SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Pindolol Tablets 5mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains pindolol 5 mg

For the full list of excipients see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White, flat bevelled edged tablet, marked “PL” breakline “5” on one side of the tablet and “G” on the reverse.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Essential hypertension: For reduction of blood pressure in essential hypertension. Onset of action of Pindolol is usually rapid, most patients showing a response within the first one to two weeks of treatment. However, maximum response may take several weeks to develop.

Prophylactic treatment of angina pectoris: Prophylactic treatment with Pindolol reduces the frequency and severity of anginal attacks and increases work capacity.

4.2    Posology and method of administration

Posology

Adults:

Hypertension: Initially one 5 mg tablet two or three times a day. According to the response of the patient the dose may be increased at weekly intervals to a maximum of 45 mg given in divided doses twice or three times daily.

Once daily dosage schedule: Further work shows that many patients respond to a once daily dosage regime. Initially 15 mg (3 tablets) should be taken once a day with breakfast and adjusted according to individual response up to a maximum of 45 mg (9 tablets). Most patients respond to a once daily dose of between 15-30 mg (3-6 tablets).

Patients not responding after three to four weeks at this dosage level rarely benefit from further elevations in dosage. Addition of Pindolol to existing diuretic therapy increases the hypotensive effect and combination with other antihypertensives enables reduction in dosage of these agents.

Angina Pectoris: Usually 2.5 mg or 5 mg of Pindolol up to three times a day according to response.

Elderly patients: No evidence exists that elderly patients require different dosages or show different side-effects from younger patients.

Paediatric population: Experience with pindolol in children is limited. Pindolol tablets are therefore not recommended for use in children.

Method of administration For oral administration only.

4.3 Contraindications

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1, untreated cardiac failure, atrioventricular block, cardiogenic shock, pronounced bradycardia, second and third degree heart block, obstructive pulmonary disease, bronchial asthma and history of bronchospasm, history of cor pulmonale, metabolic acidosis, prolonged fasting, severe renal failure, sick sinus syndrome, Prinzmetals angina, untreated phaeochromocytoma, speripheral circulatory disturbances. Pindolol should not be taken in conjunction with agents which inhibit calcium transport e.g. verapamil.

4.4 Special warnings and precautions for use

Patients with a poor cardiac reserve should be stabilised with digitalis before treatment with pindolol to prevent impairment of myocardial contractility.

As for other beta blockers, and especially in patients with ischaemic heart disease, therapy should not be discontinued suddenly. The dosage should gradually be reduced, i.e. over 1-2 weeks, if necessary at the same time initiating replacement therapy, to prevent exacerbation of angina pectoris.

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

As with all beta-blockers, pindolol should be used with caution in patients with a history of bronchial asthma, non-asthmatic chronic obstructive lung disease or recent myocardial infarction. Caution must be exercised when beta-blocking agents are administered to patients with spontaneous hypoglycaemia or diabetes under treatment with insulin or oral hypoglycaemic agents, since hypoglycaemia may occur during prolonged fasting and some of its symptoms (tachycardia, tremor) may be masked. Beta-blockers may also mask the symptoms of thyrotoxicosis.

During treatment with pindolol, patients should not undergo anaesthesia with agents causing myocardial depression (e.g. halothane, cyclopropane, trichloroethylene, ether, chloroform). Pindolol should be gradually withdrawn before elective surgery. In emergency surgery or cases where withdrawal of pindolol would cause deterioration in cardiac condition, atropine sulphate 1 to 2 mg intravenously should be given to prevent severe bradycardia.

If a beta-blocker is indicated in a patient with a phaeochromocytoma it must always be given in conjunction with an alpha-blocker. Pre-existing peripheral vascular disorders may be aggravated by beta-blockers.

In severe renal failure a further impairment of renal function following beta blockade has been reported in a few cases.

There have been reports of skin rashes and/or dry eyes associated with the use of beta-adrenoceptor blocking drugs. The reported incidence is small and in most cases the symptoms have cleared when treatment is withdrawn. Discontinuance of the drug should be considered if any such reaction is not otherwise explicable.

Cessation of therapy with a beta-blocker should be gradual.

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

The label will state ‘do not use this medicine if you have a history of wheezing or asthma’.

