INDAPAMIDE HEMIHYDRATE 2.5 MG TABLETS, NATRAMID/OPUMIDE - summary of medicine characteristics

1 NAME OF THE MEDICINAL PRODUCT

Indapamide Hemihydrate 2.5mg Tablets

2 QUALITATIVE AND QUANTITATIVE COMPOSITION

Each tablet contains 2.5mg of Indapamide Hemihydrate.

Excipients with known effect:

Lactose

Sucrose

Ponceau 4R (E124)

Methyl Hydroxybenzoate (E128)

Propylhydroxy­benzoate (E216)

For the full list of excipients, see section 6.1

3 PHARMACEUTICAL FORM

Tablet

Pink sugar-coated tablets.

4.1 Therapeutic indications

Indapamide Tablets are indicated for the treatment of essential hypertension in adults.

4.2 Posology and method of administration

For oral administration.

Posology

Adults:

The dosage is one tablet, containing 2.5mg indapamide hemihydrate, daily to be taken in the morning. The action of indapamide is progressive and the reduction in blood pressure may reach a maximum until several months after the start of therapy.

A larger dose than 2.5mg daily is not recommended as there is no appreciable additional antihypertensive effect, but a diuretic effect may become apparent.

If one indapamide tablet daily 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. Co- administration of indapamide with diuretics may cause hypokalaemia and, therefore, is not recommended.

There is no evidence of rebound hypertension following 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 Tablets when renal function is normal or only minimally impaired.

Paediatric , population:

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

Method of administration:

Oral use.

4.3 Contraindications

Indapamide is contraindicated in patients with:

Hypersensitivity to the active substance, to other sulfonamides or to any of the excipients listed in section 6.1

Severe renal failure.

Hepatic encephalopathy or severe impairment of liver function.

Hypokalaemia.

4.4

Special warnings and precautions for use

Special warnings

When liver function is impaired, thiazide-related diuretics may cause, particularly in case of electrolyte imbalance. hepatic encephalopathy which can progress to hepatic coma.

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.

Lactose and Sucrose:

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

Sodium:

This medicine contains less than 1mmol (23mg) of sodium in each tablet, that is to say essentially sodium-free.

Special precautions ~ for use

Plasma sodium:

This must be measured before starting treatment, then at regular intervals subsequently. 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). Any diuretic treatment may cause hyponatraemia, sometimes with very serious consequences. Hyponatraemia with hypovolaemia may be 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.

Plasma potassium:

Potassium depletion with hypokalaemia is the major risk of thiazide and related diuretics. Hypokalaemia may cause muscle disorders. Cases of Rhabdomyolysis have been reported, mainly in the context of severe hypokalaemia. 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 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.

Detection of hypokalaemia requires its correction. Hypokalaemia found in association with low serum magnesium concentration can be refractory to treatment unless serum magnesium is corrected.

Plasma magnesium:

Thiazides and related diuretics including indapamide have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia (see section 4.5 and 4.8).

Plasma calcium:

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

Treatment should be withdrawn before the investigation of parathyroid function.

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.

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 pmol/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 preexisting renal insufficiency.

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

Sulfonamide or sulfonamide derivative drugs can cause an idiosyncratic reaction resulting in choroidal effusion with visual field defect, transient myopia and acute angle-closure glaucoma. Untreated acute angle-closure glaucoma can lead to permanent vision loss. The primary treatment is to discontinue drug intake as rapidly as possible. Prompt medical or surgical treatments may need to be considered if the intraocular pressure remains uncontrolled. Risk factors for developing acute angleclosure glaucoma may include a history of sulfonamide or penicillin allergy

4.5 Interaction with other medicinal products and other forms of interaction

Combinations that are not recommended:

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

Risk of sudden hypotension and/or acute renal failure when treatment with an A.C.E. 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 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 heart failure, start with a very low dose of A.C.E. 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 A.C.E. inhibitor.

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 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.

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 gmol/l) in men and 12 mg/l (110 gmol/l) 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 increased risk of orthostatic hypotension increased (additive effect).

Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.

Risk of increased plasma creatinine without any change in circulating cyclosporin 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:

Indapamide is excreted in human milk in small amounts. 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.

