Informations for option: Pindolol/Clopamide 10mg/5mg Tablets, show other option

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1. Pindolol/Clopamide 10mg/5mg Tablets
2. Pindolol/Clopamide 10mg/5mg Tablets

SUMMARY OF PRODUCT CHARACTERISTICS

1    NAME OF THE MEDICINAL PRODUCT

Viskaldix 10mg/5mg Tablets Pindolol/Clopamide 10mg/5mg Tablets

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 10 mg pindolol and 5 mg clopamide.

Excipients with known effect:

Lactose (98 mg/tablet)

For the full list of excipients, see section 6.1.

3    PHARMACEUTICAL FORM

Tablet.

White, uncoated, round, flat, bevelled tablets, marked VISKALDIX on one side and with a score line on the other.

The score line is only to facilitate breaking for ease of swallowing and not to divide into equal doses.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Viskaldix Tablets are indicated in adults for the treatment of mild to moderate hypertension.

4.2    Posology and method of administration

Posology

One tablet daily in the morning. If blood pressure is not satisfactorily lowered after 2 to 3 weeks then two tablets daily as a single dose in the morning. Maximum dose of three tablets daily, if required.

Paediatric population

The safety and efficacy of Viskaldix Tablets in children has not been established.

Use in the elderly

There is no evidence that the dosage or tolerability of Viskaldix Tablets is directly affected by advanced age. However, because of the diuretic component, such patients should be carefully supervised as factors sometimes associated with aging, such as poor diet or impaired renal function may indirectly affect the dosage or tolerability.

Method of administration Oral.

4.3 Contraindications

Hypersensitivity to the active substances or to any of the excipients listed in section 6.1.

Pindolol:

•    Untreated cardiac failure

•    Cardiogenic shock, sick sinus syndrome

•    Sino-atrial block

•    Second and third degree heart block

•    Prinzmetals angina

•    History of bronchospasm and bronchial asthma (a warning stating “do not take this medicine if you have a history of wheezing or asthma” will appear on the label)

•    Untreated phaeochromocytoma

•    Peripheral circulatory disease

•    Pronounced bradycardia

•    Hypotension

•    Chronic obstructive pulmonary disease

•    History of cor pulmonale

•    Metabolic acidosis

•    Prolonged fasting

•    Severe renal failure

•    Use of anaesthetics with a negative inotropic effect

Owing to the danger of cardiac arrest, a calcium antagonist of the verapamil type must not be administered intravenously to the patient already receiving treatment with a beta-blocker.

Clopamide:

•    Severe renal or hepatic impairment

•    Anuria

•    Refractory hypokalaemia and conditions involving increased potassium loss, e.g. salt-losing nephropathies and pre-renal (cardiogenic) impairment of kidney function.

•    Hyponatraemia

•    Hypercalcaemia

•    Addison’s disease

•    Symptomatic hyperuricaemia

•    Concomitant treatment with lithium

•    Hypertension during pregnancy

4.4 Special warnings and precautions for use Pindolol:

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

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

As beta-blockers increase the AV conduction time, beta-blockers should only be given with caution to patients with first degree AV block.

If the patient develops increasing bradycardia less than 50-55 beats per minute at rest and the patient experiences symptoms related to bradycardia, the dosage should be reduced or gradually withdrawn.

As with all antihypertensive agents, a cautious dosage schedule is indicated in patients with severe coronary or cerebral arteriosclerosis.

As with all beta-blockers, Viskaldix Tablets should be used with caution in patients with a history of a recent myocardial infarction.

Patients with spontaneous hypoglycaemia or diabetes should be monitored closely as concomitant use of beta-blockers may intensify the blood sugar lowering effect of insulin and other antidiabetic drugs and also as thiazide diuretics can lower insulin tolerance. Use of beta-blockers may mask the symptoms of hypoglycaemia (tachycardia, tremor). Beta blockers may also mask the symptoms of thyrotoxicosis.

Beta-blockers may unmask myasthenia gravis.

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

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

Since beta-blockers may potentiate the negative-inotropic and dromotropic effects of calcium antagonists, like verapamil or diltiazem, any oral comedication (e.g. in angina pectoris) requires close clinical control (see also section 4.5).

