This information is intended for use by health professionals

1. Name of the medicinal product

Indapamide 2.5mg Tablets

2. Qualitative and quantitative composition

Each tablet contains Indapamide as indapamide hemihydrate 2.5mg.

For a full list of excipients, see section 6.1.

3. Pharmaceutical form

Coated Tablets

White, biconvex, sugar coated tablet.

4. Clinical particulars
4.1 Therapeutic indications

Indapamide is indicated in the treatment of essential hypertension. Indapamide may be used as sole therapy or combined with other antihypertensive agents.

4.2 Posology and method of administration

Posology

Adults:

The dosage of one tablet, containing 2.5mg indapamide, to be taken daily in the morning. The action of indapamide is progressive and the reduction of blood pressure may continue and not reach a maximum until several months after the start of therapy. A larger dose than 2.5mg indapamide daily is not recommended, as there is no appreciable additional anti-hypertensive effect but a diuretic effect may become apparent. If a single daily tablet of indapamide does not achieve a sufficient reduction in blood pressure, another anti-hypertensive agent may be added such as beta-blockers, ACE inhibitors, methyldopa, clonidine and other adrenergic blocking agents.

The co-administration of indapamide with diuretics which may cause hypokalaemia is not recommended.

There is no evidence of rebound hypertension on withdrawal of indapamide

Renal impairment (see sections 4.3 and 4.4):

In severe renal failure (creatinine clearance below 30 ml/min), treatment is contraindicated.

Thiazide and related diuretics are fully effective only when renal function is normal or only minimally impaired.

Hepatic impairment (see sections 4.3 and 4.4):

In severe hepatic impairment, treatment is contraindicated.

Elderly (see section 4.4):

In the elderly, the plasma creatinine must be adjusted in relation to age, weight and gender. Elderly patients can be treated with Indapamide SR when renal function is normal or only minimally impaired.

Paediatric populations:

The safety and efficacy of indapamide 2.5mg in children and adolescents have not been established. No data are available.

Method of administration

Oral use.

4.3 Contraindications

Severe renal failure.

Hepatic encephalopathy or severe impairment of liver function.

Hypokalaemia.

Hypersensitivity to Indapamide, Sulphonamide derivatives, and any of the ingredients.

4.4 Special warnings and precautions for use

Special warnings:

When liver function is impaired, Thiazide-related diuretics may cause hepatic encephalopathy particularly in case of electrolyte imbalance. Administration of the diuretic must be stopped immediately if this occurs or there are signs of renal insufficiency.

A slight weight loss has been reported in some patients taking Indapamide.

Excipients:

Patients with rare hereditary problems of fructose, galactose intolerance, the Lapp lactose deficiency or glucose-galactose malabsorption, or sucrase-isomaltase insufficiency should not take this medicine.

Photosensitivity:

Cases 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 the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.'

Special precautions for use:

Water and electrolyte balance:

- Plasma Sodium:

This must be measured before starting treatment, then at regular intervals subsequently. Any diuretics treatment may cause hyponatraemia, sometimes with very serious consequences. The fall in plasma sodium may be asymptomatic initially and regular monitoring is therefore essential, and should be even more frequent in the elderly and cirrhotic patients (see sections 4.8 and 4.9).

- Plasma Potassium:

Potassium depletion with hypokalaemia is the major risk of Thiazide and related diuretics. The risk of onset of hypokalaemia (<3.4mmol/l) must be prevented in certain high risk populations, i.e. the elderly, malnourished and / or poly-medicated, cirrhotic patients with oedema and ascites, coronary artery disease and cardiac failure patients.

In this latter 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 pre-disposing factor to the onset of severe arrhythmias, in particular, potentially fatal torsades de pointes.

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

Detection of hypokalaemia requires its correction.

- Plasma calcium:

Thiazide and related diuretics may decrease urinary calcium excretion and cause a slight and transitory rise in plasma calcium. Hypercalcaemia may be due to previously unrecognised hyperparathyroidism.

Treatment should be withdrawn before the investigation of parathyroid function. Indapamide may reduce the level of PTH.

Blood Glucose:

Monitoring of blood glucose is important in diabetics, 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 25mg/ml, i.e. 220µmol/l in an adult). 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 transitory functional renal insufficiency is of no consequence in individuals with normal renal function but may worsen pre-existing renal insufficiency.

Athletes:

The attention of athletes is drawn to the fact that this drug contains an active ingredient which may give a positive reaction in doping tests.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations that are not recommended:

Lithium:

Increased plasma Lithium with signs of overdose, as with a salt-free diet (decreased urinary Lithium secretion). However, if the use of diuretics is necessary, careful monitoring of plasma Lithium and dose adjustment are required.

