SUMMARY OF PRODUCT CHARACTERISTICS

1 NAME OF THE MEDICINAL PRODUCT

Rawel XL prolonged-release tablets 1.5 mg

2    QUALITATIVE AND QUANTITATIVE COMPOSITION

Each prolonged-release tablet contains 1.5 mg indapamide.

Also contains lactose monohydrate 97.58 mg.

For a full list of excipients, see 6.1.

3    PHARMACEUTICAL FORM

Prolonged-release tablet White, round, slightly biconvex.

4    CLINICAL PARTICULARS

4.1    Therapeutic indications

Essential hypertension.

4.2    Posology and method of administration

Indapamide is administered orally.

One tablet should be taken once a day, preferably in the morning. It should be swallowed whole with water and not chewed.

At higher doses the antihypertensive effect of indapamide is not enhanced but the excretion of salt is increased (saluretic effect).

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

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

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.

Patients with hepatic impairment (see sections 4.3 and 4.4):

In severe hepatic impairment, treatment is contraindicated.

4.3 Contraindications

Indapamide is contraindicated in:

•    Hypersensitivity to indapamide, to other sulfonamides or to any of the excipients

•    Severe renal failure

•    Hepatic encephalopathy or severe impairment of liver function

•    Hypokalaemia

4.4 Special warnings and precautions for use

Warning

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

Precautions for use

1. Water and electrolyte balance

Plasma sodium

Diuretics may cause hyponatraemia, sometimes with very serious consequences. Plasma sodium is measured before treatment is started and then at regular intervals subsequently. The fall in plasma sodium may be asymptomatic initially and regular monitoring is therefore essential. In the elderly and cirrhotic patients, monitoring should be even more frequent (see Undesirable effects and Overdose sections).

Plasma potassium

The major risk of treatment with thiazide and related diuretics is hypokalaemia. The risk of onset of hypokalaemia (< 3.4 mmol/l) must be prevented in certain high risk groups, i.e. patients that are malnourished and/or are taking several drugs concomitantly, the elderly, cirrhotic patients with oedema and ascites, patients with coronary artery disease and cardiac failure. In these patients, hypokalaemia increases the cardiotoxicity of digitalis preparations and the risks of arrhythmias.

Patients with a long QT interval are also at risk, whether the origin is congenital or drug-induced. Hypokalaemia (as well as bradycardia) is then a predisposing factor to the onset of severe arrhythmias, in particular, potentially fatal heart rhythm disorders of the type “torsades de pointes”.

In these patients, more frequent monitoring of plasma potassium is required. The first measurement of plasma potassium should be obtained during the first week of treatment.

If low potassium levels are detected, correction is required.

Plasma calcium

Thiazide and related diuretics may decrease urinary calcium excretion and cause a slight and transitory rise in plasma calcium. Evident hypercalcaemia may be due to previously unrecognised hyperparathyroidism. Treatment with the diuretic should be withdrawn before any planned 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.

2.    Renal function and diuretics

Thiazide and related diuretics are fully effective only when renal function is normal or only minimally impaired (plasma creatinine levels below 25 mg/l, i.e. 220 pmol/l in adults). 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 transient renal dysfunction has no consequences in patients with normal renal function but it may deteriorate the existing renal insufficiency.

3.    Athletes

Athletes should note that this product contains an active substance which may cause a positive reaction in doping tests.

4.    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 indapamide is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.

This medicinal product contains 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

1. Combinations that are not recommended

Lithium

Concomitant use of lithium may lead to increase of plasma lithium concentration with signs of overdosage, as with a sodium-free diet (decreased urinary lithium excretion). However, if the use of diuretics is necessary, careful monitoring of plasma lithium and dose adjustment is required.

2. Combinations that require precaution

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.

Non-steroidal anti-inflammatory drugs (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

When treatment with an ACE inhibitor is initiated, sudden hypotension and/or acute renal failure may occur in patients with pre-existing depletion of sodium (particularly in patients with renal artery stenosis).

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

•    to stop the diuretic 3 days before starting treatment with the ACE inhibitor and restart a non-potassium-sparing diuretic if necessary;

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

In patients with congestive heart failure, start with a very low dose of ACE inhibitor, preferably after a reduction in the dose of a non-potassium-sparing diuretic.

In all patients, renal function (plasma creatinine) should be monitored during the first weeks of treatment with an ACE inhibitor.

Other drugs causing hypokalaemia:

•    Amphotericin B (IV)

•    Gluco- and mineralo-corticoids (systemic)

•    Tetracosactide

•    Stimulant laxatives

The risk of hypokalaemia is increased (additive effect). Plasma potassium should be monitored and corrected if necessary. Caution is required in patients concomitantly taking digitalis. These patients should take non-stimulant laxatives.

Baclofen

Increased antihypertensive effect.

The patient should drink sufficient quantity of liquid; renal function is monitored at the start of treatment.

Digitalis preparations

Hypokalaemia increases the risk of toxic effects of digitalis.

Plasma potassium and ECG should be monitored and, if necessary, the treatment adjusted.

