1. NAME OF THE MEDICINAL PRODUCT

Indapamide Hemihydrate tablets 2.5 mg

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5 mg indapamide hemihydrate.

Excipient with known effect:

Each tablet contains 50 mg lactose.

For the full list of excipients, see section 6.1.

3.    PHARMACEUTICAL FORM

Film-coated tablet.

Indapamide tablets are 6.5 mm white biconvex film coated tablet, marked “IE 2.5” on one side and “G” on the other side.

4.    CLINICAL PARTICULARS

4.1    Therapeutic indications

Indapamide hemihydrate tablets are indicated for the oral treatment of essential hypertension.

Indapamide hemihydrate tablets may be used as sole therapy or combined with other antihypertensive agents.

4.2    Posology and method of administration

Posology

Adults

The dosage is one tablet, containing 2.5 mg indapamide hemihydrate, daily to be taken in the morning. Renal failure (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.

Older people (see section 4.4)

In the older people, the plasma creatinine must be adjusted in relation to age, weight and gender. Older people can be treated with indapamide when renal function is normal or only minimally impaired.

Patients with hepatic impairment (see sections 4.3 and 4.4)

In severe hepatic impairment, treatment is contraindicated.

Children and adolescents

Indapamide is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

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 2.5 mg indapamide daily is not recommended as there is no appreciable additional antihypertensive 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; those which have been used in combination with indapamide include beta-blockers, ACE inhibitors, methyldopa, clonidine and other adrenergic blocking agents. The co-administration of indapamide with diuretics may cause hypokalaemia and, therefore, is not recommended.

There is no evidence of rebound hypertension on withdrawal of indapamide.

Method of administration

Indapamide tablets are for oral administration only.

4.3    Contraindications

Indapamide hemihydrate is contraindicated in patients who are hypersensitive to the active substance, to other sulphonamides or to any of the excipients listed in section 6.1.

Indapamide hemihydrate is contraindicated in patients with severe renal failure, hepatic encephalopathy or severe impairment of liver function, hypokalaemia or recent cerebrovascular accident and in those with severe hepatic failure.

4.4    Special warnings and precautions for use

Treatment with indapamide hemihydrate should be stopped if hypercalcaemia occurs in patients with hyperparathyroidism.

In case of hepatic impairment, thiazide-related diuretics may cause hepatic encephalopathy, particularly in case of electrolyte imbalance. Administration of the diuretic must be stopped immediately if this occurs.

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.

Patients likely to be exposed to direct sunlight or ultraviolet light should be advised that photosensitivity leading to exaggerated sunburn may occur and treatment should be discontinued at the first sign of skin erythema.

Angioneurotic oedema

Angioneurotic oedema of the face, extremities, lips, tongue, glottis and/or larynx has been reported infrequently in patients receiving treatment with indapamide. In such cases, treatment with indapamide should be stopped immediately and the patient should be monitored until the oedema has disappeared.

Water and electrolyte balance

Plasma sodium

Plasma sodium must be measured before treatment is initiated and subsequently at regular intervals. Any kind of treatment with diuretics may cause hyponatraemia, sometimes with very serious consequences. A drop in plasma sodium may be asymptomatic in the beginning. Therefore, regular monitoring is essential and should be carried out even more frequently in elderly patients and in cirrhotic patients (see sections 4.8 and 4.9).

Plasma potassium

Potassium depletion with hypokalaemia constitutes the greatest risk in the treatment with thiazides 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 (see section 4.5), cirrhotic patients with oedema and ascites, coronary artery disease, cardiac failure patients, patients with hyperaldosteronism, patients predisposed to or suffering from gout, cardiac patients as hypokalemia increases the sensitivity to digoxin and the risk of arrhythmia. 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 torsades de pointes.

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 and subsequently at regular intervals, especially in the mentioned risk patients.

If hypokalaemia (< 3.4 mmol potassium) is detected, it must be corrected and it should be prevented in risk patients.

Plasma calcium

Thiazides and related diuretics may decrease urinary calcium excretion and cause a slight and transitory increase in plasma calcium. Frank hypercalcaemia may be due to previously unrecognised hyperparathyroidism.

Treatment should be withdrawn before the investigation of parathyroid function.

Blood glucose

Monitoring of blood glucose is important in diabetic patients, especially in the presence of hypokalaemia.

Uric acid

Serum urate should be monitored in patients with gout. Tendency to gout attacks may be increased in hyperuricaemic patients.

Renal function and diuretics

Caution should be exercised when administering indapamide hemihydrate to patients with severe renal impairment. However, the drug has been safely given to patients with impaired renal function. However, if renal insufficiency worsens, treatment should be stopped.

Thiazides and related diuretics are fully effective at normal or only minimally impaired renal function (plasma creatinine below levels of the order of 25 mg/l, i.e. < 220 pmol/l in an adult). In elderly patients, the plasma creatinine values must be adjusted according to age, body weight and sex.

Secondary hypovolaemia, as a result of loss of water and sodium induced by the diuretic at the start of treatment results in reduced glomerular filtration which, may increase plasma concentrations of blood urea and creatinine. This temporary impairment of renal function is harmless to patients with normal renal function but may exacerbate pre-existing renal insufficiency.

Athletes

The attention of athletes is drawn to the fact that this medicinal product contains a drug substance, which may give a positive result in doping tests.

Lactose

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Combinations that are not recommended

Lithium

Increased plasma lithium with signs of overdosage, 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

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.

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

Angiotensin converting enzyme (ACE) inhibitors

Risk of sudden hypotension and/or acute renal failure when treatment with an ACE inhibitor is initiated in the presence of pre-existing sodium depletion (particularly 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 ACE inhibitor, and restart a hypokalaemic diuretic if necessary;

-    or give low initial doses of the ACE inhibitor and increase the dose gradually.

