Natrilix SR

Indapamide.

Treatment of essential hypertension.

Dosage: One tablet per day.
In all cases, strictly comply with the physician's prescription.
Route and mode of administration: Oral route.
Frequency and time at which the drug should be taken: One dose only per 24 hours, preferably in the morning in view of the diuretic effect of this drug, with the aim of avoiding having to get up several times at night.
Treatment duration: Keep to the physician's prescription.
What to do in case one or several doses have been missed: Contact the physician. Do not take a double dose the day after the omitted doses.

Symptoms: Indapamide has been found to be 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, there is the possibility of nausea, vomiting, hypotension, cramps, dizziness, 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 in a specialised centre.

This drug must not be taken in the following situations: Hypersensitivity to the active substance, to other sulfonamides or to any of the excipients; Severe renal failure; Hepatic encephalopathy or severe impairment of liver function; Hypokalaemia.

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. If a 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: This medicine contains lactose. Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.

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 high-risk populations, i.e. the elderly and cirrhotic patients. Any diuretic treatment may cause hyponatraemia, sometimes with very serious consequences. Hyponatraemia associated with hypovolaemia may lead to 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 previously. 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.
Choroidal effusion, acute myopia and secondary angle-closure glaucoma: 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. Symptoms include acute onset of decreased visual acuity or ocular pain and typically occur within hours to weeks of drug initiation. 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 angle-closure glaucoma may include a history of sulfonamide or penicillin allergy.
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.

Pregnancy: There is no data or only limited data (fewer than 300 pregnancy outcomes) on the use of indapamide in pregnant women. Prolonged exposure to thiazide diuretics during the third trimester of pregnancy can reduce maternal plasma volume as well as uteroplacental blood flow, which may cause feto-placental ischaemia and growth retardation.
Animal studies do not indicate direct or indirect harmful effects on reproduction.
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 sulphonamide-derived medicines and hypokalaemia might occur. A risk to the newborns/infants cannot be excluded.
Indapamide is structurally very close to thiazide diuretics which have been associated, during breast-feeding, with a decrease or even suppression of lactation.
Indapamide is not recommended while breast-feeding.
Fertility: Reproductive toxicity studies showed no effect on fertility in female and male rats. No effects on human fertility are anticipated.

Summary of the safety profile: The most commonly reported adverse reactions are hypersensitivity reactions (mainly dermatological) in patients predisposed to allergic or asthmatic reactions or to maculopapular rashes.
During clinical trials, hypokalaemia (plasma potassium <3.4 mmol/l) was observed in 10% of patients and plasma potassium <3.2 mmol/l in 4% of patients after 4 to 6 weeks of treatment. After 12 weeks of treatment, the mean fall in plasma potassium was 0.23 mmol/l.
The biological and clinical adverse reactions are for the most part dose-dependent.
Tabulated list of adverse reactions: The following adverse reactions have been reported during treatment and are categorised according to the following frequencies: Very common (≥1/10); Common (≥1/100, <1/10); Uncommon (≥1/1,000, <1/100); Rare (≥1/10,000, <1/1,000); Very rare (<1/10,000), Not known (cannot be estimated from the available data). (See table.)

Click on icon to see table/diagram/image

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 national reporting system.

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 such as but not limited to: Class Ia antiarrhythmic agents (e.g quinidine, hydroquinidine, disopyramide); Class III antiarrhythmic agents (e.g amiodarone, sotalol, dofetilide, ibutilide, bretylium); Some antipsychotics: Phenothiazines (e.g chlorpromazine, cyamemazine, levomepromazine, thioridazine, trifluoperazine); Benzamides (e.g amisulpride, sulpiride, sultopride, tiapride); Butyrophenones (e.g droperidol, haloperidol); other antipsychotic (e.g pimozide).
Other substances: (e.g bepridil, cisapride, diphemanil, erythromycin IV, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin, vincamine IV, methadone, astemizole, terfenadine).
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. Perform clinical, plasma electrolyte and ECG monitoring.
Use substances which do not present a risk of torsades de pointes in the presence of hypokalaemia.
N.S.A.I.Ds. (systemic route) including COX-2 selective inhibitors, high dose acetylsalicylic 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. inhibitor is initiated in the presence of preexisting sodium depletion (particularly in patients with renal artery stenosis).
In essential 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 route), 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 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 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 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 (tricyclics), neuroleptics: Antihypertensive effect and increased risk of orthostatic hypotension (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).

This medicine should be protected from humidity and stored at below 30°C.

Diuretics

C03BA11 - indapamide ; Belongs to the class of low-ceiling sulfonamide diuretics.

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