Data Sheet
Hygroton
Chlorthalidone 25 mg tablets
Presentation
Hygroton 25 mg tablets are speckled pale orange, round, approximately 7.1 mm diameter, flat tablets with bevelled edges. The tablets are imprinted CG on one side and C score line W on the other side. Each tablets contains 25 mg of chlorthalidone.
Uses
Actions
Chlorthalidone is a benzothiadiazine (thiazide)-related diuretic with a long duration of action.
Thiazide and thiazide-like diuretics act primarily on the distal renal tubule (early convoluted part), inhibiting NaCl- reabsorption (by antagonising the Na+-Cl- cotransporter) and promoting Ca++ reabsorption (by an unknown mechanism). The enhanced delivery of Na+ and water to the cortical collecting tubule and/or the increased flow rate leads to increased secretion and excretion of K+ and H+.
In persons with normal renal function, diuresis is induced after the administration of 12.5 mg Hygroton. The resulting increase in urinary excretion of sodium and chloride and the less prominent increase in urinary potassium are dose dependent and occur both in normal and in oedematous patients. The diuretic effect sets in after 2-3 hours, reaches its maximum after 4-24 hours, and may persist for 2-3 days.
Thiazide-induced diuresis initially leads to decreases in plasma volume, cardiac output, and systemic blood pressure. The renin-angiotensin-aldosterone system may possibly become activated.
In hypertensive individuals, chlorthalidone gently reduces blood pressure. On continued administration, the hypotensive effect is maintained, probably due to the fall in peripheral resistance; cardiac output returns to pretreatment values, plasma volume remains somewhat reduced and plasma renin activity may be elevated.
On chronic administration, the antihypertensive effect of Hygroton is dose dependent between 12.5 and 50 mg/day. Raising the dose above 50 mg increases metabolic complications and is rarely of therapeutic benefit.
As with other diuretics, when Hygroton is given as monotherapy, blood pressure control is achieved in about half of patients with mild to moderate hypertension. In general, elderly and black patients are found to respond well to diuretics given as primary therapy. Randomised clinical trials in the elderly have shown that treatment of hypertension or predominant systolic hypertension in older persons with low-dose thiazide diuretics, including chlorthalidone, reduces cerebrovascular (stroke), coronary heart and total cardiovascular morbidity and mortality.
Combined treatment with other antihypertensives potentiates the blood-pressure-lowering effects. In a large proportion of patients failing to respond adequately to monotherapy, a further decrease in blood pressure can thus be achieved.
Because thiazide diuretics including Hygroton reduce Ca++ excretion, they have been used to prevent the formation of recurrent renal calcium oxalate stones. In addition, bone loss in elderly women was reduced.
Thiazide diuretics have been found to be useful in nephrogenic diabetes insipidus. The mechanism of action has not been elucidated.
Pharmacokinetics
Absorption and plasma concentration
The bioavailability of an oral dose of 50 mg Hygroton is approximately 64%, peak blood concentrations being attained after 8-12 hours. For doses of 25 and 50 mg, Cmax values average 1.5 µg/mL (4.4 µmol/L) and 3.2 µg/mL (9.4 µmol/L) respectively. For doses up to 100 mg there is a proportional increase in AUC. On repeated daily doses of 50 mg, mean steady-state blood concentrations of 7.2 µg/mL (21.2 µmol/L), measured at the end of the 24-hour dosage interval, are reached after 1-2 weeks.
Distribution
In blood, only a small fraction of chlorthalidone 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 chlorthalidone in whole blood was found in plasma at steady state during treatment with 50 mg doses. In vitro, plasma protein binding of chlorthalidone is about 76%, and the major binding protein is albumin.
Chlorthalidone crosses the placental barrier and passes into the breast milk. In mothers treated with 50 mg chlorthalidone daily before and after delivery, chlorthalidone levels in fetal whole blood are about 15% of those found in maternal blood. Chlorthalidone concentrations in amniotic fluid and in the maternal milk are approximately 4% of the corresponding maternal blood level.
Metabolism
Metabolism 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 in the faeces, mainly in unchanged form.
Elimination
Chlorthalidone 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 chlorthalidone is excreted by the kidneys, with a mean renal plasma clearance of 60 mL/min.
Special patient groups
Renal dysfunction does not alter the pharmacokinetics of chlorthalidone, 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 chlorthalidone 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 chlorthalidone.
Indications
Arterial hypertension, essential or nephrogenic or isolated systolic, as primary therapy or in combination with other antihypertensive agents.
Stable, chronic heart failure of mild to moderate degree (New York Heart Association, NHYA: functional class II or III).