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), frequency not known (cannot be estimated from the available data).

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

Rare: Hypochloraemia, Hypomagnesaemia

Very Rare: hypercalcaemia

Common: Hypokalaemia (see section 4.4)

Uncommon: Hyponatraemia (see section 4.4)

Uncommon: Erectile dysfunction

Rare: vertigo, fatigue, headache, paresthesia

Not known: Syncope

Not known: Choroidal effusion, Myopia, Blurred vision, Visual impairment, Acute angle-closure glaucoma

Very rare: arrhythmia,

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

Very rare: Hypotension

Uncommon: vomiting,

Rare: dry mouth, nausea, constipation

Very rare: pancreatitis

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.

Common: maculopapular rashes, hypersensitivity reactions

Uncommon: purpura

Very rare: Angioedema, urticaria, toxic epidermal necrolysis, Steven Johnson syndrome, Not known: Possible worsening of pre-existing acute disseminated lupus erythematosus, Photosensitivity reactions (see section 4.4)

Very rare: renal failure.

Not known: Muscle spasms, Muscular weakness, Myalgia, Rhabdomyolysis

Not known: Electrocardiogram QT prolonged (see sections 4.4 and 4.5), Blood glucose increased (see section 4.4), blood uric acid increased (see section 4.4), elevated liver enzyme levels

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 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 at: 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 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.

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Sulfonamides, plain

ATC Code: C03BA11

Mechanism of action

Indapamide is a non-thiazide sulfonamide with an indole ring, belonging to the diuretic family. At the dose of 2.5mg, 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 is sub-clinical.

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

The vascular mechanism of action of Indapamide Tablets 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 Tablets:

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 Tablets in diabetic hypertensive subjects.

Lastly, the co-prescription of Indapamide Tablets 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

Absorption

Indapamide is rapidly and completely absorbed from the gastro-intestinal tract. Peak blood levels are obtained after 1 to 2 hours.

Distribution

The drug is preferentially and reversibly taken up by red blood cells and is about 79% bound to plasma proteins 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.

6.1

Lactose B.P.

Di-basic Calcium Phosphate B.P

Maize Starch B.P

(Purified Water B.P)

Magnesium Stearate B.P

Croscarmellose Sodium (Type A) N.F

CS7 Shellac Solution dilute:-

Shellac (1963) B.P.C.

Castor Oil (No. 1) B.P./Ph.Eur.

(Industrial Methylated Spirits)

CS4 White Coating Paste:-

Coating Paste C53

Titanium Dioxide B.P (E171)

Coating Paste C53.-

Sugar Syrup C31

Acacia Gum CS83

Talc B.P

Sugar Syrup CSI

Sucrose B.P

(Purified Water B.P)

Preservative Solution CS26

Preservative Solution CS26:-Methylhydroxy­benzoate B.P Propylhydroxy­benzoate B.P (Industrial Methylated Spirits) Acacia Gum CS83.-

Acacia B.P.

(Purified Water B.P)

(Chloroform BP) *

Pink Sugar Syrup CS116:-

Opalux AS-F- 1312

Sugar Syrup 70% CSS4

Sugar Syrup 70% CSS4:-(Purified Water B.P) Sucrose B.P

CS9 Polyethylene Glycol Polishing Solution:-Polyethylene Glycol 6000 B.P (Industrial Methylated Spirits)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

36 months

6.4 Special precautions for storage

Protect from light.

Do not store above 25°C.

6.5 Nature and contents of container

Blister packs which consist of strips made from hard PVC with a foil lid.

Pack sizes 28 tablets in blister packs of 14 (2 × 14); 30 tablets in blister packs of 15 (2 × 15); 56 tablets in blister packs of 14(4 × 14) and 60 tablets in blister packs of 15 (4 × 15).

6.6 Special precautions for disposal

No special requirements for disposal.

Crescent Pharma Limited

3&4 Quidhampton Business Units

Polhampton Lane

Overton

Hampshire

RG25 3ED

UK

8 MARKETING AUTHORISATION NUMBER(S)

PL 20416/0315

9 DATE OF FIRST AUTHORISATION/RENEWAL OF THEAUTHORISATION

25/07/2001