Indapamide

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 antipsychotics (e.g. pimozide).

Other substances: 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. 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 acetylsalicylic acid (≥3 g/day)

ossible reduction in the antihypertensive effect of indapamide in co-administration with NSAIDs. Risk of acute renal failure in dehydrated patients (decreased glomerular filtration). Hydrate the patient; monitor renal function at the start of treatment.

Decreased antihypertensive effect (water/sodium retention due to corticosteroids).

Risk of hypercalcaemia resulting from decreased urinary elimination of calcium.

Hypokalaemia predisposing to the toxic effects of digitalis.

Monitoring of plasma potassium, magnesium and ECG and, if necessary, adjust the treatment.

(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.

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 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.

Antihypertensive effect and increased risk of orthostatic hypotension (additive effect).

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.

Concomitant treatment with indapamide may increase the incidence of hypersensitivity reactions to allopurinol.

In co-administration of indapamide with other drugs causing hypokalaemia (amphotericin B (IV), gluco- and mineralo-corticoids (systemic route), tetracosactide, stimulant laxatives) there is 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.

Increased antihypertensive effect.

Hydrate the patient; monitor renal function at the start of treatment.

Risk of increased plasma creatinine without any change in circulating ciclosporin levels, even in the absence of water/sodium depletion.

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.

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.

Tendency to gout attacks may be increased in hyperuricaemic patients.

Monitoring of blood glucose is important in diabetics, in particular in the presence of hypokalaemia.

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.

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 sulfonamidederived 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 is not recommended during breast-feeding.

Fertility

Reproductive toxicity studies showed no effect on fertility in female and male rats. No effects on human fertility are anticipated.

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.

Summary of safety profile

The most commonly reported adverse reactions are hypokalaemia, hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions and maculopapular rashes.

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 (≥1/100,000 to <1/10,000), not known (cannot be estimated from the available data).

Description of selected adverse reactions

During phase II and III studies comparing indapamide 1.5mg and 2.5mg, plasma potassium analysis showed a dosedependent effect of indapamide:

• Indapamide 1.5 mg: 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.
• Indapamide 2.5 mg: 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.