Active ingredients: Indapamide
NATRILIX 2.5 mg film-coated tablets
Natrilix package inserts are available for pack sizes:- NATRILIX 2.5 mg film-coated tablets
- Natrilix LP 1.5 mg prolonged-release tablets
Why is Natrilix used? What is it for?
Diuretic, sulfonamide-derivative.
Treatment of essential arterial hypertension.
Contraindications When Natrilix should not be used
- Hypersensitivity to the active substance, to other sulfonamide-derived drugs, or to any of the excipients.
- Severe renal insufficiency and anuria.
- Hepatic encephalopathy or severe impairment of liver function.
- Hypokalemia.
- Recent cerebral vascular accidents.
- Pheochromocytoma.
- Conn syndrome.
Precautions for use What you need to know before taking Natrilix
Hydroelectrolytic balance
Natriemia
It must be checked both before starting therapy and at regular intervals thereafter. In fact, any diuretic therapy can cause hyponatremia with sometimes serious consequences. Since the decrease in natremia may initially be asymptomatic, regular monitoring of natremia is essential even more frequently in elderly and cirrhotic patients (see "Undesirable Effects" and "Overdose").
KaliemiaPotassium depletion with hypokalaemia represents the major risk of thiazide and related diuretics. The risk of onset of hypokalaemia (<3.4 mmol / l) must be prevented especially in at-risk populations, such as elderly, undernourished and / or polytreated subjects, cirrhotic patients with edema and ascites, with coronary artery disease and heart failure. . In such situations, hypokalaemia increases cardiac toxicity of digitalis and the risk of arrhythmias.
People with a long QT interval, whether of congenital or iatrogenic origin, are also at risk. Hypokalaemia, like bradycardia, is also a predisposing factor for severe arrhythmias, particularly life-threatening torsades de pointes (see "Undesirable Effects").
In all the conditions described above, more frequent monitoring of kalaemia is required. The first check of plasma potassium should be carried out during the first week after the start of treatment. The assessment of hypokalaemia requires correction.
Calcemia
Thiazide and related diuretics can reduce urinary excretion of calcium and cause a slight and transient increase in calcium. Established hypercalcaemia may be secondary to previous undiagnosed hyperparathyroidism. Treatment should be stopped before checking for parathyroid function.
Glycemia
Control of blood glucose is important in diabetic patients, especially in the presence of hypokalaemia.
Uricemia
The 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 slightly impaired (creatinine below the level of 25 mg / l, or 220 µmol / l in adults). age, weight and gender.
Hypovolemia, secondary to the diuretic-induced loss of water and sodium at the start of therapy, induces a reduction in glomerular filtration. This may lead to an increase in plasma urea and creatinine. This transient impairment of renal function is of no consequence in the subject with normal renal function, but may aggravate pre-existing renal insufficiency.
Interactions Which drugs or foods may change the effect of Natrilix
Tell your doctor or pharmacist if you are taking or have recently taken any other medicines, even those without a prescription.
Combinations not recommended
Lithium
There is an increase in plasma lithium with signs of overdose, as with a sodium-free diet (reduced urinary lithium excretion). If the use of diuretics is nevertheless necessary, careful monitoring of plasma lithium and dosage adjustment are required.
Associations requiring precautions for use
Drugs that cause "torsades de pointes":
- class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide)
- class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide)
- some antipsychotics: phenothiazines (chlorpromazine, ciamemazine, levopromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, thiapride), butyrophenones (droperidol, haloperidol); other drugs: bepridil, cisapride, difemanil, erythromycin i.v., halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine i.v.
Increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalaemia is a risk factor).
Check for hypokalaemia and correct if necessary before administering this combination and conducting clinical, plasma electrolyte and ECG monitoring.
Use drugs that do not cause torsades de pointes in the presence of hypokalemia.
Non-steroidal anti-inflammatory drugs (systemic route), including selective COX-2 inhibitors, high doses of salicylic acid (> 3g / day)Possible reduction of the antihypertensive effect of indapamide.
Risk of acute renal failure in the dehydrated patient (decreased glomerular filtration).
