Indapamide 2.5mg Tablets
Out of date information, search anotherSUMMARY OF PRODUCT CHARACTERISTICS
1 NAME OF THE MEDICINAL PRODUCT
Indapamide 2.5mg Tablets
2
QUALITATIVE AND QUANTITATIVE COMPOSITION
One tablet contains 2.5mg of the active substance Indapamide Ph. Eur.
Excipients with known effect:
Each tablet contains 82.75mg Lactose Monohydrate.
For the full list of excipients, see secion 6.1.
3 PHARMACEUTICAL FORM
Tablet
White, round, flat bevelled edge tablet; embossed with I and 2.5 on one side, plain on the other side.
4 CLINICAL PARTICULARS
4.1 Therapeutic indications
Indapamide is indicated in adults for the treatment of essential hypertension. Indapamide may be used as sole therapy or combined with other antihypertensive agents.
4.2 Posology and method of administration
Posology
Adults:
The dosage is one tablet, containing 2.5mg Indapamide, daily, to be taken in the morning. The action of Indapamide is progressive and the reduction in blood pressure may continue and not reach a maximum until several months after the start of therapy. A larger dose than 2.5mg Indapamide daily is not recommended as there is no appreciable additional antihypertensive effect but a diuretic effect may become apparent. If a single daily tablet of Indapamide does not achieve a sufficient reduction in blood pressure, another antihypertensive agent may be added; those which have been used in combination with Indapamide include beta-blockers, ACT inhibitors, methyldopa, clonidine and other adrenergic blocking agents. The coadministration of Indapamide with diuretics which may cause hypokalaemia is not recommended.
There is no evidence of rebound hypertension on withdrawal of Indapamide 2.5mg Tablets.
Patients with 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.
Older _people (see section 4.4):
Inolder people, the plasma creatinine must be adjusted in relation to age, weight and gender. Older patients can be treated with Indapamide 2.5mg Tablets when renal function is normal or only minimally impaired.
Patients with hepatic impairment (see sections 4.3 and 4.4):
In severe hepatic impairment, treatment is contraindicated.
Paediatric _ population:
The safety and efficacy of Indapamide 2.5mg Tablets in children and adolescents has not been established.
Method of administration
Oral use. Indapamide 2.5mg Tablets can be taken with or without food.
4.3 Contraindications
- Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.
- Severe renal failure.
- Hepatic encephalopathy or severe impairment of liver function.
- Hypokalaemia.
4.4 Special warnings and precautions for use
Hepatic impairment:
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 readministration 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.
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 older people 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 hypokalaemia (< 3.4 mmol/l) must be prevented in certain high risk populations, i.e.older people, 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.
Direction 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 pmol/l in an adult). Inolder people, 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.
4.5 Interaction with other medicinal products and other forms of interaction
Combinations that are not recommended:
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 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 pre-existing 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 minerallo-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 affects 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, hypokalaeia (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 pmol/l) in men and 12 mg/l (110 pmol/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 cyclosporine levels, even in the absence of water/sodium depletion.
Corticosteroids, tetracosactide (systemic route):
Decreased antihypertensive effect (water/sodium retention due to corticosteroids).
Fertility, pregnancy and lactation
4.6
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.
Breast-feeding
Breast-feeding is inadvisable (Indapamide is excreted in human milk).
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.
4.8 Undesirable effects
The majority of adverse reactions concerning clinical or laboratory parameters are dose-dependent.
Tabulated list of adverse reactions
|
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 lymphatic system disorders | |||||
|
Thrombocytop enia Leucopenia Agranulocytos is Aplastic anaemia Haemolytic anaemia | |||||
|
Nervous system disorders | |||||
|
Vertigo Fatigue Headache Paresthesia |
Syncope | ||||
|
Arrhythmia Hypotension |
Torsade de pointes (potentially fatal) (see sections 4.4 and 4.5) | ||||
|
Gastrointestinal disorders | |||||
|
Vomiting |
Nausea Constipation Dry mouth |
Pancreatitis | |||
|
Renal and urinary disorders | |||||
|
Renal failure | |||||
|
Hepato-biliary disorders | |||||
|
Abnormal hepatic function |
Possibility of onset of hepatic encephalopathy in case of hepatic insufficiency (see sections 4.3 and 4.4). Hepatitis | ||||
|
Skin and subcutaneous tissue disorders1 | |||||
|
Maculopap ular rashes |
Purpura |
Angioneurotic oedema and/or urticaria, Toxic epidermic necrolysis Steven Johnson syndrome |
Possible worsening of pre-existing acute disseminated lupus erythematosus. Cases of photosensitivity reactions have been reported (see section 4.4). | ||
|
Investigations | |||||
|
Electrocardiogr am QT prolonged (see sections 4.4 and 4.5) Blood glucose increased and blood uric acid increased during treatment: appropriateness of these diuretics must be very carefully weighed in patients with gout or diabetes. Elevated liver enzyme levels. | |||||
|
Metabolism |
and nutrition d |
lisorder2 | |||
Hypercalcaem
Potassium
|
ia |
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. |
1 Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions.