Oedema of specific origin
- Oedema due to peripheral (chronic) venous insufficiency; short-term therapy if physical measures prove insufficient.
- Fluid retention in premenstrual syndrome only if the gain in weight is the main symptom and is well documented.
- Ascites due to cirrhosis of the liver in stable patients under close control.
- Oedema due to nephrotic syndrome.
- Prophylaxis against recurrent calcium oxalate calculi in patients with idiopathic, normocalcaemic hypercalciuria.
Dosage and Administration
As with all diuretics, therapy should be initiated with the lowest possible dose. This dose should be titrated according to the individual patient's response to gain maximum therapeutic benefit while keeping side effects to a minimum.
A single dose is recommended, either daily or every other day, to be taken in the morning with food.
Hypertension
The range of clinically useful doses is 12.5-50 mg/day. Recommended starting doses are either 12.5 or 25 mg/day, the latter being sufficient to produce the maximum hypotensive effect in most patients. For a given dose, the full effect is reached after 3-4 weeks. If the decrease in blood pressure proves inadequate with 25 or 50 mg/day, combined treatment with other antihypertensive drugs, such as β-blockers, reserpine, and ACE inhibitors (see Warnings and Precautions), is recommended.
Stable, chronic heart failure (functional class II/III)
The recommended starting dose is 25-50 mg/day; in severe cases, it may be increased up to 100-200 mg/day. The usual maintenance dose is the lowest effective dose, e.g. 25-50 mg either daily or every other day. If the response proves inadequate, digitalis or an ACE inhibitor or both, may be added (see Warnings and Precautions).
Oedema of specific origin
The lowest effective dose is to be identified by titration and administered over limited periods only. It is recommended that doses should not exceed 50 mg/day.
Prophylaxis against recurrent calcium oxalate calculi in normocalcaemic hypercalciuria
In most cases the optimum prophylactic dose is 25 mg/day. Efficacy is not enhanced by doses higher than 50 mg/day.
Children
The lowest effective dose should also be used in children. For example, an initial dose of 0.5-1 mg/kg/48 hours and a maximum dose of 1.7 mg/kg/48 hours have been used.
Elderly patients and patients with renal impairment
The standard lowest effective dose of Hygroton is also recommended for patients with mild renal insufficiency and for elderly patients. In elderly patients, the elimination of chlorthalidone 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 chlorthalidone.
Hygroton and thiazide diuretics lose their diuretic effect when the creatinine clearance is <30 mL/min.
Contraindications
- Anuria, severe renal failure (creatinine clearance lower than 30 mL/min), and severe hepatic failure.
- Hypersensitivity to chlorthalidone and other sulfonamide derivatives or to any of the excipients.
- Refractory hypokalaemia or conditions involving enhanced potassium loss, hyponatraemia and hypercalcaemia.
- Symptomatic hyperuricaemia (history of gout or uric acid calculi). Hypertension during pregnancy.
Warnings and Precautions
Hygroton 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.
Hygroton 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.
Electrolytes
Treatment with thiazide diuretics has been associated with electrolyte disturbance such as hypokalaemia, hypomagnesaemia, hypercalcaemia, and hyponatraemia. Hypokalaemia can sensitise the heart or exaggerate its response to the toxic effects of digitalis.
Like all thiazide diuretics, kaluresis induced by Hygroton is dose dependent and varies in extent from one subject to another. With 25-50 mg/day, the decrease in serum potassium concentrations averages 0.5 mmol/L. For chronic treatment, serum potassium concentrations should be monitored at the start of therapy and then after 3-4 weeks. Thereafter - if the potassium balance is not disturbed by additional factors (e.g. vomiting, diarrhoea, change in renal function, etc.) - checks should be carried out every 4-6 months.
If necessary, Hygroton may be combined with oral potassium supplements or a potassium-sparing diuretic (e.g. triamterene). In cases of combined treatment, serum potassium should be monitored. If hypokalaemia is accompanied by clinical signs (e.g. muscular weakness, paresis,and ECG alteration), Hygroton should be discontinued.
Combined treatment consisting of Hygroton 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. For the latter condition, Hygroton should be used only under close control in normokalaemic patients with no signs of volume depletion.
Metabolic effects
Hygroton may raise the serum uric acid level, but attacks of gout are rarely observed during chronic treatment.
Although glucose tolerance may be adversely affected, diabetes mellitus very seldom occurs under 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 a matter for debate.
Hygroton 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).
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 2-3 days and/or that the ACE inhibitor therapy be started with a low initial dose of the ACE inhibitor.
