Store below 25°C.

Glass bottles of 30 tablets, 100 and 500 tablets.

Glass bottle of 14 tablets (sample pack).

Not all pack sizes may be marketed

No special requirements.

Meda Pharmaceuticals Ltd

Skyway House

Parsonage Road

Takeley

Bishop's Stortford

CM22 6PU

UK

PL 15142/0025

31 December 2000

24 November 2011