It is therefore recommended to hydrate the patient and to monitor renal function at the start of therapy and during treatment. Angiotensin converting enzyme inhibitors (ACE inhibitors) There is a risk of sudden hypotension and / or renal failure acute if treatment with an ACE inhibitor is initiated in the presence of pre-existing sodium depletion (particularly in patients with renal artery stenosis).
In arterial hypertension, when previous diuretic treatment may have caused sodium depletion, it is necessary to:
- o discontinue the diuretic 3 days prior to initiation of ACE inhibitor therapy and reintroduce a hypokalaemic diuretic if necessary
- o administer reduced initial doses of ACE inhibitors and gradually increase them.
In congestive heart failure, start with a very low dose of ACE inhibitor, possibly after a dose reduction of the associated hypokalaemic diuretic.
In all cases, monitor renal function (plasma creatinine) during the first weeks of treatment with an ACE inhibitor.
Other compounds that can cause hypokalaemia: amphotericin B (i.v.), gluco- and mineralocorticoids (systemic), tetracosactide, stimulant laxatives
Increased risk of hypokalaemia (additive effect).
Check for kalaemia and, if necessary, correct it. This must be particularly taken into account in the case of concomitant digitalis therapy. Use non-stimulant laxatives.
Baclofen
Increased antihypertensive effect.
Hydrate the patient; check renal function at the start of therapy.
Digital
Hypokalaemia predisposes to the toxic effects of digitalis.
Check for kalaemia and ECG, and if necessary, adjust therapy.
Allopurinol Concomitant treatment with indapamide may increase the incidence of hypersensitivity reactions to allopurinol.
Associations to be considered
Potassium-sparing diuretics (amiloride, spironolactone, triamterene)
Although such rational combinations are useful in some patients, hypokalaemia or hyperkalaemia may occur (especially in patients with renal insufficiency or diabetes).
Kalaemia and ECG should be monitored and, if necessary, therapy adjusted.
Metformin
Increased risk of metformin-induced lactic acidosis, due to the possibility of "functional renal failure associated with the use of diuretics, especially 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.
Iodine contrast media
In the presence of diuretic-induced dehydration, the risk of acute renal failure increases, particularly when high doses of iodinated contrast media are used.
Rehydrate the patient before administering the iodized compound.
Imipramine-like antidepressants, neuroleptics
Increased antihypertensive effect and risk of orthostatic hypotension (additive effect).
Calcium salts
Risk of hypercalcemia due to reduced urinary elimination of calcium.
Ciclosporin, tacrolimus
Risk of increased blood creatinine without any change in circulating cyclosporine levels, even in the absence of hydrosodium depletion.
Corticosteroids, tetracosactide (systemic)
Reduction of the antihypertensive effect (hydrosodic retention due to corticosteroids).
Warnings It is important to know that:
Ask your doctor or pharmacist for advice if you have recently taken any other medicines, even those without a prescription
In the case of impaired liver function, thiazide and related diuretics can cause hepatic encephalopathy, particularly in the case of electrolyte imbalance. Should this occur, the administration of the diuretic should be discontinued immediately.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide and related diuretics (see "Undesirable Effects"). If photosensitivity reactions occur during treatment, it is recommended that treatment be discontinued. If it is necessary to resume treatment with indapamide, it is recommended to protect the areas exposed to the sun or to artificial UVA rays. Inform your physician if photosensitivity reactions occur.
Pregnancy
Ask your doctor or pharmacist for advice before taking any medicine.
As a precautionary measure, it is preferable to avoid the use of indapamide during pregnancy.
Data on the use of indapamide in pregnant women are not available or are limited (less than 300 exposed pregnancies). Prolonged exposure to thiazide during the third trimester of pregnancy may reduce maternal plasma volume as well as blood flow uteroplacental, which can cause fetal placental ischaemia and growth retardation.
Feeding time
Insufficient information is available on the excretion of indapamide / its metabolites in human milk. Indapamide is very similar to thiazide diuretics, which have been associated with decreased or even suppression of breast milk production during lactation. Hypersensitivity to sulfonamide-derived drugs and hypokalaemia may occur. A risk to the newborn / infant cannot be excluded. Indapamide should not be used during breastfeeding.
