POM: Prescription only medicine
This information is intended for use by health professionals
WarningIn patients with impaired liver function, thiazide-related diuretics may cause hepatic encephalopathy particularly in case of electrolyte imbalance. Administration of the diuretic must be stopped immediately if this occurs.
Precautions for use
1. Water and electrolyte balance
Plasma sodiumDiuretics may cause hyponatraemia, sometimes with very serious consequences. Plasma sodium is measured before treatment is started and then at regular intervals subsequently. The fall in plasma sodium may be asymptomatic initially and regular monitoring is therefore essential. In the elderly and cirrhotic patients, monitoring should be even more frequent (see Undesirable effects and Overdose sections).
Plasma potassiumThe major risk of treatment with thiazide and related diuretics is hypokalaemia. The risk of onset of hypokalaemia (< 3.4 mmol/l) must be prevented in certain high risk groups, i.e. patients that are malnourished and/or are taking several drugs concomitantly, the elderly, cirrhotic patients with oedema and ascites, patients with coronary artery disease and cardiac failure. In these patients, hypokalaemia increases the cardiotoxicity of digitalis preparations and the risks of arrhythmias.Patients with a long QT interval are also at risk, whether the origin is congenital or drug-induced. Hypokalaemia (as well as bradycardia) is then a predisposing factor to the onset of severe arrhythmias, in particular, potentially fatal heart rhythm disorders of the type torsades de pointes.In these patients, more frequent monitoring of plasma potassium is required. The first measurement of plasma potassium should be obtained during the first week of treatment.If low potassium levels are detected, correction is required.
Plasma calciumThiazide and related diuretics may decrease urinary calcium excretion and cause a slight and transitory rise in plasma calcium. Evident hypercalcaemia may be due to previously unrecognised hyperparathyroidism. Treatment with the diuretic should be withdrawn before any planned investigation of parathyroid function.
Blood glucoseMonitoring of blood glucose is important in diabetics, in particular in the presence of hypokalaemia.
Uric acidTendency to gout attacks may be increased in hyperuricaemic patients.
2. Renal function and diureticsThiazide and related diuretics are fully effective only when renal function is normal or only minimally impaired (plasma creatinine levels below 25 mg/l, i.e. 220 µ mol/l in adults). In the elderly, this plasma creatinine must be adjusted in relation to age, weight and gender.Hypovolaemia, secondary to the loss of water and sodium induced by the diuretic at the start of treatment causes a reduction in glomerular filtration. This may lead to an increase in blood urea and plasma creatinine. This transient renal dysfunction has no consequences in patients with normal renal function but it may deteriorate the existing renal insufficiency.
3. AthletesAthletes should note that this product contains an active substance which may cause a positive reaction in doping tests.
4. PhotosensitivityCases of photosensitivity reactions have been reported with thiazides and thiazide- related diuretics (see section 4.8). If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of indapamide is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.This medicinal product contains lactose. Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
LithiumConcomitant use of lithium may lead to increase of plasma lithium concentration with signs of overdosage, as with a sodium-free diet (decreased urinary lithium excretion). However, if the use of diuretics is necessary, careful monitoring of plasma lithium and dose adjustment is required.
2. Combinations that require precaution
Torsades de pointes-inducing drugs:• Class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide)• Class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide)• Some antipsychotics: phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine)• Benzamides (amisulpride, sulpiride, sultopride, tiapride),• Butyrophenones (droperidol, haloperidol);• Others: bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine IV.Increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalaemia is a risk factor). Monitor for hypokalaemia and correct, if required, before introducing this combination. Clinical, plasma electrolytes and ECG monitoring. Use substances which do not have the disadvantage of causing torsades de pointes in the presence of hypokalaemia. Non-steroidal anti-inflammatory drugs (systemic route) including COX-2 selective inhibitors, high dose salicylic acid (≥3 g/day):Possible reduction in the antihypertensive effect of indapamide. Risk of acute renal failure in dehydrated patients (decreased glomerular filtration). Hydrate the patient; monitor renal function at the start of treatment.
Angiotensin converting enzyme (ACE) inhibitorsWhen treatment with an ACE inhibitor is initiated, sudden hypotension and/or acute renal failure may occur in patients with pre-existing depletion of sodium (particularly in patients with renal artery stenosis).In hypertension, when prior diuretic treatment may have caused sodium depletion, it is necessary:• to stop the diuretic 3 days before starting treatment with the ACE inhibitor and restart a non-potassium-sparing diuretic if necessary;• or give low initial doses of the ACE inhibitor and increase the dose gradually.In patients with congestive heart failure, start with a very low dose of ACE inhibitor, preferably after a reduction in the dose of a non-potassium-sparing diuretic.In all patients, renal function (plasma creatinine) should be monitored during the first weeks of treatment with an ACE inhibitor.
