Composition

Each sustained-release film-coated tablet contains indapamide 1.5 mg.

Indications

Essential hypertension.

Dosage and method of administration

This medicine must be prescribed by physicians.

Oral administration.

One tablet per 24 hours, preferably in the morning, to be swallowed with water and not chewed.

At higher doses the antihypertensive action of indapamide is not enhanced but the saluretic effect is increased.

Pharmacological properties

Pharmacodynamic properties

Indapamide is a sulphonamide derivative with an indole ring, pharmacologically related to thiazide diuretics, which acts by inhibiting the reabsorption of sodium in the cortical dilution segment. It increases the urinary excretion of sodium and chlorides and, reduces the excretion of potassium and magnesium, thereby increasing urine output to have antihypertensive effect.

Clinical Phase II and III studies using monotherapy with Indapamide have demonstrated the antihypertensive effect will last 24 hours. Under one tablet per day regimen the diuretic effect was of mild intensity. The antihypertensive activity of indapamide is related to an improvement in arterial compliance and a reduction in arteriolar and total peripheral resistance.

Indapamide reduces left ventricular hypertrophy.

Thiazide and related diuretics have a plateau therapeutic effect beyond a certain dose, while adverse effects continue to increase. The dose should not be increased if treatment is ineffective.

It has also been shown, in the short-, mid- and long-term hypertensive patients, that indapamide:

- does not interfere with lipid metabolism: eg. triglycerides, LDL-cholesterol and HDL-cholesterol;

- does not interfere with carbohydrate metabolism, even in diabetic hypertensive patients.

Pharmacokinetic properties

This product (Indapamide 1.5 mg) is supplied in a sustained-release dosage form based on a matrix system in which the active ingredient is dispersed. The system allows sustained release of indapamide after oral administration.

Absorption

The fraction of indapamide released is rapidly and totally absorbed via the gastrointestinal tract. Foods will slightly increase the rate of absorption but has no influence on the extent of the drug absorption. Peak blood drug concentration following a single dose occurs about 12 hours after ingestion, repeated administration reduces the variation of blood drug concentration between the dosing. There are intra-individual variability in drug absorption.

Distribution

Binding of indapamide to plasma proteins is 79%. The plasma elimination half-life is 14 to 24 hours (mean 18 hours). Steady state is achieved after 7 days. Repeated administration does not lead to drug accumulation.

Metabolism

Elimination is essentially renal (70% of the dose) and faecal (22%) in the form of inactive metabolites.

High risk individuals

Pharmacokinetic parameters are unchanged in renal insufficient patients.

Contraindications

- Hypersensitivity to sulphonamides.

- Severe renal failure.

- Hepatic encephalopathy or severe impairment of hepatic function.

- Hypokalaemia

Special warnings and precautions for use

Special Warnings

When hepatic function is impaired, thiazide-related diuretics may cause hepatic encephalopathy. Administration of the diuretic must be stopped immediately if this occurs.

Those patients who have the following diseases are contraindicated to administer this medicine because it contains lactose, eg. congenital galactosemia, glucose and galactose malabsorption, lactase deficiency.

Special precautionsin using this drug

Water and electrolytes balance:

＊Plasma sodium:

The plasma sodium concentration must be measured before starting treatment, then at regular intervals subsequently. Any diuretic treatment may cause hyponatraemia, sometimes with very serious consequences. The fall in plasma sodium may be asymptomatic in initial phase and regular monitoring is therefore essential, and should be even more frequent in the elderly and cirrhotic patients (see Undesirable Effects and Overdose sections).

＊Plasma potassium:

Potassium depletion with hypokalaemia is the major risk of thiazide and related diuretics. The risk of onset of hypokalaemia (< 3.4 mmol/l) must be prevented in certain high risk populations, i.e. the elderly, malnourished and/or polymedicated, cirrhotic patients with oedema and ascites, coronary artery disease and cardiac failure patients. In this situation, hypokalaemia increases the cardiac toxicity of digitalis preparations and the risks of arrhythmias.

Individuals with a long QT interval are also at risk, whether the origin is congenital or iatrogenic. Hypokalaemia, as well as bradycardia, is then a predisposing factor to the onset of severe arrhythmias, in particular, potentially fatal wave burst.

More frequent monitoring of plasma potassium is required in all the situations indicated above. The first measurement of plasma potassium should be obtained during the first week following the start of treatment.

If hypokalaemia is detected, dose adjustment is required.

＊Plasma calcium:

Thiazide and related diuretics may decrease urinary calcium excretion and cause a slight and transitory rise in plasma calcium. Simple hypercalcaemia may be related to previously unrecognised hyperparathyroidism. Treatment should be withdrawn before the investigation of parathyroid function.

＊Blood glucose:

Monitoring of blood glucose should be performed in diabetic patients, in particular in the presence of hypokalaemia.

＊Uric acid:

Tendency to gout attacks may be increased in hyperuricaemic patients.

＊Renal function and diuretics:

Thiazide and related diuretics are fully effective only when renal function is normal or only minimally impaired (plasma creatinine below levels of the order of 25 mg/l, i.e. 220 µmol/l in an adult). In the elderly, the plasma creatinine concentration 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 transitory functional renal insufficiency is of no consequence in individuals with normal renal function but may worsen preexisting renal insufficiency.

＊Athletes:

This drug contains an active ingredient which may give a positive reaction in doping tests.

Interaction with other medicinal products

Combinations that are not recommended

＊Lithium:

Increased plasma lithium concentration will lead to overdose intoxication, as with a salt-free diet (decreased urinary lithium excretion). However, if the use of diuretics is necessary, careful monitoring of plasma lithium and dose adjustment are required.