Fertility
Reproductive toxicity studies in animals have shown no effects on fertility. No effects on fertility are expected in humans.
Effects on ability to drive and use machines
Natrilix 2.5 mg does not affect the degree of alertness but, in individual cases, different reactions related to the reduction of blood pressure may occur, especially at the start of treatment or when another antihypertensive agent is combined. As a result, capacity may be impaired. to drive vehicles or to operate machinery.
If you have been told by your doctor that you have an intolerance to some sugars, contact your doctor before taking this medicinal product.
For those who carry out sports activities
The use of the drug without therapeutic necessity constitutes doping and can in any case determine positive anti-doping tests.
Dosage and method of use How to use Natrilix: Dosage
One tablet in a single administration preferably in the morning to be swallowed whole with water without chewing.
At higher doses, an increase in side effects may occur, not accompanied by greater efficacy.
Renal failure (see "Contraindications" and "Precautions for" use ")
thiazide and related diuretics are fully effective only when renal function is normal or only minimally impaired.
Posology should be adjusted based on renal function.
A reduction in dosage should be made according to the degree of renal insufficiency.
In case of severe renal insufficiency (creatinine clearance less than 30 ml / min), treatment is contraindicated (see "Contraindications").
Patients with hepatic insufficiency (see "Contraindications" and "Precautions for" use "):
Indapamide is extensively metabolised by the liver and dose reduction should be made in hepatic insufficiency.
Indapamide treatment is contraindicated in severe hepatic insufficiency (see "Contraindications").
Elderly (see "Contraindications" and "Precautions for" use "):
in elderly patients the serum creatinine level must be adjusted for age, weight and gender. Elderly patients can be treated with Natrilix 2.5 mg when renal function is normal or only minimally impaired.
Children and adolescents
Natrilix 2.5 mg is not recommended in children and adolescents due to a lack of data on safety and efficacy.
If you have any further questions on the use of this medicine, ask your doctor or pharmacist.
Overdose What to do if you have taken too much Natrilix
Indapamide did not show toxicity up to 40 mg, ie 16 times the therapeutic dose. The signs of acute intoxication are mainly manifested by disturbances in the hydroelectrolytic balance (hyponatremia, hypokalaemia). Clinically, the possibility of nausea, vomiting, hypotension, cramps, dizziness, somnolence, confusional state, polyuria or oliguria up to possible anuria (due to hypovolemia).
Initial rescue measures must include rapid elimination of ingested substances by gastric lavage and / or administration of activated charcoal; then the normalization of the hydroelectrolytic balance, in a specialized center.
In case of accidental intake of an excessive dose of the medicine, notify your doctor immediately or go to the nearest hospital.
Side Effects What are the side effects of Natrilix
Like all medicines, this medicine can cause side effects, although not everybody gets them.
Most undesirable effects on clinical or laboratory parameters are dose dependent. Thiazide-related diuretics, including indapamide, may cause the following undesirable effects grouped by frequency according to the following convention: very common (≥1 / 10); common (≥1 / 100 to
Disorders of the blood and lymphatic system
Very rare: thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, haemolytic anemia.
Nervous system disorders
Rare: dizziness, fatigue, headache, paraesthesia, somnolence. Not known: syncope.
Eye disorders
Not known: myopia, blurred vision, visual impairment.
Psychiatric disorders
Not known: mental confusion.
Cardiac pathologies
Very rare: arrhythmia.
Not known: torsades de pointes (potentially fatal) (see "Precautions for use" and "Interactions").
Vascular pathologies
Very rare: hypotension.
Not known: orthostatic hypotension.
Gastrointestinal disorders
Uncommon: vomiting.
Rare: nausea, constipation, dry mouth.
Very rare: pancreatitis.
Hepato-biliary disorders
Very rare: liver function abnormalities.
Not known:
- in case of hepatic insufficiency, there is the possibility of developing a "hepatic encephalopathy" (see "Contraindications" and "Special Warnings").
- hepatitis.
Skin and subcutaneous tissue disorders
Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions.
Common: maculo-papular eruptions.
Uncommon: purpura.