Other drugs causing hypokalaemia:• Amphotericin B (IV)• Gluco- and mineralo-corticoids (systemic)• Tetracosactide• Stimulant laxativesThe risk of hypokalaemia is increased (additive effect). Plasma potassium should be monitored and corrected if necessary. Caution is required in patients concomitantly taking digitalis. These patients should take non-stimulant laxatives.
BaclofenIncreased antihypertensive effect.The patient should drink sufficient quantity of liquid; renal function is monitored at the start of treatment.
Digitalis preparationsHypokalaemia increases the risk of toxic effects of digitalis.Plasma potassium and ECG should be monitored and, if necessary, the treatment adjusted.
3. Combinations to be taken into considerationPotassium-sparing diuretics (amiloride, spironolactone, triamterene): Whilst rational combinations are useful in some patients, hypokalaemia or hyperkalaemia (particularly in patients with renal failure or diabetes) may still occur.Plasma potassium and ECG should be monitored and, if necessary, treatment reviewed.
MetforminIncreased risk of metformin induced lactic acidosis due to the possibility of functional renal failure associated with diuretics and more particularly with loop diuretics. Do not use metformin when plasma creatinine exceeds 15 mg/l (135 µ mol/l) in men and 12 mg/l (110 µ mol/l) in women.
Iodinated contrast mediaIn patients dehydrated due to diuretics, the risk of acute renal failure is increased, particularly when large doses of iodinated contrast media are used. The patient should be rehydrated prior to administration of the ionated compound.
Imipramine-like antidepressants, neurolepticsAntihypertensive effect and risk of orthostatic hypotension are increased (additive effect).
Calcium (salts)Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.
Cyclosporin, tacrolimusRisk of increased plasma creatinine without any change in circulating cyclosporin levels, even in the absence of water/sodium depletion.
Corticosteroids, tetracosactide (systemic)Antihypertensive effect may be decreased (water and sodium retention).
PregnancyAs a general rule, the administration of diuretics to pregnant women should be avoided and diuretics should never be used to treat physiological oedema of pregnancy. Diuretics can cause fetoplacental ischemia with a risk of impaired fetal growth.
LactationIndapamide is excreted in human milk and effects on the breast-fed child are likely. Breast-feeding is not recommended during treatment with indapamide.
|Blood and the lymphatic system disorders|
|Very rare:||thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia|
|Nervous system disorders|
|Rare:||vertigo, fatigue, headache, paresthesia.|
|Very rare:||arrhythmia, hypotension|
|Rare:||nausea, constipation, dry mouth.|
|Very rare:||abnormal hepatic function.|
|Not known:||possibility of onset of hepatic encephalopathy in case of hepatic insufficiency (see sections 4.3 and 4.4)|
|Skin and subcutaneous tissue disorders Hypersensitivity reactions, mainly dermatological in subjects with a predisposition to allergic and asthmatic reactions|
|Very rare:||angioneurotic oedema and/or urticaria, toxic epidermic necrolysis, Stevens-Johnson syndrome|
|Not known:||Possible worsening of pre-existing acute disseminated lupus erythematosus Cases of photosensitivity reactions have been reported (see section 4.4)|
|Investigations During clinical trials, hypokalaemia (plasma potassium <3.4 mmol/l) was seen in 10% of patients and < 3.2 mmol/l in 4% of patients after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.23 mmol/l.|
|Not known:||Potassium depletion with hypokalaemia, particularly serious in certain high risk populations (see section 4).Hyponatraemia with hypovolaemia responsible for dehydration and orthostatic hypotension. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkalosis: the incidence and degree of this effect are slight.Increase in plasma uric acid and blood glucose during treatment: appropriateness of these diuretics must be very carefully weighed in patients with gout or diabetes.|
AbsorptionThe fraction of indapamide released is rapidly and almost totally absorbed via the gastrointestinal tract. Food slightly affects the speed of absorption but has no influence on the amount of the drug absorbed. Peak serum level occurs about 12 hours after ingestion of the drug. After achieving the steady-state concentration, the variation in serum levels between two doses is reduced. However, variability among individual patients exists.
Distribution, metabolism and eliminationBinding of indapamide to plasma proteins is 79%. The plasma elimination half-life is 14 to 24 hours (mean 18 hours). The steady-state is reached in 7 days. Repeated administration does not lead to accumulation of indapamide.Indapamide is metabolised mainly in the liver. 70% of indapamide is eliminated via the kidneys, to a larger extent in the form of metabolites (fraction of the unchanged drug is about 5%). About 20% of it is excreted in the faeces in the form of inactive metabolites.The pharmacokinetic parameters of the drug are not significantly changed in patients with renal function impairment.