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

Anaphylactic reactions precipitated by other agents may be particularly severe in patients taking beta-blockers, especially non-selective drugs, and may require higher than normal doses of adrenaline for treatment. Whenever possible, beta-blockers should be discontinued in patients who are at increased risk for anaphylaxis.

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 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.

In severe renal failure a further impairment of renal function following beta blockade has been reported in a few cases. In patients with renal impairment, the elimination half-life for unchanged pindolol is not expected to be significantly different from the subjects with normal renal function. Creatinine clearance, urea and electrolytes should be monitored in patients with renal impairment since they might be more susceptible to the effects of antihypertensive drugs.

Clopamide:

Electrolytes

All patients receiving thiazide therapy should be observed for clinical signs of fluid or electrolyte unbalance, namely dose dependent hyponatraemia, hypochloraemic alkalosis and hypokalaemia. Since the excretion of electrolytes is increased during thiazide treatment, an excessively strict low salt diet should be avoided.

Periodic serum electrolyte determinations should be carried out, especially in digitalised patients, in the elderly, especially in those suffering from chronic diseases, in patients with liver cirrhosis, who are more susceptible to regulatory disorders affecting the electrolytes and fluid balance, and in patients with oedema due to nephrotic syndrome.

Serum potassium concentrations should be checked initially and 3-4 weeks after the start of therapy. Unless the potassium balance is disturbed by other factors (e.g. vomiting, diarrhoea, change in renal function, malnutrition, liver cirrhosis, hyperaldosteronism, treatment with ACTH or corticosteroids) checks should be repeated every 4-6 months.

Hypokalaemia may be avoided or treated by the use of potassium supplements and/or foods with a high potassium content.

Oral potassium supplementation (e.g. KCl) may be considered in patients receiving digitalis and diuretics, particularly if their plasma potassium concentrations are <3.0mmol/L. If oral potassium supplementation is not well tolerated, Viskaldix Tablets may be combined with a potassium sparing diuretic e.g. amiloride.

Combined treatment consisting of Viskaldix Tablets and a potassium salt or a potassium-sparing diuretic must be avoided in patients also receiving ACE inhibitors.

If hypokalaemia is accompanied by clinical signs (e.g. muscular weakness, paresis, or ECG changes), Viskaldix Tablets should be discontinued.

During treatment with thiazides, hyponatraemia accompanied by neurological symptoms (nausea, asthenia, progressive disorientation, apathy) has been observed in isolated cases.

Patients receiving relatively high doses of thiazides may develop hypomagnesaemia accompanied by signs and symptoms such as irritability, muscle cramps, and cardiac arrhythmias.

Metabolic effects

Like other diuretics, thiazides may raise serum uric acid levels, but attacks of gout are rarely observed during chronic treatment.

Small and partly reversible increases in plasma concentrations of total cholesterol, triglycerides, or low-density lipoprotein cholesterol were reported in patients during long-term treatment with thiazides and thiazide-like diuretics. The clinical relevance of these findings is not clear.

Calcium excretion is decreased by thiazides. Pathological changes in the parathyroid gland associated with hypercalcaemia and hypophosphataemia have been observed in a few patients on prolonged thiazide therapy. If hypercalcaemia occurs, further diagnostic clarification is necessary. The usual complications of hyperparathyroidism, e.g. renal lithiasis, bone resorption, and peptic ulceration, have not been observed.

Others

Lupus erythematosus may become activated under treatment with thiazides. Viskaldix Tablets contain lactose.

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

The antihypertensive effect of Viskaldix Tablets is enhanced by concomitant treatment with other antihypertensives.

In addition, the following interactions may occur with the individual components.

Pindolol:

Calcium-channel blocking agents: Viskaldix Tablets should not be used with calcium-channel blockers with negative inotropic effects e.g. verapamil and to a lesser extent diltiazem. 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-blockers 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. Use of beta-blockers may prevent appearance of the signs of hypoglycaemia (tachycardia). During concurrent therapy with antidiabetics a close watch should therefore be kept on carbohydrate metabolism, and the dosage of hypoglycaemic medication may have to be readjusted.

Cimetidine, hydralazine and alcohol may induce increased plasma level of beta-blockers.