Very rare: angioneurotic edema and / or urticaria, toxic epidermal necrolysis, Steven-Johnson syndrome.
Not known: Possible worsening of pre-existing acute disseminated lupus erythematosus, rash, cases of photosensitivity reactions have been reported (see "Special Warnings").
Musculoskeletal and connective tissue disorders
Rare: muscle cramps.
Not known: falls.
Renal and urinary disorders
Very rare: renal failure.
Not known: acute renal failure.
Investigations Not known:
- electrocardiogram: QT interval prolongation (see "Precautions for use" and "Interactions");
- increase in blood glucose and uric acid levels during treatment: the appropriateness of using these diuretics should be carefully considered in patients with gout or diabetes
- slight increase in urea nitrogen
- elevated levels of liver enzymes.
Metabolism and nutrition disorders
During clinical trials, hypokalaemia (plasma potassium concentrations
Very rare: hypercalcaemia.
Not known:
- potassium depletion with hypokalaemia, particularly severe in certain high-risk patient populations (see "Precautions for use" section).
- hyponatremia with hypovolemia responsible for dehydration and orthostatic hypotension. Concomitant loss of chloride ions can lead to compensatory secondary metabolic alkalosis: the incidence and magnitude of this effect are mild.
Compliance with the instructions contained in the package leaflet reduces the risk of undesirable effects.
Reporting of side effects
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. Side effects can also be reported directly via the national reporting system at www.agenziafarmaco.it/it/responsabili. By reporting side effects you can help provide more information on the safety of this medicine.
Expiry and Retention
Expiry: see the expiry date printed on the package.
The expiry date refers to the product in intact packaging, correctly stored. Do not store above 25 ° C.
Warning: Do not use this medicine after the expiry date stated on the carton and blister.
Medicines should not be disposed of via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. This will help protect the environment.
Keep this medicine out of the sight and reach of children.
Other Information
COMPOSITION
One tablet contains:
Active ingredient: indapamide 2.5 mg
Excipients: Tablet: corn starch; lactose monohydrate; povidone, magnesium stearate, talc.
Film coating: white wax, titanium dioxide, glycerol, sodium lauryl sulfate, hypromellose, macrogol 6000, magnesium stearate.
PHARMACEUTICAL FORM AND CONTENT
Film-coated tablets.
Pack of 30 tablets, in blister packs
Source Package Leaflet: AIFA (Italian Medicines Agency). Content published in January 2016. The information present may not be up-to-date.
To have access to the most up-to-date version, it is advisable to access the AIFA (Italian Medicines Agency) website. Disclaimer and useful information.
01.0 NAME OF THE MEDICINAL PRODUCT
NATRILIX 2.5 MG TABLETS COATED WITH FILM
02.0 QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains:
Active ingredient: indapamide 2.5 mg
Excipients: lactose monohydrate
For the full list of excipients see section 6.1
03.0 PHARMACEUTICAL FORM
Film-coated tablet
04.0 CLINICAL INFORMATION
04.1 Therapeutic indications
Treatment of essential arterial hypertension.
04.2 Posology and method of administration
One tablet in a single administration, preferably in the morning, to be swallowed whole with water, without chewing.
At higher doses, an increase in side effects may occur, not accompanied by greater efficacy.
Renal failure (see sections 4.3 and 4.4)
Thiazide and related diuretics are fully effective only when renal function is normal or only minimally impaired.
Posology should be adjusted based on renal function. A reduction in dosage should be made according to the degree of renal insufficiency.
In case of severe renal insufficiency (creatinine clearance less than 30 ml / min), treatment is contraindicated.
Patients with hepatic insufficiency (see sections 4.3 and 4.4)
Indapamide is extensively metabolised by the liver and dose reduction should be made in hepatic insufficiency.
Indapamide treatment is contraindicated in severe hepatic insufficiency.
Elderly (see section 4.4)
In elderly patients, serum creatinine should be adjusted for age, weight and gender. Elderly patients can be treated with Natrilix 2.5 mg when renal function is normal or only minimally impaired.
Children and adolescents
Natrilix 2.5 mg is not recommended in children and adolescents due to a lack of data on safety and efficacy.
