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FLUDEX 1.5MG SR TABLETS

Active substance(s): INDAPAMIDE

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SUMMARY OF PRODUCT CHARACTERISTICS

1

NAME OF THE MEDICINAL PRODUCT
Fludex 1.5 mg SR Tablets

2

QUALITATIVE AND QUANTITATIVE COMPOSITION
One prolonged-release film-coated tablet contains 1.5 mg indapamide.
Excipient with known effect: 124.5 mg lactose monohydrate
For the full list of excipients, see section 6.1.

3

PHARMACEUTICAL FORM

Prolonged-release tablet.
White, round, film-coated tablet.

4
4.1

CLINICAL PARTICULARS
Therapeutic indications
Fludex 1.5 mg SR is indicated in essential hypertension in adults.

4.2

Posology and method of administration
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.
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 Fludex 1.5mg SR Tablets when renal
function is normal or only minimally impaired.

Paediatric population:
The safety and efficacy of Indapamide Arrow 1.5 mg in children and adolescents have
not been established. No data are available.
Method of administration
Oral use.

4.3

Contraindications
- 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 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 thiaziderelated 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.
Excipients:
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase
deficiency or glucose-galactose malabsorption should not take this medicine.
Special precautions for use
- Water and electrolyte balance:
• 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 of 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. 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.
• 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 medicinal product contains a
drug substance, which may give a positive reaction in doping tests.

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 (A.C.E.) inhibitors:
Risk of sudden hypotension and/or acute renal failure when treatment with an A.C.E.
is initiated in the presence of preexisting 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.
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 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 µmol/l) in men and
12 mg/l (110 µmol/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

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 decrease 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 hypersensitivity reactions, mainly
dermatological, in subjects with a predisposition to allergic and asthmatic reactions
and maculopapular rashes.
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.
The majority of adverse reactions concerning clinical or laboratory parameters are
dose-dependent.
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 (≥1/100,000 to <1/10,000), not known
(cannot be estimated from the available data).

MedDRA
System Organ Class

Frequency
Undesirable Effects

Agranulocytosis
Aplastic anaemia
Blood and the
lymphatic System
Haemolytic anaemia
Disorders
Leucopenia
Thrombocytopenia
Hypercalcaemia
Metabolism and
Potassium depletion with hypokalaemia, particularly
Nutrition Disorders serious in certain high risk populations (see section 4.4)
Hyponatraemia (see section 4.4)
Vertigo
Fatigue
Nervous System
Headache
disorders
Paraesthesia
Syncope
Myopia
Eye disorders
Blurred vision
Visual impairment

Very rare
Very rare
Very rare
Very rare
Very rare
Very rare
Not known
Not know
Rare
Rare
Rare
Rare
Not known
Not known
Not known
Not known

Frequency

MedDRA
System Organ Class
Cardiac Disorders
Vascular Disorders
Gastrointestinal
Disorders

Hepatobiliary
Disorders

Skin and
Subcutaneous
Tissue Disorder

Undesirable Effects
Arrhythmia
Torsade de pointes (potentially fatal) (see sections 4.4
and 4.5)
Hypotension
Vomiting
Nausea
Constipation
Dry mouth
Pancreatitis
Abnormal hepatic function
Possibility of onset of hepatic encephalopathy in case of
hepatic insufficiency (see sections 4.3 and 4.4)
Hepatitis
Hypersensitivity reactions
Maculopapular rashes
Purpura
Angioedema
Urticaria
Toxic epidermal necrolysis
Stevens-Johnson Syndrome
Possible worsening of pre-existing acute disseminated
lupus erythematosus
Photosensitivity reactions (see section 4.4)

Renal and Urinary
Disorders

Renal failure

Investigations

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

Very rare
Not known
Very rare
Uncommon
Rare
Rare
Rare
Very rare
Very rare
Not known
Not known
Common
Common
Uncommon
Very rare
Very rare
Very rare
Very rare
Not known
Not known
Very rare
Not known
Not known
Not known
Not known

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.

4.9

Overdose
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).
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
5.1

PHARMACOLOGICAL PROPERTIES
Pharmacodynamic properties
Pharmacotherapeutic group: Sulfonamides, plain
ATC code: C 03 BA 11
Mechanism of action
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.
Pharmacodynamic effects
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
FLUDEX 1.5 mg SR Tablets is supplied in a prolonged release dosage based
on a matrix system in which the drug substance 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.

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
Tablet:
Silica, colloidal anhydrous
Hypromellose
Lactose monohydrate
Magnesium stearate
Povidone
Film-coating:
Glycerol
Hypromellose
Macrogol 6000
Magnesium stearate

Titanium dioxide

6.2

Incompatibilities

Not applicable

6.3
2 years

Shelf life

6.4

Special precautions for storage
Store below 30°C.

6.5
Nature and contents of container
10, 14, 15, 20, 30, 50, 60, 90, 100 tablets in blisters (PVC/aluminium).
Not all pack sizes may be marketed.

6.6

Special precautions for disposal

No special requirements

7

MARKETING AUTHORISATION HOLDER

Les Laboratoires Servier
50, rue Carnot
92284 Suresnes cedex
France

8

MARKETING AUTHORISATION NUMBER(S)

PL 05815/0016

9

DATE OF FIRST AUTHORISATION/RENEWAL OF THE
AUTHORISATION
25/02/2007

10

DATE OF REVISION OF THE TEXT
27/11/2015

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Source: Medicines and Healthcare Products Regulatory Agency

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