Concomitant administration with beta-blockers may enhance the vasoconstrictive action of ergot alkaloids.

Non-steroidal anti-inflammatory drugs (NSAIDs), such as indomethacin, may decrease the hypotensive effects of beta-blockers, and there have been isolated reports of a deterioration in renal function in predisposed patients.

Sympathomimetics with beta-adrenergic stimulant activity and xanthines such as adrenaline, noradrenaline, isoprenaline, ephedrine and phenylephrine (e.g. local anaesthetics in dentistry, nasal and ocular drops: 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, rifampicin and phenothiazines as well as other anti-hypertensive agents may increase the blood pressure lowering effect.

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

Beta-blockers and certain anaesthetics (e.g. halothane) are additive in their cardiodepressant effect. However, continuation of beta-blockers reduces the risk of arrhythmia and hypertension during anaesthesia (see section 4.4).

Fluoxetine can increase pindolol levels.

Antimalarials such as mefloquine can cause arrhythmias and caution is necessary if used with beta-blockers.

Excessive caffeine and nicotine intake may oppose the beneficial effects of pindolol.

Concomitant administration of sulfinpyrazone with pindolol may reduce or abolish its antihyperntensive effect.

Clopamide:

Viskaldix Tablets should not be used during concomitant administration of lithium, or by patients with known hypersensitivity to sulphonamides.

Thiazides potentiate the action of curare derivatives and antihypertensive drugs (e.g. methyldopa, beta-blockers, vasodilators, ACE inhibitors).

Potassium lowering drugs (such as corticosteroids, ACTH, amphotericin B, carbenoxolone) may increase the hypokalaemic effect of thiazides.

Co-administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol.

Co-administration of thiazide diuretics may increase the risk of adverse effects caused by amantadine.

Concomitant use of thiazide diuretics may reduce renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.

The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. atropine, biperiden), apparently owing to a decrease in gastrointestinal motility and stomach-emptying rate.

Absorption of thiazide diuretics is decreased by cholestyramine. A decrease in the pharmacological effect of thiazides may be expected.

Thiazide diuretics may reduce urinary calcium excretion caused by vitamin D, while vitamin D may potentiate the increase in serum calcium caused by thiazides.

Concomitant use of thiazide-type diuretics and cyclosporin may increase the risk of hyperuricaemia and gout-type complications.

Concomitant use of thiazide-type diuretics and calcium salts may cause hypercalcaemia by increasing tubular calcium reabsorption.

Thiazide diuretics may enhance the hyperglycaemic effect of diazoxide.

There have been reports in the literature of haemolytic anaemia occurring when a thiazide diuretic and methyldopa were administered concomitantly.

4.6 Fertility, pregnancy and lactation

Pregnancy

Viskaldix is contraindicated in pregnancy.

Breast-feeding

Viskaldix Tablets may suppress lactation. Breastfeeding is therefore not recommended following administration.

4.7 Effects on ability to drive and use machines

Because dizziness or fatigue may occur during initiation of treatment with antihypertensive drugs, patients driving vehicles or operating machinery should exercise caution until their individual reaction to treatment has been determined.

4.8 Undesirable effects

Blood and lymphatic system disorders

Thrombocytopenia (sometimes with purpura), agranulocytosis, neutropenia Metabolism and nutrition disorders

Diabetes mellitus, hypoglycaemia, hyperglycaemia, hypokalaemia, hypomagnesaemia, hyponatraemia, hypercalcaemia, hyperchloraemia, hyperuricaemia, gout

Psychiatric disorders

Hallucination, acute psychosis, sleep disorder, depression, nightmare, confusional state, libido disorder

Nervous system disorders Headache, dizziness, tremor

Eye disorders

Visual impairment, vision blurred, keratoconjunctivitis, dry eyes Cardiac disorders

Bradycardia, complete atrioventricular block, cardiac failure, cardiac arrhythmia

Vascular disorders

Hypotension, orthostatic hypotension, peripheral coldness, Raynaud’s phenomenon, paraesthesia, intermittent claudication, necrotising vasculitis

Respiratory, thoracic and mediastinal disorders

Bronchospasm (in patients with bronchial asthma or a history of bronchial complaints), dyspnoea, pneumonitis, pulmonary oedema