04.3 Contraindications
• Hypersensitivity to the active substance (indapamide), to other sulfonamide-derived drugs or to any of the excipients.
• Severe renal failure and anuria.
• Hepatic encephalopathy or severe impairment of liver function.
• Hypokalaemia.
• Recent cerebral vascular accidents.
• Pheochromocytoma.
• Conn syndrome.
04.4 Special warnings and appropriate precautions for use
Special warnings
In the case of impaired liver function, thiazide and related diuretics can cause hepatic encephalopathy, particularly in the case of electrolyte imbalance. Should this occur, the administration of the diuretic should be discontinued immediately.
Photosensitivity
Cases of photosensitivity reactions have been reported with thiazide and related diuretics (see section 4.8). If photosensitivity reactions occur during treatment, it is recommended that treatment be discontinued. If it is necessary to resume treatment with indapamide, it is recommended to protect the areas exposed to the sun or to artificial UVA rays.
Pregnancy
As a precautionary measure, it is preferable to avoid the use of indapamide during pregnancy (see section 4.6).
Excipients
Patients with rare hereditary problems of galactose intolerance, LAPP-lactase deficiency or glucose-galactose malabsorption should not take this drug.
Precautions for use
Hydroelectrolytic balance
Natriemia
It must be checked both before starting therapy and at regular intervals thereafter. In fact, any diuretic therapy can cause hyponatremia with sometimes serious consequences. Since the decrease in natraemia may initially be asymptomatic, regular monitoring of the same is essential even more frequently in elderly and cirrhotic patients (see sections 4.8 and 4.9).
Kaliemia
Potassium depletion with hypokalaemia represents the major risk of thiazide and related diuretics. The risk of onset of hypokalaemia (edema and ascites, with coronary heart disease and heart failure. In such situations, hypokalaemia increases cardiac toxicity of digitalis and the risk of arrhythmias.
People with a long QT interval, whether of congenital or iatrogenic origin, are also at risk. Hypokalaemia, like bradycardia, is also a predisposing factor to severe arrhythmias, particularly torsades de pointes, which is potentially fatal (see section 4.8).
In all the conditions described above, more frequent monitoring of kalaemia is required. The first check of plasma potassium should be done during the first week after the start of treatment.
Determination of hypokalaemia requires correction.
Calcemia
Thiazide and related diuretics can reduce urinary excretion of calcium and cause a slight and transient increase in calcium. Established hypercalcaemia may be secondary to previous undiagnosed hyperparathyroidism.
Treatment should be stopped before checking for parathyroid function.
Glycemia
Control of blood glucose is important in diabetic patients, especially in the presence of hypokalaemia.
Uricemia
The 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 (creatinine below the level of 25 mg / l, or 220 μmol / l in the adult). a function of age, weight and sex.
Hypovolemia, secondary to the diuretic-induced loss of water and sodium at the start of therapy, induces a reduction in glomerular filtration. This can lead to an increase in plasma urea and creatinine. This transient impairment of renal function is of no consequence in the subject with normal renal function, but may aggravate pre-existing renal insufficiency.
Athletes
Athletes should be advised that this medicine contains an active substance which may have positive effects on doping tests.
04.5 Interactions with other medicinal products and other forms of interaction
Combinations not recommended
Lithium
There is an increase in plasma lithium with signs of overdose, as with a sodium-free diet (reduced urinary lithium excretion). If the use of diuretics is nevertheless necessary, careful monitoring of plasma lithium and dosage adjustment are required.
Associations requiring precautions for use
Drugs that cause "torsades de pointes"
- class Ia antiarrhythmics (quinidine, hydroquinidine, disopyramide),
- class III antiarrhythmics (amiodarone, sotalol, dofetilide, ibutilide),
- some antipsychotics:
phenothiazines (chlorpromazine, ciamemazine, levomepromazine, thioridazine, trifluoperazine), benzamides (amisulpride, sulpiride, sultopride, thiapride), butyrophenones (droperidol, haloperidol);
other drugs: bepridil, cisapride, difemanil, erythromycin i.v., halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine i.v.
