Source: Medicines & Healthcare Products Regulatory Agency (GB) Revision Year: 2014 Publisher: Alliance Pharmaceuticals Limited, Avonbridge House, Bath Road, Chippenham, Wiltshire, SN15 2BB
Known hypersensitivity to chlortalidone or any of the excipients. Anuria, severe hepatic or renal failure (creatinine clearance <30ml/min), hypersensitivity to chlortalidone and other sulphonamide derivatives, refractory hypokalaemia, hyponatraemia and hypercalcaemia, symptomatic hyperuricaemia (history of gout or uric acid calculi), hypertension during pregnancy, untreated Addison’s disease and concomitant lithium therapy.
Hygroton/Chlortalidone should be used with caution in patients with impaired hepatic function or progressive liver disease since minor changes in the fluid and electrolyte balance due to thiazide diuretics may precipitate hepatic coma, especially in patients with liver cirrhosis (see Section 4.3 “Contra-indications”).
Hygroton/Chlortalidone should also be used with caution in patients with severe renal disease. Thiazides may precipitate azotaemia in such patients, and the effects of repeated administration may be cumulative.
Treatment with thiazide diuretics has been associated with electrolyte disturbances such as hypokalaemia, hypomagnesaemia, hyperglycaemia and hyponatraemia. Since the excretion of electrolytes is increased, a very strict low-salt diet should be avoided.
Hypokalaemia can sensitise the heart or exaggerate its response to the toxic effects of digitalis.
Like all thiazide diuretics, kaluresis induced by Hygroton/Chlortalidone is dose dependent and varies in extent from one subject to another. With 25 to 50mg/day, the decrease in serum potassium concentrations averages 0.5mmol/l. Periodic serum electrolyte determinations should be carried out, particularly in digitalised patients.
If necessary, Hygroton/Chlortalidone may be combined with oral potassium supplements or a potassium-sparing diuretic (eg triamterene).
If hypokalaemia is accompanied by clinical signs (eg muscular weakness, paresis and ECG alteration), Hygroton/Chlortalidone should be discontinued.
Combined treatment consisting of Hygroton/Chlortalidone and a potassium salt or a potassium-sparing diuretic should be avoided in patients also receiving ACE inhibitors.
Monitoring of serum electrolytes is particularly indicated in the elderly, in patients with ascites due to liver cirrhosis, and in patients with oedema due to nephrotic syndrome. There have been isolated reports of hyponatraemia with neurological symptoms (eg nausea, debility, progressive disorientation and apathy) following thiazide treatment.
For nephrotic syndrome, Hygroton/Chlortalidone should be used only under close control in normokalaemic patients with no signs of volume depletion.
Hygroton/Chlortalidone may raise the serum uric acid level, but attacks of gout are uncommon during chronic treatment.
As with the use of other thiazide diuretics, glucose intolerance may occur; this is manifest as hyperglycaemia and glycosuria. Hygroton/Chlortalidone may very seldom aggravate or precipitate diabetes mellitus; this is usually reversible on stopping therapy.
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 a matter for debate.
Hygroton/Chlortalidone should not be used as a first-line drug for long-term treatment in patients with overt diabetes mellitus or in subjects receiving therapy for hypercholesterolaemia (diet or combined).
As with all antihypertensive agents, a cautious dosage schedule is indicated in patients with severe coronary or cerebral arteriosclerosis.
The antihypertensive effect of ACE inhibitors is potentiated by agents that increase plasma renin activity (diuretics). It is recommended that the diuretic be reduced in dosage or withdrawn for 2 to 3 days and/or that the ACE inhibitor therapy be started with a low initial dose of the ACE inhibitor. Patients should be monitored for several hours after the first dose.
Diuretics potentiate the action of curare derivatives and antihypertensive drugs (e.g. guanethidine, methyldopa, β-blockers, vasodilators, calcium antagonists and ACE inhibitors).
The hypokalaemic effect of diuretics may be potentiated by corticosteroids, ACTH, β2–agonists, amphotericin and carbenoxolone.
It may prove necessary to adjust the dosage of insulin and oral anti-diabetic agents.
Thiazide-induced hypokalaemia or hypomagnesaemia may favour the occurrence of digitalis-induced cardiac arrhythmias (see Section 4.4 “Special warnings and precautions for use”).
Concomitant administration of certain non-steroidal anti-inflammatory drugs (e.g. indometacin) may reduce the diuretic and antihypertensive activity of Hygroton/Chlortalidone; there have been isolated reports of a deterioration in renal function in predisposed patients.
The bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (eg atropine, biperiden), apparently due to a decrease in gastrointestinal motility and stomach-emptying rate.
Absorption of thiazide diuretics is impaired in the presence of anionic exchange resins such as colestyramine. A decrease in the pharmacological effect may be expected.
Concurrent administration of thiazide diuretics may increase the incidence of hypersensitivity reactions to allopurinol, increase the risk of adverse effects caused by amantadine, enhance the hyperglycaemic effect of diazoxide, and reduce renal excretion of cytotoxic agents (e.g. cyclophosphamide, methotrexate) and potentiate their myelosuppressive effects.
The pharmacological effects of both calcium salts and vitamin D may be increased to clinically significant levels if given with thiazide diuretics. The resultant hypercalcaemia is usually transient but may be persistent and symptomatic (weakness, fatigue, anorexia) in patients with hyperparathyroidism.
Concomitant treatment with cyclosporin may increase the risk of hyperuricaemia and gout-type complications.
Thiazide and related diuretics can cause a rapid rise in serum lithium levels as the renal clearance of lithium is reduced by these compounds.
Diuretics are best avoided for the management of oedema or hypertension in pregnancy as their use may be associated with hypovolaemia, increased blood viscosity and reduced placental perfusion. There have been reports of foetal bone marrow depression, thrombocytopenia, and foetal and neonatal jaundice associated with the use of thiazide diuretics.
Chlortalidone passes into the breast milk; mothers taking Hygroton/Chlortalidone should refrain from breast-feeding their infants.
Patients should be warned of the potential hazards of driving or operating machinery if they experience side effects such as dizziness.
Frequency estimate: very rare <0.01%, rare ≤0.01% to ≤0.1%;uncommon ≤0.1% to <1%; common ≤1% to <10%; very common ≥10%.
Very common: mainly at higher doses, hypokalaemia, hyperuricaemia, and rise in blood lipids.
Common: hyponatraemia, hypomagnesaemia and hyperglycaemia.
Uncommon: gout.
Rare: hypercalcaemia, glycosuria, worsening of diabetic metabolic state.
Very rare: hypochloraemic alkalosis.
Common: urticaria and other forms of skin rash.
Rare: photosensitisation.
Rare: intrahepatic cholestasis or jaundice.
Common: postural hypotension.
Rare: cardiac arrhythmias.
Common: Dizziness.
Rare: paraesthesia, headache.
Common: loss of appetite and minor gastrointestinal distress.
Rare: mild nausea and vomiting, gastric pain, constipation and diarrhoea.
Very rare: pancreatitis.
Rare: Thrombocytopenia, leucopenia, agranulocytosis and eosinophilia.
Common: impotence
Rare: Idiosyncratic pulmonary oedema (respiratory disorders), allergic interstitial nephritis.
None known.
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