PHARMACOLOGICAL CLASSIFICATION: A 7.1.3 Other hypotensives.
PHARMACOLOGICAL ACTION: ZIAK is a combination of two antihypertensive agents, bisoprolol and hydrochlorothiazide. Bisoprolol is a beta1-selective beta-adrenoceptor antagonist with low beta2-receptor affinity. It has no intrinsic sympathomimetic activity nor membrane-stabilising properties. It reduces blood pressure, and by blockade of the cardiac beta1-receptors, reduces the heart rate and depresses plasma renin levels.
Bisoprolol is rapidly absorbed after oral administration in man and excreted predominantly via the urine as unaltered substance and metabolites. In man, 50% of a dose is metabolised in the liver while the other 50% is eliminated unchanged via the kidneys. None of the metabolites have beta1-receptor blocking action.
The plasma elimination half-life is 10-12 hours, resulting in a duration of action of 24 hours. Because of its moderate hepatic metabolism, it is subject only to a very small hepatic first pass metabolism. Therefore, bisoprolol displays a high bioavailability of 90% after an oral dose. Hydrochlorothiazide is a benzothiadiazine diuretic. Thiazides inhibit sodium and chloride reabsorption in the kidney tubules and produce a corresponding increase in potassium excretion. It is readily absorbed from the gastro-intestinal tract. It is reported to have a bioavailability of about 65 to 70%; the plasma half-life is about 5 hours with a subsequent longer terminal phase; its biological half-life is up to about 15 hours. It is excreted unchanged in the urine.
INDICATIONS: ZIAK is indicated for the treatment of hypertension.
CONTRA-INDICATIONS: Hypersensitivity to any component of this product or other sulphonamide derived agent.
Uncontrolled cardiac failure excluding that due to hypertrophic obstructive cardiomyopathy.
Patients with metabolic acidosis and sinus bradycardia.
Patients suffering from second and third degree heart block.
Bisoprolol should be given with caution, when there is no alternative treatment, to patients with bronchospasm or asthma or to those with a history of obstructive airways disease.
Renal insufficiency (anuria, acute renal failure, severe progressive renal disease and diabetic nephropathy). Not to be used during pregnancy or lactation.
Safety and efficacy in children have not been established.
WARNINGS: If bisoprolol is to be withdrawn prior to surgery, at least 48 hours should be allowed to elapse between the last dose and anaesthesia. If bisoprolol treatment is to be continued during surgery, care should be taken when using anaesthetic agents such as ether, cyclopropane and trichloroethylene. Vagal dominance, if it occurs, may be corrected with atropine (1-2 mg i.v.).
In the perioperative period it is generally unwise to reduce the dosage to which the patient is accustomed, as there may be danger of aggravation of angina pectoris or of hypertension.
A patients normal tachycardiac response to hypovolaemia or blood loss may be obscured during or after surgery. Particular caution should be taken in this regard.
In patients suffering from ischaemic heart disease, treatment should not be discontinued abruptly.
Caution should be taken in prescribing bisoprolol with Class 1 antidysrhythmic agents such as disopyramide, myocardial depressants, and inhibitors of AV conduction such as calcium antagonists.
Use with caution in combination with verapamil in patients with impaired ventricular function. This combination should not be given to patients with conduction abnormalities. Nether drug should be administered intravenously within 48 hours of discontinuing the other.
The intravenous administration of calcium antagonists and antiarrhythmic agents is not recommended during bisoprolol therapy.
Caution should be exercised when transferring a patient from clonidine. The withdrawal of clonidine may result in the release of large amounts of catecholamines, which may give rise to a hypertensive crisis. If beta-blockers are administered in these circumstances, the unopposed alpha receptor stimulation may potentiate this effect. If a beta-blocker and clonidine are given concurrently, the clonidine should not be discontinued until several days after the withdrawal of the beta-blocker, as severe rebound hypertension may occur.
Bisoprolol modifies the tachycardia of hypoglycaemia. The dosage of bisoprolol should be adjusted in cases of severe renal impairment.
Pregnancy: Administration to pregnant mothers shortly before giving birth or during labour may result in the newborn infant being born hypotonic, collapsed or hypoglycaemic.
DOSAGE AND DIRECTIONS FOR USE: Antihypertensive therapy may be initiated with the lowest dose of ZIAK, one 2,5 mg/6,25 mg tablet once daily. Subsequent dose adjustment may be carried out with ZIAK tablets up to the maximum recommended dose of one 10 mg/6,25 mg tablet once daily, as appropriate.
Dosage adjustment on the basis of age is not usually necessary, unless there is also significant renal or hepatic dysfunction.
There is no paediatric experience with ZIAK.
If withdrawal of ZIAK therapy is planned, it should be achieved gradually over a period of about 2 weeks. Patients should be carefully observed.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Bisoprolol: Among the most serious adverse effects are heart failure, heart block and bronchospasm.
Troublesome subjective side-effects include fatigue and coldness of the extremities.
Cardiovascular effects include bradycardia and hypotension; congestive heart failure or heart block may be precipitated in patients with underlying cardiac disorders.
Central nervous system effects include depression, hallucinations, confusion and sleep disturbances.
Fatigue is a common side-effect experienced with beta blockers. Paraesthesia, peripheral neuropathy and myopathies have been reported.