Combinations requiring precautions for use

＊Wave burst-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 wave burst (hypokalaemia is a risk factor). Monitor for hypokalaemia and make dose adjustment, before introducing this combination. Clinical examination, plasma electrolytes and ECG monitoring are required. Use drugs which do not have the disadvantage of causing wave burst in the presence of hypokalaemia.

＊N.S.A.I.Ds. (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). Therefore, hydrate the patient, and monitor renal function at the start of treatment are required.

＊Angiotensin converting enzyme inhibitors (A.C.E.I):

There may be the presence of risk of sudden hypotension and/or acute renal failure when treat with an A.C.E. inhibitor in the presence of preexisting sodium depletion (particularly in patients with renal artery stenosis).

For the patients with essential hypertension, initial diuretic treatment may cause sodium depletion.

− either stop the diuretic 3 days before starting treatment with the A.C.E. inhibitor, and restart a hypokalaemic diuretic if necessary;

− or give low initial dose of the A.C.E. inhibitor and increase the dose gradually.

For the patients with congestive heart failure, start with a very low dose of A.C.E. inhibitor, after a reduction in the dose of the concomitant hypokalaemic diuretic.

In all cases, monitor renal function (plasma creatinine) during the first weeks of treatment with an A.C.E. inhibitor.

＊Other compounds causing hypokalaemia: amphotericin B (IV), gluco- and mineralo-corticoids (systemic route), tetracosactide, stimulant laxatives these drugs will increase the risk of hypokalaemia (additive effect). Monitoring of plasma potassium and dose adjustment are required. Particular caution is required in case of concomitant digitalis treatment. Use non-stimulant laxatives if necessary.

＊Baclofen:

Increase antihypertensive effect. Hydrate the patient; monitor renal function at the start of treatment.

＊Digitalis preparations:

Hypokalaemia predisposing will increase the toxic effects of digitalis. Monitoring of plasma potassium and ECG and, if necessary, reconsider the therapeutic method.

Combinations to be taken into consideration :

＊Potassium-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, reconsider the therapeutic method.

＊Metformin:

Increased risk of metformin induced lactic acidosis due to the possibility of functional renal insufficiency associated with diuretics and more particularly with loop diuretics. Do not use metformin when plasma creatinine exceeds 15 mg/l (135 µmol/l) in men and 12 mg/l (110 µmol/l) in women.

＊Iodinated contrast media:

In the presence of dehydration caused by diuretics, increased risk of acute renal failure, in particular when large doses of iodinated contrast media are used. Rehydrate the patients before administration of the iodinated compound.

＊Imipramine-like antidepressants, neuroleptics:

Antihypertensive effect and increased risk of orthostatic hypotension due to additive effect.

＊Calcium (salts):

Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.

＊Cyclosporin, tacrolimus:

Risk of increased plasma creatinine without any change in circulating cyclosporin levels, even in the absence of water/sodium depletion.

＊Corticosteroids, tetracosactide (systemic route):

Decreased antihypertensive effect (water/sodium retention due to corticosteroids).

Pregnancy and lactation

Pregnancy

As a general rule, the administration of diuretics should be avoided in pregnant women and should never be used to treat physiological oedema of pregnancy. Diuretics can cause foetoplacental ischaemia, with a risk of impaired foetal growth.

Lactation

Lactation should be avoided (Indapamide can be excreted in human milk).

Effects on driving and using machines

Indapamide does not affect vigilance but different reactions in relation with the decrease in blood pressure may occur in individual cases, especially at the start of the treatment or when another antihypertensive agent is added. As a result the ability to drive vehicles or to operate machinery may be impaired.

Adverse effects

The majority of adverse effects concerning clinical or laboratory parameters are dose-dependent. Thiazide-related diuretics, including indapamide, may cause:

＊Blood and the lymphatic system disorders:

Very rare: thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia

＊Nervous system disorders:

Rare: vertigo, fatigue, headache, paresthesia.

＊Cardiac disorders:

Very rare: arrhythmia, hypotension.

＊Gastrointestinal disorders:

Rare: nausea, constipation, dry mouth.

Very rare: pancreatitis.

＊Hepato-biliary disorders:

In case of hepatic insufficiency, there is a possibility of onset of hepatic encephalopathy (See Contra-indications and special warnings).

Very rare: abnormal hepatic function.

＊Skin and subcutaneous tissue disorders:

Hypersensitivity reactions, mainly dermatological (common: maculopapular rashes; uncommon: purpura) in subjects with a predisposition to allergic and asthmatic reactions

Possible worsening of pre-existing acute disseminated lupus erythematosus

Laboratory parameters:

＊During clinical trials, hypokalaemia (plasma potassium <3.4 mmol/l) was observed 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.

＊Potassium depletion with hypokalaemia, particularly serious in certain high risk populations (see Special Warnings and Special Precautions for Use).

＊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.

＊Very rare: Hypercalcaemia.

Overdose

Indapamide has been found to be safe up to 40 mg, i.e. 27 times the therapeutic dose. Majority of the acute toxic symptoms are water/electrolyte disturbances (hyponatraemia, hypokalaemia). Clinical signs are nausea, vomiting, hypotension, cramps, vertigo, drowsiness, confusion, polyuria or oliguria possibly to the point of anuria (by hypovolaemia). Initial treatment for intoxication involve the rapid elimination of the ingested substance(s) by gastric wash-out and/or administration of activated charcoal, followed by restoration of water/electrolyte balance to normal in a specialised centre.

Storage instructions

Store below 25°C in a dry place.

Package

2-1000 tablets in blisters (PVC/aluminium) or bottles (plastic).

 

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