POM: Prescription only medicine
This information is intended for use by health professionals
Rawel XL 1.5 mg prolonged-release tablets
Rawel XL 1.5 mg prolonged-release tablets
Each prolonged-release tablet contains 1.5 mg indapamide.
Excipient with known effect
Each prolonged release tablet contains 97.58 mg lactose monohydrate.
For the full list of excipients, see section 6.1.
White, round, slightly biconvex film-coated tablet.
Rawel XL is indicated in essential hypertension in adults.
One tablet per 24 hours, preferably in the morning, to 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.
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.
The safety and efficacy of Rawel XL in children and adolescents have not been established. No data are available.
Method of administration
Indapamide is administered orally.
Indapamide is contraindicated in:
• 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;
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.
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 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, total lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Special precautions for use
Water and electrolyte balance
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. In the elderly and cirrhotic patients, monitoring should be even more frequent (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.
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 iatrogenic. 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 pointes”.
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.
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 the investigation of parathyroid function.
Monitoring of blood glucose is important in diabetics, in particular in the presence of hypokalaemia.
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 levels below 25 mg/l, i.e. 220 µmol/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.
The attention of athletes is drawn to the fact that this product contains an active substance which may cause a positive reaction in doping tests.
Combinations that are not recommended
Concomitant use of lithium may lead to increase of plasma lithium concentration with signs of overdosage, as with a sodium-free diet (decreased urinary lithium excretion). However, if the use of diuretics is necessary, careful monitoring of plasma lithium and dose adjustment is required.
Combinations requiring precaution 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.
Non-steroidal anti-inflammatory drugs (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 (ACE) inhibitors
When treatment with an ACE inhibitor is initiated, sudden hypotension and/or acute renal failure may occur in patients with pre-existing depletion of sodium (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 ACE inhibitor and restart a non-potassium-sparing diuretic if necessary;
- or give low initial doses of the ACE inhibitor and increase the dose gradually.
In congestive heart failure, start with a very low dose of ACE inhibitor, possibly after a reduction in the dose of the concomitant hypokalaemicdiuretic.
In all cases, monitor renal function (plasma creatinine) during the first weeks of treatment with an ACE inhibitor.
Other compounds causing hypokalaemia amphotericin B (IV), gluco- and mineralo-corticoids (systemic), tetracosactide, stimulant laxatives
The risk of hypokalaemia is increased (additive effect).
Plasma potassium should be monitored and corrected if necessary. Caution is required in patients concomitantly taking digitalis. These patients should take non-stimulant laxatives.
Increased antihypertensive effect.
The patient should drink sufficient quantity of liquid; renal function is monitored at the start of treatment.
Hypokalaemia increases the risk of toxic effects of digitalis.
Plasma potassium and ECG should be monitored and, if necessary, the treatment adjusted.
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.
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 patients dehydrated due to diuretics, the risk of acute renal failure is increased, particularly when large doses of iodinated contrast media are used. The patient should be rehydrated prior to administration of the iodinated compound.
Imipramine-like antidepressants, neuroleptics
Antihypertensive effect and risk of orthostatic hypotension are increased (additive effect).
Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.
Risk of increased plasma creatinine without any change in circulating cyclosporin levels, even in the absence of water/sodium depletion.
Corticosteroids, tetracosactide (systemic)
Antihypertensive effect may be decreased (water and sodium retention due to corticosteroids).
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.
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.
Reproductive toxicity studies showed no effect on fertility in female and male rats (see section 5.3). No effects on human fertility are anticipated.
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.
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 (< 1/10,000)
- Not known (cannot be estimated from the available data)
Blood and the lymphatic system disorders
Very rare: thrombocytopenia, leucopenia, agranulocytosis, aplastic anaemia, haemolytic anaemia.
Metabolism and nutrition disorders
Very rare: hypercalcaemia.
Not known: potassium depletion with hypokalaemia, particularly serious in certain high risk populations (see section 4.4), hyponatraemia (see section 4.4).
Nervous system disorders
Rare: vertigo, fatigue, headache, paraesthesia.
Not known: syncope.
Not known: myopia, blurred vision, visual impairment.
Very rare: arrhythmia,
Not known: Torsade de pointes (potentially fatal) (see sections 4.4 and 4.5)
Very rare: hypotension.
Rare: nausea, constipation, dry mouth.
Very rare: pancreatitis.
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), hepatitis.
Skin and subcutaneous tissue disorders
Common: hypersensitivity reactions, maculopapular rashes.
Very rare: angioneurotic oedema, urticaria, toxic epidermic necrolysis, Steven Johnson syndrome.
Not known: possible worsening of pre-existing acute disseminated lupus erythematosus, photosensitivity reactions (see section 4.4).
Renal and urinary disorders
Very rare: renal failure.
Not known: 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.
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 Yellow Card Scheme, Website: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.
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.
Pharmacotherapeutic group: diuretics; sulphonamides, plain, ATC code: C03BA11.
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.
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.
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.
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.
Elimination is essentially urinary (70% of the dose) and faecal (22%) in the form of inactive metabolites.
Other special populations
The pharmacokinetic parameters of the drug are not significantly changed in patients with renal function impairment.
Indapamide has been tested negative concerning mutagenic and carcinogenic properties.
The highest doses of indapamide administered orally to different animal species (40 to 8000 times the therapeutic dose) have shown an exacerbation of the pharmacological properties of the drug.
The major symptoms of intoxication 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.
Anhydrous colloidal silica
Titanium dioxide (E171)
Do not store above 25°C.
Blister (Alu 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.
No special requirements.
KRKA, d.d., Novo mesto, Šmarješka cesta 6, 8501 Novo mesto, Slovenia