Combinations requiring precautions for use:

- Torsades de pointes-inducing drugs:

Class Ia antiarrhythmic drugs (Quinidine, Hydroquinidine, Disopyramide), Class III antiarrhythmics (Amiodarone, Bretylium, Sotalol dofetilide, ibutilide)

- some antipsychotics:

phenothiazines (chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, tiapride) butyrophenones (droperidol, haloperidol)

others: bepridil, cisapride, diphemanil, mizolastine, sparfloxacin, moxifloxacin, IV-erythromycin, Halofantrine, Pentamidine, Sultopride Terfenadine, Vincamine IV.

Increased risk of ventricular arrhythmias, particularly Torsade 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 torsade de pointes 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 decrease in anti-hypertensive 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 (A.C.E) inhibitors:

Risk of sudden hypotension and / or acute renal failure when treatment with an A.C.E inhibitor is started in the presence of pre-existing sodium depletion (in particular in individuals with renal artery stenosis).

In hypertension, when prior diuretic treatment may have caused sodium depletion, it is necessary:

- Either to 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 doses of the A.C.E inhibitor and increase the dose gradually.

In congestive cardiac failure, start with a very low dose of A.C.E inhibitor, possibly after a reduction in the dose of the combined 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 mineralocorticoids (systemic route), tetracosactide, stimulant laxatives

Increased risk of hypokalaemia (additive effect).

Monitoring of plasma potassium and correction if required. Must be particularly borne in mind in case of concomitant digitalis treatment. Use non-stimulant laxatives.

Baclofen:

Increased anti-hypertensive effect.

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

Digitalis preparations:

Hypokalaemia predisposing to the toxic effects of Digitalis.

Monitor plasma potassium, ECG and, adjust treatment if necessary.

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, treatment reviewed.

Metformin:

Increased 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 15mg/litre (135µmol/litre) in men and 12mg/ litre (110µmol/litre) 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. Rehydration before administration of the iodinated compound.

Imipramine-like Antidepressants (Tricyclics), Neuroleptics:

Anti-hypertensive effect and risk of orthostatic hypotensive increased (additive effect).

Calcium salts:

Risk of hypercalcaemia resulting from decreased urinary calcium elimination.

Ciclosporin/ Tacrolimus:

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

Corticosteroids, tetracosactide (systemic route):

Decreased anti-hypertensive effect (water/ sodium retention due to corticosteroids).

4.6 Fertility, pregnancy and lactation

Pregnancy

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

Breast-feeding

Breast-feeding is inadvisable, because indapamide is excreted in human milk.

4.7 Effects on ability to drive and use 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.

4.8 Undesirable effects

The majority of adverse effects concerning clinical or laboratory parameters are dose-dependent.

Thiazide-related diuretics, including indapamide, may cause the following undesirable effects ranked under the following frequency:

Very common (≥1/10); common (≥1/100, <1/10); uncommon (≥1/1000, <1/100); rare (≥1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).

Nervous system disorders:

Rare: vertigo, fatigue, headache, paraesthesia

Not known: syncope

Blood and lymphatic system disorders:

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

Cardiovascular disorders:

Very rare: arrhythmia, hypotension

Not known: Torsade de pointes (potentially fatal) (see sections 4.4 and 4.5)

Endocrine disorders:

Diabetes mellitus very rarely reported.

Gastrointestinal disorders:

Uncommon: vomiting

Rare: nausea, constipation, dry mouth

Very rarely: pancreatitis.

General disorders:

Dizziness, muscle cramps, impotence, reversible acute myopia, occurring rarely and responding in most instances to a dose reduction.

Renal and urinary disorders:

Very rare: renal failure

Hepatobiliary disorders:

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)

• Hepatitis

Investigations:

Not known:

• Electrocardiogram QT prolonged (see sections 4.4 and 4.5)

Blood glucose increased and blood uric acid increased during treatment: appropriateness of these diuretics must be very carefully weighed in patients with gout or diabetes

• Elevated liver enzyme levels

Skin and subcutaneous tissue disorders:

Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions:

Common: maculopapular rashes

Uncommon: purpura

Very rare: angioneurotic oedema and/or urticaria, toxic epidermal necrolysis, Stevens Johnson syndrome

Not known: possible worsening of pre-existing acute disseminated lupus erythematosus. erythema multiforme

Cases of photosensitivity reactions have been reported.

Metabolism and nutrition disorders

During clinical trials, hypokalaemia (plasma potassium <3.4 mmol/l) was seen in 25% of patients and <3.2mmol/l in 10% of patients after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.41mmol/l.

Very rare: Hypercalcaemia

Not known:

• Potassium depletion with hypokalaemia, particularly serious in certain high risk populations (see section 4.4).