In congestive heart failure, start with a very low dose of ACE inhibitor, possibly 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 ACE inhibitor.

Other compounds causing hypokalaemia: amphotericin B (IV), gluco- and mineralo-corticoids (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 antihypertensive effect.

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

Digitalis preparations

Hypokalaemia predisposing to the toxic effects of digitalis.

Monitoring of plasma potassium and ECG and, if necessary, adjust the treatment.

Combinations to be taken into consideration

Potassium-sparing diuretics (amiloride, spironolactone, triamterene)

Whilst rational combinations are useful in some patients, hypokalaemia (particularly in patients with renal failure or diabetes) or hyperkalaemia 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 15 mg/l (135 pmol/l) in men and 12 mg/l (110 gmol/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.

Rehydration before administration of the iodinated compound.

Imipramine-like antidepressants, neuroleptics

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

Calcium (salts)

Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.

Ciclosporin, tacrolimus

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

Corticosteroids, tetracosactide (systemic route)

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

4.6    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.

Breastfeeding

Breastfeeding is inadvisable (indapamide is excreted in human milk).

4.7    Effects on ability to drive and use machines

Indapamide hemihydrate 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 reactions concerning clinical or laboratory parameters are dose-dependent.

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

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 (<1/10,000) and not known (cannot be estimated from the available data).

System Organ Class	Adverse Event	Frequency
Blood and lymphatic system disorders	Thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia	Very rare
Metabolism and nutrition disorders	Hypercalcaemia Hypokalaemia, serious especially in risk patients (see section 4.4) Increased serum urate Hyponatraemia with hypovolaemia and the risk of dehydration. Concomitant loss of chloride ions may lead to secondary compensatory metabolic alkaloses; however, the frequency and severity is small. Loss of weight, hyperglycaemia	Very rare Not known Not known Not known Not known
Nervous system disorders	Fatigue, headache, paraesthesia, vertigo Dizziness, syncope	Rare Not known
Cardiac disorders	Arrhythmia Torsades de pointes (potentially fatal) (see sections 4.4 and 4.5)	Very rare Not known
Vascular disorders	Orthostatic hypotension Hypotension	Uncommon Very rare
Gastrointestinal disorders	Vomiting Nausea, constipation, dryness of the mouth Pancreatitis	Uncommon Rare Very rare
Hepatobiliary disorders	Possibility of onset of hepatic encephalopathy in patients with impaired liver function (see sections 4.3 and 4.4), hepatitis	Not known
Skin and subcutaneous tissue disorders	Hypersensitivity reactions, mainly dermatological, may be observed in patients predisposed to allergic and asthmatic manifestations Maculopapular rash Purpura Erythema multiforme Angioneurotic oedema, urticaria, toxic epidermal necrolysis, Steven Johnson syndrome Photosensitivity (see section 4.4) Possible exacerbation of acute disseminated lupus erythematosus	Common Uncommon Rare Very rare Not known Not known
Musculoskeletal and connective tissue disorders	Muscular cramps	Rare

System Organ Class	Adverse Event	Frequency
Renal and urinary	Renal failure	Very rare
disorders	Renal insufficiency	Not known
Reproductive system and breast disorders	Impotence	Not known

Investigations

Very rare:

•    Abnormal liver function tests

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 Metabolism and nutrition disorder

During clinical trials, hypokalaemia (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.

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:

Yellow Card Scheme

Website: www.mhra.gov.uk/yellowcard

4.9 Overdose

Symptoms

Indapamide has been found free of toxicity at up to 40 mg, 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 sulphonamide with an indole ring, belonging to the diuretic family which has certain structural similarities to Furosemide as well as the thiazides and has actions and uses similar to those of chlorothiazide. Diuresis is initiated within about 1 to 2 hours and has been reported to last for up to 36 hours. Its inhibitory action on carbonic anhydrase is only weak. At the dose of 2.5 mg per day indapamide exerts a prolonged antihypertensive activity in hypertensive human subjects.

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 sub-clinical.

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 (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

Absorption

Indapamide is rapidly and completely absorbed from the gastrointestinal tract and peak plasma concentrations are seen 1-2 hours after oral dosing.

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. 70% of a single oral dose is eliminated by the kidneys and 23% by the gastrointestinal tract.

Biotransformation and elimination

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

There are no additional pre-clinical data that would be of relevance to the prescriber.

6. PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core Lactose

Cellulose, microcrystalline Sodium Starch Glycolate Croscarmellose Sodium Type A Magnesium stearate

Tablet film coat

Opadry White Y-1-7000, which contains:

Hydroxypropylmethylcellulose Polyethylene Glycol 400 Titanium dioxide (E171)

6.2    Incompatibilities

None stated.

6.3    Shelf life

3 years

6.4    Special precautions for storage

Store in a cool dry place.

Use as directed by a physician

Keep out of the sight and reach of children.

6.5    Nature and contents of container

Securitainers with urea white caps and “Jayfilla” ullage filler, containing 30, 60, 100, 250 or 500 tablets.

Blister packs containing 28, 30, 56 or 60 tablets.

Not all pack sizes may be marketed.

6.6    Special precautions for disposal

Not applicable

7. MARKETING AUTHORISATION HOLDER

Generics [UK] Limited t/a Mylan Station Close Potters Bar

Herts EN6 1TL

8.    MARKETING AUTHORISATION NUMBER

PL 04569/0232

9.    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

05/07/1991 / 11/09/1996

10 DATE OF REVISION OF THE TEXT

22/01/2015