Adverse gastro-intestinal effects include nausea and vomiting, diarrhoea, constipation and abdominal cramping.
Skin rash, pruritus and reversible alopecia have occurred with use of beta blockers.
Haematological reactions include nonthrombocytopenic purpura, thrombocytopenia and rarely agranulocytosis. Transient eosinophilia can occur.
Hydrochlorothiazide: Thiazide diuretics may cause a number of metabolic disturbances. They may provoke hyperglycaemia and glycosuria in diabetic and other susceptible patients. They may cause hyperuricaemia and precipitate attacks of gout in some patients. Administration of thiazide diuretics may be associated with electrolyte imbalances including hypochloraemic alkalosis, hyponatraemia and hypokalaemia. Signs of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain and cramps, seizures, oliguria and gastro-intestinal disturbances.
Other side-effects include anorexia, gastric irritation, nausea, vomiting, constipation, diarrhoea, headache, dizziness, photosensitivity reactions, postural hypotension, paraesthesia, impotence and yellow vision.
Hypersensitivity reactions include skin rashes, pulmonary oedema and pneumonitis.
Bisoprolol: Abrupt discontinuation of therapy may cause exacerbation of angina pectoris in patients suffering from ischaemic heart disease. Discontinuation of therapy should be gradual and patients should be advised to limit the extent of their physical activity during the period in which the medicine is being discontinued. Bronchoconstriction may occur in patients suffering from asthma, bronchitis and other chronic pulmonary diseases. Since bisoprolol is a selective beta1 adrenoceptor blocking agent, it may be used with caution in patients with chronic obstructive airway disease. However, in some asthmatic patients, an increase in airway resistance may occur. Congestive cardiac failure and marked bradycardia may occur.
Bisoprolol may mask the symptoms of hyperthyroidism.
It should be used with caution in patients with hypoglycaemia.
Hydrochlorothiazide: Thiazide diuretics should be used with caution in patients with impaired hepatic function since they may increase the risk of hepatic encephalopathy. They should also be given with caution in renal impairment since they can further reduce renal function.
Bisoprolol: It can be dangerous to administer bisoprolol concomitantly with the following medicines:
Hypoglycaemic agents, phenothiazines and various antiarrhythmic agents. N.B. - Such medicine interactions can have life-threatening consequences. It may enhance the effects of hypoglycaemic agents in patients with diabetes mellitus as well as the effects of myocardial depressants such as lignocaine, procainamide and quinidine.
The effects may be antagonised by beta-adrenoceptor stimulating agents (e.g. isoprenaline). The hypotensive effects may be dangerously reversed by alpha-adrenoceptor stimulants. The vasoconstrictor effects may be dangerously enhanced by alpha-adrenoceptor stimulates. The effects may be enhanced by adrenergic neurone blocking agents such as guanethidine and reserpine. The anaesthetist should be informed of bisoprolol therapy prior to any operation.
The half-life of bisoprolol can be slightly shortened by the simultaneous administration of rifampicin. An increase in the dose is generally unnecessary.
The pharmacokinetics of bisoprolol are not significantly influenced by cimetidine.
Hydrochlorothiazide: Thiazide diuretics can enhance the hypotensive effects of antihypertensive agents and central nervous system depressants. They may enhance the effects of neuromuscular blocking agents and diminish those of pressor amines. The hypokalaemic effect may increase the toxicity of digitalis glycosides and may be enhanced by administration of corticosteroids, corticotrophin or carbenoxolone. Thiazide diuretics may alter the requirements for hypoglycaemic agents in diabetic patients.
Symptomatic hyponatraemia has been reported associated with concomitant use with carbamazepine.
Severe hyponatraemia has been reported in patients taking trimethoprim with hydrochlorothiazide.
Patients who are stabilised on lithium therapy and been taking thiazide diuretics are at significant risk of developing lithium toxicity.
Antagonism has been reported of the diuretic actions of thiazides by non-steroidal anti-inflammatory drugs.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: Overdosage may produce bradycardia and severe hypotension. Bronchospasm and heart failure may be produced in certain individuals.
Bradycardia associated with severe hypotension should be treated with intravenous atropine (1-2 mg). If necessary, this should be followed up by a slow intravenous infusion of 25 micrograms isoprenaline. Bronchospasm should be treated with intravenous aminophylline and heart failure with digitalis and diuretics.
In massive overdosage with hydrochlorothiazide hypokalaemia may be treated by administration of potassium. Other treatment should be symptomatic and directed at fluid and electrolyte replacement.
IDENTIFICATION: ZIAK 2,5 mg/6,25 mg: Round, yellow biconvex film-coated tablets engraved with a script "LL" within an engraved heart shape on one side and "B" above "12" on the other side.
ZIAK 5 mg/6,25 mg: Round, pink, biconvex film-coated tablets engraved with a script "LL" within an engraved heart shape on one side and "B" above "13" on the other side.
ZIAK 10 mg/6,25 mg: Round, white, biconvex film-coated tablets engraved with a script "LL" within an engraved heart shape on one side and "B" above "14" on the other side.
PRESENTATION: 30 tablets packed in white HDPE containers with white PP caps.
Blister packs of 30 tablets.
STORAGE INSTRUCTIONS: Store below 30°C.
KEEP OUT OF REACH OF CHILDREN