4.5 Interaction with other medicinal products and other forms of interaction

During treatment with pindolol patients should not undergo anaesthesia with agents causing myocardial depression (e.g. halothane, cyclopropane, trichlorethylene, ether, chloroform). Pindolol should be gradually withdrawn before elective surgery. In emergency surgery or cases where withdrawal of pindolol would cause deterioration in cardiac condition, atropine sulphate 1 to 2 mg intravenously should be given to prevent severe bradycardia.

Calcium-channel blocking agents: pindolol should not be used with calcium-channel blockers with negative inotropic effects e.g. verapamil and to a lesser extent diltiazem as combined use can lead to an exaggeration of their effects, particularly in patients with impaired ventricular function and/or sino-atrial or atrio-ventricular abnormalities. This may result in severe hypotension, bradycardia and cardiac failure. The concomitant use of oral beta-blockers and calcium antagonists of the dihydropyridine type can be useful in hypertension or angina pectoris. However, because of their potential effect on the cardiac conduction system and contractility, the i.v. route must be avoided. The concomitant use with dihydropyridines e.g. nifedipine may increase the risk of hypotension. In patients with cardiac insufficiency, treatment with betablocking agents may lead to cardiac failure.

Use of digitalis glycosides, in association with beta-adrenoceptor blocking drugs, may increase atrio-ventricular conduction time.

Clonidine: when therapy is discontinued in patients receiving a beta-blocker and clonidine concurrently, the beta-blockers should be gradually discontinued several days before clonidine is discontinued, in order to reduce the potential risk of a clonidine withdrawal hypertensive crisis.

MAO inhibitors: concurrent use with beta-blockers is not recommended. Possibly significant hypertension may theoretically occur up to 14 days following discontinuation of the MAO inhibitor.

Caution should be exercised in the concurrent use of beta-blocking agents with class 1 antiarrhythmics (e.g. disopyramide, quinidine) and amiodarone.

Concomitant use of beta-blockers may intensify the blood sugar lowering effect of insulin and other antidiabetic drugs since hypoglycaemia may occur during prolonged fasting. Use of beta-blockers may prevent appearance of the signs of hypocalcaemia (tachycardia).

Cimetidine, hydralazine and alcohol may induce increased plasma levels of hepatically metabolised beta-blockers.

Prostaglandin synthetase inhibiting drugs (e.g. Non-steroidal antiinflammatory drugs - NSAIDs) may decrease the hypotensive effects of beta-blockers.

Sympathomimetics with beta-adrenergic stimulant activity and xanthines: concurrent use with beta-blockers may result in mutual inhibition of therapeutic effects; in addition, beta-blockers may decrease theophylline clearance.

Concomitant use of beta-blockers with tricyclic antidepressants, barbiturates and phenothiazines as well as other antihypertensive agents may increase the blood pressure lowering effect.

Reserpine: concurrent use may result in an additive and possibly excessive beta-adrenergic blockade.

4.6 Pregnancy and lactation

Pregnancy

Pindolol is contraindicated in pregnancy.

Breast-feeding

Pindolol passes in small quantities into breast milk Breast-feeding is therefore not recommended following administration.

4.7 Effects on ability to drive and use machines

Because dizziness or fatigue may occur during the initial phase of treatment with beta-adrenoceptor blocking drugs, patients driving vehicles or operating machinery should exercise caution until their individual response to treatment has been determined.

4.8 Undesirable effects

The following undesirable effects have been observed with the following frequencies: not known (frequency cannot be estimated from the available data).

Metabolism and nutrition disorders
Not known	Beta-blockers may mask the signs of thyrotoxicosis or hypoglycaemia.
Psychiatric disorders
Not known	Hallucinations, psychoses, sleep disturbances, insomnia, depression, nightmares.
Nervous system disorders
Not known	Fatigue, headaches, paraesthesia of the extremities, dizziness, confusion, tremor
Eye disorders
Not known	Impaired vision, dry eyes.
Cardiac disorders
Not known	Bradycardia, a slowed AV-conduction or increase of an existing AV-block, hypotension, heart failure, cold and cyanotic extremities, Raynaud's phenomenon, increase of an existing intermittent claudication.
Respiratory, thoracic and mediastinal disorders
Not known	Bronchospasm in patients with bronchial asthma or a history of asthmatic complaints.
Gastrointestinal disorders
Not known	Gastrointestinal disturbances (including epigastric pain, diarrhoea, nausea and vomiting).
Musculoskeletal and connective tissue disorders
Not known	Muscle cramps.
Skin and subcutaneous tissue c	isorders
Not known	Disorders of the skin including allergic skin reactions, especially rashes.
Reproductive system and breast disorders
Not known	Impotence.
Investigations

Depression, diarrhoea, nausea, insomnia, headaches, sleep disturbance, epigastric pain, fatigue, dizziness, muscle cramps, tremors, hypotension are usually transient and disappear if dosage is reduced.