Increased risk of ventricular arrhythmias, especially torsades de pointes (hypokalaemia is a risk factor).
Check for hypokalaemia and correct if necessary before administering this combination and conducting clinical monitoring of plasma electrolytes and ECG.
Use drugs that do not cause torsades de pointes in the presence of hypokalemia.
Non-steroidal anti-inflammatory drugs (systemic route), including selective COX-2 inhibitors, high doses of salicylic acid (≥ 3g / day)
Possible reduction of the antihypertensive effect of indapamide.
Risk of acute renal failure in the dehydrated patient (decreased glomerular filtration). It is therefore recommended to hydrate the patient and to monitor renal function at the start of therapy and during treatment.
Angiotensin converting enzyme inhibitors (ACE inhibitors)
There is a risk of sudden hypotension and / or acute renal failure if treatment with an ACE inhibitor is initiated in the presence of pre-existing sodium depletion (particularly in individuals with renal artery stenosis).
- In the "arterial hypertension, when previous diuretic treatment may have caused sodium depletion, it is necessary to:
- or discontinue the diuretic 3 days before the start of therapy with the ACE inhibitor and if necessary reintroduce a hypokalaemic diuretic;
- or administer reduced initial doses of ACE inhibitor, gradually increasing them.
- In "congestive heart failure, start with a very low dose of ACE inhibitor, possibly after a dose reduction of the associated hypokalaemic diuretic.
- In all cases, monitor renal function (plasma creatinine) during the first few weeks of treatment with an ACE inhibitor.
Other compounds that can cause hypokalaemia: amphotericin B (i.v.), gluco- and mineralocorticoids (systemic), tetracosactide, stimulant laxatives
Increased risk of hypokalaemia (additive effect).
Check for kalaemia and, if necessary, correct it. This must be particularly taken into account in the case of concomitant digitalis therapy. Use non-stimulant laxatives.
Baclofen
Increased antihypertensive effect.
Hydrate the patient; check renal function at the start of therapy.
Digital
Hypokalaemia predisposes to the toxic effects of digitalis.
Check for kalaemia and ECG, and if necessary, adjust therapy.
Allopurinol
Concomitant treatment with indapamide may increase the incidence of hypersensitivity reactions to allopurinol.
Associations to be considered:
Potassium-sparing diuretics (amiloride, spironolactone, triamterene)
Although such rational combinations are useful in some patients, hypokalaemia or hyperkalaemia may occur (especially in patients with renal insufficiency or diabetes).
Kalaemia and ECG should be monitored and, if necessary, therapy adjusted.
Metformin
Increased risk of metformin-induced lactic acidosis, due to the possibility of functional renal failure associated with the use of diuretics, especially loop diuretics.
Do not use metformin when plasma creatinine exceeds 15 mg / l (135 mcmol / l) in men and 12 mg / l (110 mcmol / l) in women.
Iodine contrast media
In the presence of diuretic-induced dehydration, the risk of acute renal failure increases, particularly when high doses of iodinated contrast media are used.
Rehydrate the patient before administering the iodized compound.
Imipramine-like antidepressants, neuroleptics
Increased antihypertensive effect and risk of orthostatic hypotension (additive effect).
Calcium salts
Risk of hypercalcemia due to reduced urinary elimination of calcium.
Ciclosporin, tacrolimus
Risk of increased blood creatinine without any modification of circulating cyclosporine levels, even in the absence of hydrosodium depletion.
Corticosteroids, tetracosactide (systemic)
Reduction of the antihypertensive effect (hydrosodic retention due to corticosteroids).
04.6 Pregnancy and breastfeeding
Pregnancy
Data on the use of indapamide in pregnant women are not available or are limited (less than 300 exposed pregnancies). Prolonged exposure to thiazide during the third trimester of pregnancy may reduce maternal plasma volume as well as blood flow uteroplacental, which can cause fetal 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.
Feeding time
Insufficient information is available on the excretion of indapamide / its metabolites in human milk. Indapamide is very similar to thiazide diuretics, which have been associated with decreased or even suppression of breast milk production during lactation. Hypersensitivity to sulfonamide-derived drugs and hypokalaemia may occur.