Gastrointestinal disorders

Diarrhoea, nausea, vomiting, constipation, dry mouth, sclerosing peritonitis, retroperitoneal fibrosis, abdominal discomfort, dyspepsia, flatulence, pancreatitis

Musculoskeletal and connective tissue disorders Muscle spasms, arthralgia, myalgia, myasthenia gravis

Hepatobiliary disorders Cholestasis

Skin and subcutaneous tissue disorders

Rash, psoriasis, toxic epidermal necrolysis, cutaneous lupus erythematosus, pruritus, hyperhidrosis, photosensitivity

Reproductive system and breast disorders

Erectile dysfunction and impotence (reversible on withdrawal of treatment)

Renal and urinary disorders Glycosuria

General disorders and administration site conditions Fatigue, hyperpyrexia

Investigations

Increased antinuclear antibodies, increased blood cholesterol.

Chronic treatment with pindolol increases very low density lipoprotein and decreases high density lipoprotein, which may have an adverse effect on the risk of cardiovascular events.

Beta-blockers may mask the symptoms of thyrotoxicosis or hypoglycaemia. 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

Symptoms

Overdosage may cause alterations in heart rate, nausea, vomiting, orthostatic disturbances, collapse, hypokalaemia and its accompanying disorders.

Management

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

Plasma electrolytes should be closely monitored. Marked bradycardia, as a result of overdosage (or idiosyncrasy) should be treated with atropine sulphate 1-2mg i.v.

If necessary isoprenaline hydrochloride can be administered by slow i.v. under constant supervision beginning with 25mcg (5mcg/min) until desired effect is achieved. A cardiac pacemaker may be required. Intravenous glucagon (5 to 10mg) has been reported to overcome some of the features of serious overdosage.

5    PHARMACOLOGICAL PROPERTIES

5.1    Pharmacodynamic properties

Pharmacotherapeutic group: beta blocking agents, non-selective, and other diuretics.

ATC code: C07CA03 Mechanism of action

Viskaldix Tablets are a combination of pindolol and clopamide, both acting to lower blood pressure, although by two separate mechanisms.

Pharmacodynamic effects

Pindolol is a non-selective beta-adrenergic antagonist which blocks both B1 and B2 adrenoceptors for more than 24 hours following administration. It has negligible membrane stabilising activity. The intrinsic sympathomimetic activity (ISA) provides the heart with basal stimulation similar to that elicited by normal resting sympathetic activity. Thus, resting cardiac output and heart rate are not unduly depressed, subsequently reducing the risk of bradycardia.

Clopamide enhances the elimination of sodium and chloride by inhibiting their reabsorption in the renal tubules which, in turn, leads to increased water excretion. The mechanistic relationship to the diuretic action and reduced blood pressure is not fully understood, however the diuretic effect is proportional to the dosage. Diuresis is initiated after about 2 hours and can last for up to 24 hours with maximal effect after 3 to 6 hours.

Clinical efficacy and safety

This combination can produce a clear antihypertensive effect after a few days, but, in some cases, to achieve the full effect, two to three weeks treatment may be necessary.

5.2 Pharmacokinetic properties

Absorption

The pharmacokinetics of the two active ingredients are very similar and are not influenced by their combination or by being taken with food. Both components are rapidly and almost completely absorbed. They show negligible hepatic first-pass metabolism. Thus, the bioavailability of both is at least 85%.

Distribution

The maximum plasma concentration of pindolol is reached within one hour after ingestion, and that of clopamide, one or two hours after ingestion. Plasma protein binding is 40% for pindolol, and 46% for clopamide. The volume of distribution is about 2L/Kg for pindolol, and 1.5L/Kg for clopamide.

Elimination

The total body clearance of pindolol is 400ml/min that of clopamide is 165ml/min. The elimination half-life is 3-4 hours for pindolol, and 6 hours for clopamide. Approximately one third of the dose of both drugs is excreted unchanged in the urine. The excretion of clopamide occurs mainly via the kidneys, whereas pindolol shows a balanced excretion between the renal and hepatic routes.

5.3 Preclinical safety data

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

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Magnesium stearate, maize starch and lactose.

6.2 Incompatibilities

Not applicable.

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