POM: Prescription only medicine
This information is intended for use by health professionals
Oedema of specific origin Ascites due to cirrhosis of the liver in stable patients under close control. Oedema due to nephrotic syndrome.Diabetes Insipidus.
HypertensionThe recommended starting dose is 25mg/day. This is sufficient to produce the maximum hypotensive effect in most patients. If the decrease in blood pressure proves inadequate with 25mg/day, then the dose can be increased to 50mg/day. If a further reduction in blood pressure is required, additional hypertensive therapy may be added to the dosage regime.
Stable, chronic heart failure (NYHA: functional class II /III):The recommended starting dose is 25 to 50mg/day, in severe cases it may be increased up to 100 to 200mg/day. The usual maintenance dose is the lowest effective dose, eg 25 to 50mg/day either daily or every other day. If the response proves inadequate, digitalis or an ACE inhibitor, or both, may be added. (See Section 4.4 Special warnings and precautions for use).
Oedema of specific origin (see Section 4.1 Therapeutic indications)The lowest effective dose is to be identified by titration and administered over limited periods only. It is recommended that doses should not exceed 50mg/day.
Diabetes insipidus:Initially 100mg twice daily but reducing where possible to a daily maintenance dose of 50mg.
Children:The lowest effective dose should also be used in children. For example, an initial dose of 0.5 to 1mg/kg/48hours and a maximum dose of 1.7mg/kg/48hours have been used.
Elderly patients and patients with renal impairment:The lowest effective dose of Hygroton/Chlortalidone is also recommended for patients with mild renal insufficiency and for elderly patients (see Section 5.2 Pharmacokinetic properties).In elderly patients, the elimination of chlortalidone is slower than in healthy young adults, although absorption is the same. Therefore, a reduction in the recommended adult dosage may be needed. Close medical observation is indicated when treating patients of advanced age with chlortalidone.Hygroton/Chlortalidone and the thiazide diuretics lose their diuretic effect when the creatinine clearance is <30ml/min.
Warnings: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.
Precautions:Electrolytes: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.
Metabolic effects: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.
Other effects: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.
Electrolytes and metabolic disorders: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.
Skin:Common: urticaria and other forms of skin rash. Rare: photosensitisation.
Liver:Rare: intrahepatic cholestasis or jaundice.
Cardiovascular system:Common: postural hypotension.Rare: cardiac arrhythmias.
Central nervous system:Common: Dizziness. Rare: paraesthesia, headache.
Gastro-intestinal tract:Common: loss of appetite and minor gastrointestinal distress.Rare: mild nausea and vomiting, gastric pain, constipation and diarrhoea.Very rare: pancreatitis.
Blood:Rare: Thrombocytopenia, leucopenia, agranulocytosis and eosinophilia.
Other effects:Common: impotenceRare: Idiosyncratic pulmonary oedema (respiratory disorders), allergic interstitial nephritis.
Absorption and plasma concentrationThe bioavailability of an oral dose of 50mg Hygroton/Chlortalidone is approximately 64%, peak blood concentrations being attained after 8 to 12 hours. For doses of 25 and 50mg, Cmax values average 1.5µg/ml (4.4µmol/L) and 3.2µg/ml (9.4µmol/L) respectively. For doses up to 100mg there is a proportional increase in AUC. On repeated daily doses of 50mg, mean steady-state blood concentrations of 7.2µg/ml (21.2µmol/L), measured at the end of the 24 hour dosage interval, are reached after 1 to 2 weeks.
DistributionIn blood, only a small fraction of chlortalidone is free, due to extensive accumulation in erythrocytes and binding to plasma proteins. Owing to the large degree of high affinity binding to the carbonic anhydrase of erythrocytes, only some 1.4% of the total amount of chlortalidone in whole blood was found in plasma at steady state during treatment with 50mg doses. In vitro, plasma protein binding of chlortalidone is about 76% and the major binding protein is albumin.Chlortalidone crosses the placental barrier and passes into the breast milk. In mothers treated with 50mg chlortalidone daily before and after delivery, chlortalidone levels in fetal whole blood are about 15% of those found in maternal blood. Chlortalidone concentrations in amniotic fluid and in the maternal milk are approximately 4% of the corresponding maternal blood level.
MetabolismMetabolism and hepatic excretion into bile constitute a minor pathway of elimination. Within 120 hours, about 70% of the dose is excreted in the urine and the faeces, mainly in unchanged form.
EliminationChlortalidone is eliminated from whole blood and plasma with an elimination half-life averaging 50 hours. The elimination half-life is unaltered after chronic administration. The major part of an absorbed dose of chlortalidone is excreted by the kidneys, with a mean renal clearance of 60ml/min.
Special patient groupsRenal dysfunction does not alter the pharmacokinetics of chlortalidone, the rate-limiting factor in the elimination of the drug from blood or plasma being most probably the affinity of the drug to the carbonic anhydrase of erythrocytes.No dosage adjustment is needed in patients with impaired renal function.In elderly patients, the elimination of chlortalidone is slower than in healthy young adults, although absorption is the same. Therefore, close medical observation is indicated when treating patients of advanced age with chlortalidone.