A risk to the newborns / infants cannot be excluded.
Indapamide should not be used during breastfeeding.
Fertility
Reproductive toxicity studies have shown no effects on fertility in female and male rats (see section 5.3).
No effects on fertility are expected in humans.
04.7 Effects on ability to drive and use machines
Indapamide does not affect the degree of alertness but, in individual cases, different reactions related to the reduction of blood pressure may occur, especially at the start of treatment or when another antihypertensive agent is combined.
As a result, the ability to drive or use machines may be impaired.
04.8 Undesirable effects
Most undesirable effects on clinical or laboratory parameters are dose dependent.
Diuretics related to thiazides, including indapamide, may cause the following undesirable effects grouped by order of frequency according to the following convention:
very common (≥1 / 10); common (≥1 / 100 to
Disorders of the blood and lymphatic system
Very rare:
thrombocytopenia, leukopenia, agranulocytosis, aplastic anemia, haemolytic anemia
Nervous system disorders
Rare:
dizziness, fatigue, headache, paraesthesia, drowsiness
Not known:
syncope
Eye disorders
Not known:
myopia, blurred vision, visual impairment
Psychiatric disorders
Not known:
mental confusion
Cardiac pathologies
Very rare:
arrhythmia
Not known:
torsades de pointes (life-threatening) (see sections 4.4 and 4.5)
Vascular pathologies
Very rare:
hypotension
Not known:
orthostatic hypotension
Gastrointestinal disorders
Uncommon:
He retched
Rare:
nausea, constipation, dry mouth
Very rare:
pancreatitis
Hepato-biliary disorders
Very rare:
abnormal liver function
Not known:
• in case of hepatic insufficiency, there is a possibility of developing a "hepatic encephalopathy" (see sections 4.3 and 4.4)
• hepatitis.
Skin and subcutaneous tissue disorders
Hypersensitivity reactions, mainly dermatological in subjects with a predisposition to allergic and asthmatic reactions.
Common:
maculo-papular eruptions
Uncommon:
purple
Very rare:
angioneurotic edema and / or urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome
Not known:
possible worsening of pre-existing acute disseminated lupus erythematosus, rash. Cases of photosensitivity reactions have been reported (see section 4.4)
Musculoskeletal and connective tissue disorders
Rare:
muscle cramps
Not known:
falls
Renal and urinary disorders
Very rare:
kidney failure
Not known:
acute renal failure
Diagnostic tests
Not known:
• electrocardiogram: QT interval prolongation (see sections 4.4 and 4.5);
• increase in blood sugar and uric acid during treatment: the appropriateness of using these diuretics should be carefully considered in patients with gout or diabetes;
• slight increase in urea nitrogen;
• elevated levels of liver enzymes.
Metabolism and nutrition disorders
During clinical trials, hypokalaemia (plasma potassium concentrations
Very rare:
hypercalcemia
Not known:
• potassium depletion with hypokalaemia, particularly severe in certain high-risk patient populations (see section 4.4)
• hyponatremia with hypovolemia responsible for dehydration and orthostatic hypotension. Concomitant loss of chloride ions can lead to compensatory secondary metabolic alkalosis: the incidence and magnitude of this effect are mild.
Reporting of suspected adverse reactions
Reporting of suspected adverse reactions occurring after authorization of the medicinal product is important as it allows continuous monitoring of the benefit / risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system. "address www.agenziafarmaco.gov.it/it/responsabili.
04.9 Overdose
Indapamide showed no toxicity up to 40 mg, ie 16 times the therapeutic dose.
The signs of acute intoxication are manifested above all by disturbances in the hydroelectrolytic balance (hyponatremia, hypokalaemia). Clinically, possibility of nausea, vomiting, hypotension, cramps, dizziness, somnolence, confusional state, polyuria or oliguria up to possible anuria (due to hypovolemia).
Initial rescue measures must include rapid elimination of ingested substances by gastric lavage and / or administration of activated charcoal; then the normalization of the hydroelectrolytic balance in a specialized center.
