Indipam

Indipam XL 1.5 mg Prolonged-release Tablets.

Each prolonged-release tablet contains 1.5 mg of indapamide.

Excipient with known effect:

144.22 mg of lactose monohydrate/prolonged-release tablet

Prolonged-release tablet

White to off white, round, biconvex prolonged-release film-coated tablets.

Essential hypertension.

Posology

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

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

Renal failure :

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.

Elderly :

In the elderly, this plasma creatinine must be adjusted in relation to age, weight and gender. Elderly patients can be treated with Indipam XL 1.5 mg Prolonged-release Tablets when renal function is normal or only minimally impaired.

Patients with hepatic impairment :

In severe hepatic impairment, treatment is contraindicated.

Children and adolescents:

Indipam XL 1.5 mg Prolonged-release Tablets are not recommended for use in children and adolescents due to a lack of data on safety and efficacy.

Method of administration

For oral administration.

-

- Severe renal failure.

- Hepatic encephalopathy or severe impairment of liver function.

- Hypokalaemia.

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.

Lactose intolerance

This medicinal product contains lactose monohydrate. Patients with rare hereditary disorders such as galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption, should not take this medicine.

Photosensitivity

Cases of photosensitivity reactions have been reported with thiazides and thiazide-related diuretics. If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of indapamide 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 diuretic 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.

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 increase 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.

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.

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 25 mg/l, i.e. 220 µmol/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.

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.

Indapamide has a minor or moderate influence on the ability to drive and use machines. Indapamide does not affect vigilance. However, in individual cases the hypotensive effect may impact on a patient´s ability to drive and operate machinery, especially at the start of treatment or when another antihypertensive agent is added.

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

Adverse reactions are listed below by system organ class and frequency. Frequencies are defined as: Very common (>1/10); common (>1/100 to <1/10); uncommon (>1/1000 to <1/100); rare (>1/10000, <1/1000), very rare (<1/10000),not known (cannot be estimated from the available data).

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 epidermic necrolysis, Steven Johnson syndrome

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

- Cases of photosensitivity reactions have been reported.

Laboratory parameters :

During clinical trials, hypokalaemia (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.

Very rare : Hypercalcaemia

Not known:

- Potassium depletion with hypokalaemia, particularly serious in certain high risk populations.

- 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.

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

Symptoms:

Indapamide has been found free of toxicity at up to 40 mg, i. e. 27 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).

Treatment:

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.

Pharmacotherapeutic group:

Antihypertensive DIURETICS, Sulfonamides, plain

ATC code: C 03 BA 11

Indapamide is a sulfonamide derivate 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, to a lesser extent, the excretion of potassium and magnesium, thereby increasing urine output and having an antihypertensive action.

Phase II and III studies using monotherapy have demonstrated an antihypertensive effect lasting 24 hours. This was present at doses where 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-, mild- and long-term in hypertensive patients, that indapamide:

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

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

The medicinal product is supplied in a prolonged release dosage based on a matrix system in which the active ingredient is dispersed within a support which allows sustained release of indapamide.

Absorption

The fraction of indapamide released is rapidly and totally absorbed via the gastrointestinal digestive tract. Eating slightly increases the rapidity of absorption but has no influence on the amount of the drug absorbed. Peak serum level following a single dose occurs about 12 hours after ingestion, repeated administration reduces the variation in serum levels between 2 doses. Intra-individual variability exists.

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 accumulation.

Metabolism

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

High risk individuals

Pharmacokinetic parameters are unchanged in renal failure patients.

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. Indapamide has been tested negative concerning mutagenic and carcinogenic properties.

Tablet core:

Lactose monohydrate

Maize starch, pregelatinised

Hypromellose

Silica, colloidal anhydrous

Magnesium stearate

Tablet coating:

Hypromellose

Macrogol 6000

Titanium dioxide (E171)

Not applicable.

36 months.

This medicinal product does not require any special storage conditions.

Al/PVC blister

Pack sizes: 10, 14, 15, 20, 30, 50, 60, 90, 100 tablets

Not all pack sizes may be marketed.

No special requirements.

Actavis Group PTC ehf

Reykjavíkurvegur 76-78,

220 Hafnarfjordur,

Iceland

PL 30306/0010

12.08.08

13.11.2015