The reported incidence of skin rashes and/or dry eyes associated with the use of beta-adrenoceptor blocking drugs 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 a beta-blocker should be gradual.

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, website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Management

Treat by elimination of any unabsorbed drug and general supportive measures.

Marked bradycardia as a result of overdosage or idiosyncrasy should be treated with atropine sulphate 1 to 2 mg intravenously. If necessary, isoprenaline hydrochloride can be administered by a slow intravenous injection under constant supervision, beginning with 25 ^g (5 ^g/min) until the desired effect is achieved. A cardiac pacemaker may be required; i.v. glucagon (5 to 10 mg) has been reported to overcome some of the features of serious overdosage and may be useful.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: beta-adrenergic blocking agents; beta blockers ATC code: C07AA03

Mechanism of action

Pindolol is a potent beta-adrenoceptor antagonist (beta-blocker) with uses similar to those of propranolol. It is classified as non cardioselective. It blocks both B1- and B2-adrenoceptors for more than 24 hours after administration. It has negligible membrane-stabilising activity. Pindolol exhibits low cardiodepressant activity at therapeutic dose. As a beta-blocker, pindolol protects the heart from beta-adrenoceptor stimulation by acetecholamines during physical exercise and mental stress, prevents excessive sympathetic drive to the heart, resulting in a fall in heart rate and a decrease in cardiac work and myocardial oxygen consumption and also reduces the sympathetic drive to the heart at rest. Its intrinsic sympathomimetic

activity (ISA) even at low dosage, provides the heart with basal stimulation similar to that elicited by normal resting sympathetic activity, with the result that heart rate and contractility at rest and intracardiac conduction are not unduly depressed. The risk of bradycardia is therefore small and normal cardiac output is not reduced.

Pindolol is a beta-blocker with clinically relevant vasodilator activity. This results from the ISA exerted on B2-adrenoceptors in blood vessels. The high vascular resistance of established hypertension is lowered by pindolol; tissue and organ perfusion is not impaired, and may even be improved.

5.2 Pharmacokinetic properties

Absorption:

The rapid, nearly complete absorption ( >95%) and the negligible hepatic first-pass effect (13%) of pindolol result in a high bioavailability (87%). Maximum plasma concentration is reached within one hour after oral administration.

Distribution:

Pindolol has a plasma protein binding of 40%, a volume of distribution of 2-3 l/Kg and a total clearance of 500 ml/min.

Elimination:

The elimination half-life of pindolol is 3-4 hours. 30-40% is excreted unchanged in the urine, while 60-70% is excreted via kidney and liver as inactive metabolites. Pindolol crosses the placental barrier and passes in small quantities into breast milk.

Renal and hepatic impairment:

Patients with impaired kidney or liver function may usually be treated with normal doses. Only in severe cases may a reduction of the daily dose be necessary.

5.3. Preclinical safety data

There are no additional preclinical data of relevance to the prescriber.

6 PHARMACEUTICAL PARTICULARS

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Cellulose, microcrystalline Starch, pregelatinised Magnesium stearate Colloidal silicon dioxide.

Incompatibilities

Not applicable.

6.3    Shelf life

3 years.

6.4    Special precautions for storage

Store below 25°C. Store in the original package in order to protect from light.

6.5    Nature and contents of container

Polypropylene containers with polyethylene caps (with optional use of polyethylene ullage filler) and PVC/ aluminium foil blister packs containing 5, 7, 10, 14, 15, 20, 21, 25, 28, 30, 56, 60, 84, 90, 100, 112, 120, 168, 180, 250, 500 and 1000 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

No special requirements for disposal.

7    MARKETING AUTHORISATION HOLDER

Generics [UK] Limited T/A Mylan Station Close Potters Bar Hertfordshire EN6 1TL