05.0 PHARMACOLOGICAL PROPERTIES
05.1 Pharmacodynamic properties
Pharmacotherapeutic group: diuretics with minor diuretic action, excluding thiazides sulfonamides, not associated. ATC code: C03BA11
Indapamide is a derivative of sulfonamide 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, that of potassium and magnesium, thus increasing diuresis and carrying out an antihypertensive action.
Its antihypertensive activity appears at doses that show very weak diuretic activity.
On the other hand, the same antihypertensive activity is clearly demonstrated in the functionally anephric hypertensive patient.
Like other diuretics, the vascular activity of indapamide appears to involve:
• a reduction in the contractility of the vascular smooth muscle fiber related to the modification of the transmembrane ionic exchanges, especially calcium;
• a stimulation of the synthesis of prostaglandin PGE2 and of the synthesis of prostacyclin PGI2 which has vasodilator and anti-platelet aggregation activity.
Indapamide reduces left ventricular hypertrophy, thanks to a significant reduction in the thickness of the ventricular walls.
Furthermore, in the short, medium and long term, it has been shown in hypertensive subjects that indapamide:
• does not interfere with lipid metabolism: triglycerides, LDL-cholesterol and HDL-cholesterol;
• does not interfere with the metabolism of carbohydrates, even in diabetic hypertensive patients.
Beyond a certain dose, thiazide and related diuretics have a plateau of therapeutic effect, while the undesirable effects continue to increase. If the treatment is ineffective the dose should not be increased.
05.2 Pharmacokinetic properties
Absorption
Indapamide is rapidly and totally absorbed from the gastrointestinal tract (bioavailability 93%).
Peak plasma concentrations appear between 1 and 2 hours after a single dose of 2.5 mg.
Distribution
The plasma protein binding of indapamide is approximately 75%.
The plasma elimination half-life is between 14 and 24 hours (mean 18 hours).
Compared to single administration, repeated administrations of indapamide increase the plasma concentration levels in order to reach the equilibrium (plateau) which remains further stable without accumulation phenomena.
Metabolism and elimination
Elimination is essentially urinary (70% of the dose) with a clearance of 60-80% of the total and faecal clearance (22%) in the form of inactive metabolites.
The percentage of unmodified product found in the urine is 15% showing that indapamide is mostly excreted in the form of metabolites.
High-risk individuals
Pharmacokinetic parameters remain unchanged in patients with renal insufficiency.
05.3 Preclinical safety data
Very high doses administered orally to different animal species (from 40 to 8,000 times the therapeutic dose) have shown an exacerbation of the diuretic properties of indapamide.
Acute toxicity studies have shown that the main symptoms of poisoning, such as bradypnea and peripheral vasodilation, seen following intravenous or intraperitoneal administration of indapamide, are related to its pharmacological action. In experimental studies, indapamide did not show mutagenic or carcinogenic properties.
Reproductive toxicity studies did not demonstrate embryotoxicity and teratogenicity.
Fertility was not impaired in either male or female rats.
06.0 PHARMACEUTICAL INFORMATION
06.1 Excipients
Tablet:
Cornstarch
Lactose monohydrate
Povidone
Magnesium stearate
Talc
Coating (filming):
Beeswax
Titanium dioxide
Glycerol
Sodium lauryl sulfate
Hypromellose
Macrogol 6000
Magnesium stearate
06.2 Incompatibility
Not relevant.
06.3 Period of validity
5 years
06.4 Special precautions for storage
Do not store above 25 ° C.
06.5 Nature of the immediate packaging and contents of the package
Pack of 30 tablets in aluminum / PVC blister.
06.6 Instructions for use and handling
No special instructions.
07.0 MARKETING AUTHORIZATION HOLDER
Les Laboratoires SERVIER
50, rue Carnot
92284 Suresnes cedex
France
Representative for Italy:
SERVIER ITALIA S.p.A.
Via Luca Passi, 85
00166 Rome
08.0 MARKETING AUTHORIZATION NUMBER
AIC n. 024032017
09.0 DATE OF FIRST AUTHORIZATION OR RENEWAL OF THE AUTHORIZATION
Renewal date: 06/2010
10.0 DATE OF REVISION OF THE TEXT
10/2015