3. 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 15 mg/l (135 pmol/l) in men and 12 mg/l (110 pmol/l) in women.

Iodinated contrast media

In patients dehydrated due to diuretics, the risk of acute renal failure is increased, particularly when large doses of iodinated contrast media are used. The patient should be rehydrated prior to administration of the ionated compound.

Imipramine-like antidepressants, neuroleptics

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

Calcium (salts)

Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.

Cyclosporin, tacrolimus

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

Corticosteroids, tetracosactide (systemic)

Antihypertensive effect may be decreased (water and sodium retention).

Pregnancy and lactation

Pregnancy

As a general rule, the administration of diuretics to pregnant women should be avoided and diuretics should never be used to treat physiological oedema of pregnancy. Diuretics can cause fetoplacental ischemia with a risk of impaired fetal growth.

Lactation

Indapamide is excreted in human milk and effects on the breast-fed child are likely. Breast-feeding is not recommended during treatment with indapamide.

4.7 Effects on ability to drive and use machines

Indapamide does not affect alertness but different reactions related to 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 of indapamide concerning clinical and laboratory parameters are dose-dependent.

The frequencies of adverse events are ranked according to the following: Very common (> 1/10), Common (> 1/100, < 1/10), Uncommon (> 1/1000, < 1/100), Rare (> 1/10,000, < 1/1000), Very Rare (< 1/10,000) not known (cannot be estimated from the available data).

Thiazide-related diuretics, including indapamide, may cause following undesirable effects:

Blood and the lymphatic system disorders

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

haemolytic anaemia

Nervous system disorders

Rare:    vertigo, fatigue, headache, paresthesia.

Cardiac disorders

Very rare:    arrhythmia, hypotension

Gastrointestinal disorders Uncommon:    vomiting

Rare:    nausea, constipation, dry mouth.

Very rare:    pancreatitis.

Hepato-biliary 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)

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,

Stevens-Johnson syndrome

Not known:    Possible worsening of pre-existing acute disseminated lupus

erythematosus

Cases of photosensitivity reactions have been reported (see section 4.4)

Investigations

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 (see section 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.

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.

4.9 Overdose

Indapamide is not toxic at doses up to 40 mg, i.e. approximately 27 times the therapeutic dose.

Signs of acute poisoning are mostly water/electrolyte balance disturbances (hyponatraemia, hypokalaemia) which are manifested as nausea, vomiting, hypotension, convulsions, vertigo, drowsiness, confusion, polyuria or oliguria possibly to the point of anuria (due to hypovolaemia).

Initial measures involve rapid elimination of the ingested substance by gastric lavage and/or administration of activated charcoal, followed by restoration of water/electrolyte balance in a medical institution.

5 PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

According to the ATC classification, indapamide is classified into the group of diuretics (C03BA11).

Indapamide is a sulphonamide derivative 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-, mid- 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.

5.2 Pharmacokinetic properties

Indapamide 1.5 mg is supplied in a prolonged-release form.

Absorption

The fraction of indapamide released is rapidly and almost totally absorbed via the gastrointestinal tract. Food slightly affects the speed of absorption but has no influence on the amount of the drug absorbed. Peak serum level occurs about 12 hours after ingestion of the drug. After achieving the steady-state concentration, the variation in serum levels between two doses is reduced. However, variability among individual patients exists.

Distribution, metabolism and elimination

Binding of indapamide to plasma proteins is 79%. The plasma elimination half-life is 14 to 24 hours (mean 18 hours). The steady-state is reached in 7 days. Repeated administration does not lead to accumulation of indapamide.

Indapamide is metabolised mainly in the liver. 70% of indapamide is eliminated via the kidneys, to a larger extent in the form of metabolites (fraction of the unchanged drug is about 5%). About 20% of it is excreted in the faeces in the form of inactive metabolites.

The pharmacokinetic parameters of the drug are not significantly changed in patients with renal function impairment.

5.3 Preclinical safety data

The highest doses of indapamide administered orally to different animal species have shown an exacerbation of the pharmacological properties of the drug. No mutagenic or carcinogenic effects have been observed with indapamide.

6    PHARMACEUTICAL PARTICULARS

6.1    List of excipients

Tablet core: hypromellose, powdered cellulose, lactose monohydrate, anhydrous colloidal silica, magnesium stearate

Film coating:

Hypromellose, macrogol 400, titanium dioxide (E 171).

6.2 Incompatibilities

Not applicable

6.3    Shelf life

5 years.

6.4    Special precautions for storage

This medicinal product does not require any special storage conditions.

Nature and contents of container

Blister pack (Al foil, PVC/PVDC foil): 10, 14, 15, 20, 30, 50, 60, 90, 100 prolonged-release tablets in a box.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal

No special requirements.

7    MARKETING AUTHORISATION HOLDER

KRKA, d.d., Novo mesto, Smarjeska cesta 6, 8501 Novo mesto, Slovenia

8 MARKETING AUTHORISATION NUMBER(S)

PL 01656/0065

9    DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

28/03/2008

10    DATE OF REVISION OF THE TEXT

23/10/2014