| All changes reflect a harmonisation with the SPC for Natrilix SR 1.5mg Tablets
additions and deletions
Section 4.2 Posology and method of administration
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.
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 NATRILIX SR when renal function is normal or only minimally impaired.
There are no significant changes in the pharmacokinetics of indapamide in the elderly. Numerous clinical studies have shown that it can be used without problems, and, indeed has a particular benefit on systolic blood pressure in the elderly.
Patients with hepatic impairment (see sections 4.3 and 4.4)
In severe hepatic impairment, treatment is contraindicated.
Children and adolescents:
NATRILIX 2.5mg is not recommended for use in children and adolescents due to a lack of data on safety and efficacy.
Children:
There is no experience of the use of this drug in children
Section 4.3 Contraindications
- Hypersensitivity to indapamide, to other sulfonamides or to any of the excipients.
- Severe renal failure.
- Hepatic encephalopathy or severe impairment of liver function.
- Hypokalaemia.
Natrilix® is not recommended in patients with:
severe hepatic failurea known history of allergy to sulphonamide derivatives
Section 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 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 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. 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 (see sections 4.8 and 4.9).
• 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.
· Blood potassium and urate levels should be closely monitored:
in patients predisposed or sensitive to hypokalaemia (cardiac patients treated with glycosides, elderly, or patients suffering from hyperaldosteronism);
in patients suffering from gout.
· In case of an aggravation of pre-existing renal insufficiency, it is recommended to interrupt the treatment with Natrilix®.
· In patients with hyperparathyroidism, the treatment with Natrilix® should be interrupted on the occurrence of hypercalcaemia.
· Studies in functionally anephric patients for one month undergoing chronic haemodialysis, have not shown evidence of drug accumulation despite the fact that indapamide is not dialysable.
· Although indapamide 2.5 mg daily (one tablet) can be safely administered to hypertensive patients with impaired renal function, the treatment should be discontinued if there are signs of increasing renal insufficiency.
· As with all antihypertensive agents, care should be taken in patients in whom excessive hypotension could result in a myocardial infarction or cerebrovascular accident.
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 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 (particularly in patients with renal failure or diabetes) or hyperkalaemia 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 cyclosporin levels, even in the absence of water/sodium depletion.
Corticosteroids, tetracosactide (systemic route):
Decreased antihypertensive effect (water/sodium retention due to corticosteroids).
The concomitant administration of the following medicaments with Natrilix is not recommended:
· Diuretics (risk of electrolyte imbalance)
· Antiarrhythmics such as quinidine derivatives, cardiac glycosides, corticoids or laxatives in case of hypokalaemia
· Lithium (increase in blood levels due to a diminished urinary excretion of lithium)
4.6 Pregnancy and lactation
Pregnancy:
As a general rule, the administration of diuretics should be avoided in pregnant women and should never be used to treat physiological oedema of pregnancy. Diuretics can cause foetoplacental ischaemia, with a risk of impaired foetal growth.
Lactation:
Breast-feeding is inadvisable (Indapamide is excreted in human milk).
Pregnancy: no teratological effects have been seen in animals but because animal reproduction studies are not always predictive of human response, Natrilix® should be used during pregnancy only if clearly needed.
Lactation: It is not known if Natrilix® is excreted in human milk.
Because most drugs are excreted in human milk, if use of Natrilix® is deemed essential, the patient should stop nursing.
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.
There is no evidence of any adverse effect on mental alertness.
4.8 Undesirable effects
The majority of adverse reactions concerning clinical or laboratory parameters are dose-dependent.
Thiazide-related diuretics, including indapamide, may cause the following undesirable effects ranked under the following frequency:
Very common (>1/10); common (>1/100, <1/10); uncommon (>1/1000, <1/100); rare (>1/10000, <1/1000), very rare (<1/10000), not known (cannot be estimated from the available data).
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
Renal and urinary disorders:
Very rare: renal failure
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, Steven Johnson syndrome
Not known: possible worsening of pre-existing acute disseminated lupus erythematosus.
Cases of photosensitivity reactions have been reported (see section 4.4).
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 (see section 4.4).
- 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.
- Hypokalaemia, headache, dizziness, fatigue, muscular cramps, nausea, anorexia, diarrhoea, constipation, dyspepsia and cutaneous rash may occur as a result of treatment with Natrilix®.
- There have been some rare reports of orthostatic hypotension, palpitations, increase in liver enzymes, blood dyscrasias including thrombocytopenia, hyponatraemia, metabolic alkaloses, hyperglycaemia, increase in blood urate levels, paresthesia, erythema multiforme, epidermal necrolysis, photosensitivity, impotence, renal insufficiency and reversible acute myopia.
- At the dosage recommended for hypertension, indapamide does not usually adversely influence plasma triglycerides, LDL cholesterol or the LDL-HDL cholesterol ratio. Indapamide does not appear to adversely affect glucose tolerance when used in patients with diabetes and also in non diabetics.
4.7 Overdose
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).
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.
Symptoms of overdosage would be those associated with a diuretic effect: electrolyte disturbances, hypotension and muscular weakness.
Treatment would be symptomatic, directed at correcting the electrolyte abnormalities and gastric lavage or emesis should be considered.
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