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 years.
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
Not applicable
Tablet core:
hypromellose,
powdered cellulose,
lactose monohydrate,
anhydrous colloidal silica,
magnesium stearate
Film coating:
Hypromellose,
macrogol 400,
titanium dioxide (E 171).
Prolonged-release tablet
White, round, slightly biconvex.
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 |
| 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 |
| 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. |
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.
Essential hypertension.
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.
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.
23/10/2014
Rawel XL prolonged-release tablets 1.5 mg
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia
This medicinal product does not require any special storage conditions.
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.
PL 01656/0065
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.
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 pointesâ€.
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 µ mol/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. 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.
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.
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 :
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 :
In severe hepatic impairment, treatment is contraindicated.
No special requirements.
28/03/2008