2 During clinical trials, hypokalaemia (plasma potassium <3.4 mmol/l) was seen in 25 % of patients and <3.2 mmol/l in 10 % of patients after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.41 mmol/l.
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 Yellow Card Scheme website www.mhra.gov.uk/yellowcard.
4.9 Overdose
Indapamide has been found free of toxicity at up to 40 mg, i.e. 16 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.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Sulfonamides, plain ATC code: C 03 BA 11 Mechanism of action
Indapamide (indapamide) is a non-thiazide sulphonamide with an indole ring, belonging to the diuretic family. At the dose of 2.5 mg per day Indapamide exerts a prolonged antihypertensive activity in hypertensive human subjects.
Dose-effect studies have demonstrated that, at the dose of 2.5mg per day, the antihypertensive effect is maximal and the diuretic effect is sub-clinical.
Pharmacodynamic effects
As this antihypertensive dose of 2.5mg per day, Indapamide reduces vascular hyperreactivity to noradrenaline in hypertensive patients and decreases total peripheral resistance and arteriolar resistance.
The implication of an extrarenal mechanism of action in the antihypertensive effect is demonstrated by maintenance of its antihypertensive efficacy in functionally anephric hypertensive patients.
The vascular mechanism of action of Indapamide involves:
• a reduction in the contractility of vascular smooth muscle due to a modification of transmembrane ion exchanges, essentially calcium;
• vasodilatation due to stimulation of the synthesis of prostaglandin PGE2 and the vasodilator and platelet antiaggregant prostacyclin PGI2;
• potentiation of the vasodilator action of bradykinin.
It has also been demonstrated that in the short-, medium- and long-term, in hypertensive patients, Indapamide:
• reduces left ventricular hypertrophy;
• does not appear to alter lipid metabolism: triglycerides, LDL-cholesterol and HDL-cholesterol;
• does not appear to alter glucose metabolism, even in diabetic hypertensive patients. Normalisation of blood pressure and a significant reduction in microalbuminuria have been observed after prolonged administration of Indapamide in diabetic hypertensive subjects.
Lastly, the co-prescription of Indapamide with other antihypertensives (beta-blockers, calcium channel blockers, angiotensin converting enzyme inhibitors) results in an improved control of hypertension with an increased percentage of responders compared to that observed with single-agent therapy.
5.2 Pharmacokinetic properties
Absorption
Indapamide is rapidly and completely absorbed after oral administration. Peak blood levels are obtained after 1 to 2 hours.
Distribution
Indapamide is concentrated in the erythrocytes and is 79% bound to plasma protein and to erythrocytes. It is taken up by the vascular wall in smooth vascular muscle according to its high lipid solubility.
Elimination
70% of a single oral dose is eliminated by the kidneys and 23% by the gastrointestinal tract. Indapamide is metabilised to a marked degree with 7% of the unchanged product found in the urine during the 48 hours following administration. Elimination half-life (B phase) of indapamide is approximately 15 - 18 hours.
5.3 Preclinical safety data
Effects in non-clinical studies were observed only at exposures considered sufficiently in excess of the maximum human exposure indicating little relevance to clinical use.
6 PHARMACEUTICAL PARTICULARS
6.1 List of excipients
Lactose monohydrate Ph. Eur.
Sodium starch glycollate Ph. Eur.
Magnesium stearate Ph. Eur.
6.2. Incompatibilities
None.
6.3. Shelf-Life
Four years.
6.4. Special Precautions for Storage
Protect from light. Store below 25°C.
6.5. Nature and Contents of Container
Aluminium strips in cardboard cartons or blisters comprising of PVC/PVdC/aluminium foil in cardboard cartons. Each carton will contain 20, 28, 30, 56, 60, 84 or 120 tablets.
6.6 Special precautions for disposal
No special requirements.
7 MARKETING AUTHORISATION HOLDER
Niche Generics Limited
1 The Cam Centre
WilburyWay
Hitchin
Hertfordshire
SG4 0TW
United Kingdom
8 MARKETING AUTHORISATION NUMBER(S)
PL 19611/0019
9 DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION
11/06/2009
15/01/2015