• 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.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the Yellow Card Scheme Website: www.mhra.gov.uk/yellowcard.

4.9 Overdose

Symptoms:

Indapamide has been found free of toxicity at up to 40mg, i.e. 16 times the therapeutic dose.

Signs of acute poisoning take the form above all of water/electrolyte disturbances (hyponatraemia, hypokalaemia). Clinically, possibility of nausea, vomiting, hypotension, cramps, vertigo, drowsiness, confusion, polyuria or oliguria possibly to the point of anuria (by hypovolaemia).

Management:

Initial measures 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.

5. Pharmacological properties
5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sulfonamides plain ATC Code: C03BA11

Indapamide is a non-thiazide sulfonamide with an indole ring, belonging to the diuretic family. At the dose of 2.5mg per day indapamide exerts a prolonged antihypertensive activity in hypertensive human subjects.

Dose-effect studies have demonstrated that, at the dose of 2.5mg per day, the antihypertensive effect is maximal and the diuretic effect is sub-clinical.

At this antihypertensive dose of 2.5mg per day, indapamide reduces vascular hyperreactivity to noradrenaline in hypertensive patients and decreases total peripheral resistance and arteriolar resistance.

The implication of an extrarenal mechanism of action in the antihypertensive effect is demonstrated by maintenance of its antihypertensive efficacy in functionally anephric hypertensive patients.

The vascular mechanism of action of indapamide involves:

• a reduction in the contractility of vascular smooth muscle due to a modification of transmembrane ion exchanges, essentially calcium;

• vasodilatation due to stimulation of the synthesis of prostaglandin PGE2 and the vasodilator and platelet antiaggregant prostacyclin PGI2;

• potentiation of the vasodilator action of bradykinin.

It has also been demonstrated that in the short-, medium- and long-term, in hypertensive patients, Indapamide

• reduces left ventricular hypertrophy;

• does not appear to alter lipid metabolism: triglycerides, LDL-cholesterol and HDL-cholesterol;

• does not appear to alter glucose metabolism, even in diabetic hypertensive patients. Normalisation of blood pressure and a significant reduction in microalbuminuria have been observed after prolonged administration of indapamide in diabetic hypertensive subjects.

Lastly, the co-prescription of indapamide with other antihypertensives (beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors) results in an improved control of hypertension with an increased percentage of responders compared to that observed with single-agent therapy.

5.2 Pharmacokinetic properties

Indapamide is rapidly and completely absorbed after oral administration. Peak blood levels are obtained after 1 to 2 hours.

Elimination is biphasic with a terminal half-life of 14 to 18 hours only about 5% is excreted unchanged. It is extensively metabolised. About 60% to be excreted in the urine. About 70% of a single oral dose is eliminated by the kidneys and 23% by the gastrointestinal tract. Indapamide is about 71 to 79% bound to plasma proteins and it is preferentially taken up in the red blood cells. It is taken up by the vascular wall in smooth vascular muscle according to its high lipid solubility.

Indapamide is metabolised to a marked degree with 7% of the unchanged product found in the urine during the 48 hours following administration.

5.3 Preclinical safety data

Non-clinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity, carcinogenic potential, toxicity to reproduction and development.

6. Pharmaceutical particulars
6.1 List of excipients

Lactose Monohydrate

Maize Starch

Polyvidone

Purified Water*

Magnesium Stearate

Seal Coat:

Opaseal

Purified Talc

Subcoat:

Calcium Carbonate

Acacia

Titanium Dioxide (E171)

Purified Talc

Sucrose

Purified talc Ph.Eur

Smoothing Syrup:

Sucrose Ph.Eur

Colour Coat:

Sucrose Ph.Eur

Titanium Dioxide Ph.Eur (E171)

Smoothing Syrup:

Sucrose Ph.Eur

Purified Water*

Polishing Coat:

Opaglos 6000P

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Do not store above 25°C. Store in the original container. Keep the container tightly closed (Tablet containers).

Do not store above 25°C. Store in the original package (Blister packs).

6.5 Nature and contents of container

Polypropylene tubes with low-density polyethylene caps. High-density polyethylene film may be used as a packing material.

Pack sizes: 30, 50, 60, 100 and 250 tablets.

Blister packs consisting of clear PVC and hard temper aluminium foil contained in a carton.

Pack sizes: 28, 30, 50, 56, 60 and 100 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements for disposal.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.

7. Marketing authorisation holder

Special Concept Development (UK) Limited

Unit 1-7 Colonial Way

Watford

Hertfordshire

WD24 4YR

United Kingdom

8. Marketing authorisation number(s)

PL 36722/0037

9. Date of first authorisation/renewal of the authorisation

16/07/2002 / 20/12/2010

10. Date of revision of the text

24/05/2016