INDAPAMIDE TABLETS 2.5 MG - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Indapamide Tablets 2.5mg

2

Each tablet contains Indapamide Ph Eur as indapamide hemihydrate 2.5mg.

Excipients with known effect:

Lactose 56 mg

Sucrose 20mg

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Coated tablets.

Appearance: white, circular, biconvex, sugar-coated tablet printed with the company logo or printed with ‘I’

4 CLINICAL PARTICULARS

4.1 Therapeutic indications

For the treatment of essential hypertension.

4.2 Posology and method of administration

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 in blood pressure may continue and not reach a maximum until several months after the start of therapy. A larger dose than 2.5mg of 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 antihypertensive 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.

Special populations

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 when renal function is normal on only minimally impaired.

Paediatric population:

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

Administration:

Route of administration: Oral.

4.3 Contraindications

N.S.A.I.Ds. (systemic route) including COX-2 selective inhibitors, high dose salicylic acid (> 3 g/day):

Risk of sudden hypotension and/or acute renal failure when treatment with a converting enzyme inhibitor is started in the presence of pre-existing sodium depletion (in particular in patients 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), 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 nonstimulant laxatives.

Increased antihypertensive effect.

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

Hypokalaemia and/or hypomagnesaemia predispose to the toxic effects of digitalis. Monitoring of plasma potassium, magnesium and ECG is recommended and, if necessary, adjusting the treatment.

Combinations requiring special care:

Allopurinol:

Concomitant treatment with indapamide may increase the incidence of hypersensitivity reactions to allopurinol.

Combinations which must 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.

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 (135pmol/litre) in men and 12mg/litre (110pmol/litre) in women.

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.

Antihypertensive effect and risk of orthostatic hypotensive increased (additive effect).

Risk of hypercalcaemia resulting from decreased urinary calcium elimination.

Ciclosporin, tacrolimus:

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

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

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data (less than 300 pregnancy outcomes) from the use of indapamide in pregnant women. Prolonged exposure to thiazide during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause a foeto-placental ischaemia and growth retardation.

Animal studies do not indicate direct or indirect harmful effects with respect to reproductive toxicity (see section 5.3).

As a precautionary measure, it is preferable to avoid the use of indapamide during pregnancy.

Breast-feeding

There is insufficient information on the excretion of indapamide/me­tabolites in human milk. Hypersensitivity to sulfonamide-derived medicines and hypokalaemia might occur. A risk to the newborns/infants cannot be excluded. Indapamide is closely related to thiazide diuretics which have been associated, during breast-feeding, with decreased or even suppression of milk lactation. Indapamide should not be used during breast-feeding.

Fertility

Reproductive toxicity studies showed no effect on fertility in female and male rats (see section 5.3). No effects on human fertility are anticipated.

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

Summary of safety profile

The most commonly reported adverse reactions are hypokalaemia, hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions and maculopapular rashes.

Tabulated summary of adverse reactions

The following undesirable effects have been observed with indapamide during treatment ranked under the following frequency:

Very common (> 1/10); Common (> 1/100 to < 1/10); Uncommon (> 1/1,000 to < 1/100); Rare (> 1/10,000 to < 1/1,000); Very rare, including isolated reports (< 1/10,000); not known (cannot be estimated from the available data).

Description of selected adverse reactions

During phase II and III studies comparing indapamide 1.5mg and 2.5mg, plasma potassium analysis showed a dose-dependent effect of indapamide:

– Indapamide 1.5mg: 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.

– Indapamide 2.5 mg: Plasma potassium <3.4 mmol/l was seen in 25 % of patients and < 3.2 mmol/l in 10 % of patients after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.41 mmol/l.

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 or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9 Overdose

Symptoms

Indapamide has been found free of toxicity 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: C 03 BA 11

Mechanism of action

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

Pharmacodynamic effects

Dose-effect studies have demonstrated that, at the dose of 2.5 mg per day, the antihypertensive effect is maximal and the diuretic effect is of mild intensity. At this antihypertensive dose of 2.5 mg 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 (betablockers, 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

Absorption

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

Distribution

Indapamide is concentrated in the erythrocytes and is 79% bound to plasma protein and to erythrocytes. It is taken up by the vascular wall in smooth vascular muscle according to its high lipid solubility.

Metabolism

70% of a single oral dose is eliminated by the kidneys and 23% by the gastrointestinal tract. Indapamide is metabolised to a marked degree with 7% of the unchanged product found in the urine during the 48 hours following administration. Elimination half-life (P phase) of indapamide is approximately 15 – 18 hours.

5.3 Preclinical safety data

Indapamide has been tested negative concerning mutagenic and carcinogenic properties.

The highest doses administered orally to different animal species (40 to 8000 times the therapeutic dose) have shown an exacerbation of the diuretic properties of indapamide. The major symptoms of poisoning during acute toxicity studies with indapamide administered intravenously or intraperitoneally were related to the pharmacological action of indapamide, i.e. bradypnoea and peripheral vasodilation.

Reproductive toxicity studies have not shown embryotoxicity and teratogenicity. Fertility was not impaired either in male or in female rats.

6 PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Lactose monohydrate, maize starch, povidone, magnesium stearate.

Sugar coat: Opaseal (polyvinylacetate phthalate, stearic acid), talc, calcium carbonate, acacia, titanium dioxide (E171), sucrose, Opaglos 6000P (yellow carnauba wax, white beeswax, shellac).

6.2 Incompatibilities

None stated.

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store below 25°C in a dry place.

6.5 Nature and contents of container

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

Pack sizes: 28, 30, 50, 56, 60, 100, 120 and 250 tablets.

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

Pack sizes: 28, 30, 50, 56, 60 100 and 120 tablets.

6.6 Special precautions for disposal

None stated.

7 MARKETING AUTHORISATION HOLDER

Manx Healthcare Ltd

Taylor Group House

Wedgnock Lane

Warwick

CV34 5YA

United Kingdom

8 MARKETING AUTHORISATION NUMBER(S)

PL14251/0078

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

23/06/2008