Preclinical safety data
Tests for the induction of gene mutations in bacteria or cultured mammalian cells were negative. At high cytotoxic doses, chromosome aberrations were induced in cultured Chinese hamster ovary (CHO) cells. However, tests for the ability to induce DNA repair in rat hepatocytes or micronuclei in mouse bone marrow or rat liver revealed no evidence for the induction of chromosome damage. Thus, the results in the CHO cell assay are considered to arise from cytotoxicity rather than genotoxicity. It is concluded that chlorthalidone does not present a risk of mutagenicity to humans.
Long-term carcinogenicity studies have not been performed with chlorthalidone.
Teratogenicity studies in rats and rabbits revealed no teratogenic potential.
Use during Pregnancy and Lactation
Category C
Hygroton, like other diuretics, can cause placental hypoperfusion. Thiazides and related diuretics enter the fetal circulation and may cause electrolyte disturbance. Neonatal thrombocytopenia has been reported with thiazides and related diuretics. Therefore, Hygroton should not be used in pregnancy unless there are no safer alternatives.
Chlorthalidone passes into breast milk. For safety reasons, avoid use in nursing mothers.
Effects on ability to drive and use machines
Hygroton, especially at the start of treatment, may impair the patient's reactions, e.g. when driving or operating machines.
Adverse Effects
Frequency estimate: very rare < 0.01%; rare ≥ 0.01% to < 0.1%; uncommon ≥ 0.1% to < 1%; common ≥ 1% to < 10%; very common ≥ 10%
Electrolytes and metabolic disorders
Very common: mainly at higher doses, hypokalaemia, hyperuricaemia, and rise in blood lipids.
Common: hyponatraemia, hypomagnesaemia, and hyperglycaemia.
Rare: hypercalcaemia, glycosuria, worsening of diabetic metabolic state, and gout.
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, which may be aggravated by alcohol, anaesthetics or sedatives.
Rare: cardiac arrhythmias.
Central nervous system
Common: dizziness.
Rare: paraesthesia, headache.
Gastrointestinal 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
Common: impotence.
Rare: disturbances of vision.
Very rare: idiosyncratic pulmonary oedema (respiratory disorders). Allergic interstitial nephritis and vasculitis.
Interactions
Since diuretics raise blood lithium levels, the latter must be monitored in patients under lithium therapy who are taking Hygroton at the same time. Where lithium has induced polyuria, diuretics may exert a paradoxical antidiuretic effect.
Diuretics potentiate the action of curare derivatives and antihypertensive drugs (e.g. guanethidine, methyldopa, β-blockers, vasodilators, calcium antagonists, ACE inhibitors).
The hypokalaemic effect of diuretics may be increased by corticosteroids, ACTH, β2-agonists amphotericin, and carbenoxolone.
It may prove necessary to readjust the dosage of insulin and of oral antidiabetic agents.
Thiazide-induced hypokalaemia or hypomagnesaemia may favour the occurrence of digitalis-induced cardiac arrhythmias, (see "Special warnings and precautions for use").
Concomitant administration of certain non-steroidal anti-inflammatory drugs (e.g. indomethacin) may weaken the diuretic and antihypertensive activity of diuretics, and there have been isolated reports of a deterioration in renal function in predisposed patients.
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 bioavailability of thiazide-type diuretics may be increased by anticholinergic agents (e.g. 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 cholestyramine. A decrease in the pharmacological effect may be expected.
Administration of thiazide diuretics with vitamin D or with calcium salts may potentiate the increase in serum calcium.
Concomitant treatment with cyclosporin may increase the risk of hyperuricaemia and gout-type complications.
Overdosage
Symptoms
In poisoning due to an overdosage the following signs and symptoms may occur: dizziness, nausea, somnolence, hypovolaemia, hypotension, and electrolyte disturbances associated with cardiac arrhythmias and muscle spasms.
Treatment
Induction of vomiting or gastric lavage and administration of activated charcoal if the patient is conscious. Intravenous fluid and electrolyte replacement may be indicated.
Pharmaceutical Precautions
Store below 30°C. Protect from moisture.
Medicines should be kept out of the reach of children.
Medicines Classification
Prescription Medicine
Package Quantities
Bottles of 50 tablets
Further Information
Hygroton tablets also contain Silica aerogel, red iron oxide (E 172), yellow iron oxide (E 172), lactose, magnesium stearate, maize starch and talc.
Name and Address
AFT Pharmaceuticals Ltd
9 Anzac Street (Level 2)
Takapuna
Auckland
Email:customer.service@aftpharm.comx
Date of Preparation
18 August 2008