Indapen®: composition and dosage form
One tablet contains 2.5 mg of indapamide. It is taken once a day in the morning, and raising the dose makes no sense: the product information says plainly that doses above 2.5 mg a day are not recommended, because they will not lower blood pressure any further while the diuretic effect will grow stronger.
That sentence is the key to the whole medicine. Indapamide has a point at which one of its actions has already reached its maximum while the other has not yet shown itself; 2.5 mg is precisely the attempt to hit that point.
How Indapen® works
Indapamide is a non-thiazide sulfonamide containing an indole ring, used as a diuretic. But it was about the diuretic action that the dose-response studies said something curious: at 2.5 mg a day the fall in blood pressure is maximal while the diuretic action is subclinical — that is, in clinical practice it simply cannot be seen.
How, then, does the pressure fall? Through the vessels. Indapamide at 2.5 mg a day reduces the excessive vascular reactivity to adrenaline in hypertensive patients and lowers total peripheral and arteriolar resistance. An extrarenal mechanism takes part in the fall in pressure, and the proof of that is an unexpected one: the hypotensive effect persists in hypertensive patients deprived of kidney function. Hence the second practical consequence too: the action develops gradually, and the maximum fall in blood pressure may come only several months after treatment begins.
Indications
There is one indication and it fits in three words: essential arterial hypertension. Neither oedema, nor heart failure, nor the other conditions for which diuretics are usually given appear on that list — and that follows directly from the fact that the medicine's diuretic action at the therapeutic dose is subclinical.
The narrowness of the indication also determines how the medicine is combined. It may be used with beta-blockers, ACE inhibitors, methyldopa, clonidine and other agents blocking adrenergic receptors. Combining it with diuretics capable of causing hypokalaemia, on the other hand, is not recommended — for the reason to which half the warnings are devoted.
Method of administration and dosage
Adults are given one 2.5 mg tablet a day in the morning. If one tablet a day does not lower the blood pressure enough, the doctor adds another antihypertensive rather than increasing the indapamide dose.
- severe renal failure with a creatinine clearance below 30 ml/min: the medicine is contraindicated;
- thiazide diuretics and agents of similar action are fully effective only when kidney function is normal or only slightly impaired;
- in the elderly the medicine may be used where kidney function is normal or only slightly impaired, and in assessing plasma creatinine their age, body weight and sex must be taken into account;
- severe impairment of liver function: the medicine is contraindicated;
- children and adolescents are not recommended the medicine, because of the absence of data on safety and efficacy.
There is one more feature, a pleasant and rare one: after the medicine is stopped there is no rebound hypertension. Many blood pressure medicines produce a swing back when they are stopped abruptly; here that has not been described.
Contraindications
There are five prohibitions and they are short. Hypersensitivity to indapamide, to other sulfonamides or to any excipient. Severe renal failure with anuria. Hepatic encephalopathy and severe impairment of liver function. And hypokalaemia — a low blood potassium by itself closes the door on the medicine.
That last point is worth remembering, because it explains the logic of the whole treatment. Indapamide is capable of lowering potassium, so a low potassium at the outset is not a "relative caution" but an outright ban. The same goes for the liver: diuretics with a thiazide-like action can, in patients with impaired liver function, bring on hepatic encephalopathy, particularly where the electrolyte balance is disturbed, and at its first signs the medicine is stopped at once.
Special warnings and precautions
Almost all the warnings for this medicine come down to laboratory monitoring, and it is set out by timing and reason rather precisely. The simplest way through it is parameter by parameter.
| What is monitored | When | Why |
| Plasma sodium | before treatment starts, then regularly; more often in the elderly and in liver cirrhosis | any diuretic treatment can cause hyponatraemia, sometimes with serious consequences, and the initial fall in sodium is often symptomless |
| Plasma potassium | the first measurement in the first week of treatment, then regularly | loss of potassium with hypokalaemia is the main risk of thiazide diuretics; the threshold is 3.4 mmol/l, and where it is found the potassium is replaced |
| Plasma calcium | where hypercalcaemia is suspected | the medicine may reduce the urinary excretion of calcium; marked hypercalcaemia may be the consequence of unrecognised hyperparathyroidism, in which case treatment is interrupted and the glands investigated |
| Blood glucose | in patients with diabetes, especially where hypokalaemia coexists | the treatment is capable of affecting glucose levels |
| Creatinine and urea | at the start of treatment | hypovolaemia from the loss of water and sodium reduces glomerular filtration; in people with normal kidneys this transient functional insufficiency has no consequences, but it can worsen existing renal failure |
Who needs potassium monitoring particularly often, the product information lists separately: the elderly, the undernourished, those on many medicines, patients with liver cirrhosis with oedema and ascites, with coronary heart disease and heart failure. The reason lies in what a low potassium leads to: the risk of cardiotoxicity from digitalis preparations and of rhythm disturbances rises, and together with bradycardia hypokalaemia contributes to a potentially fatal ventricular tachycardia of the torsade de pointes type — particularly in patients with a prolonged QT interval, whether congenital or drug-induced. Of the rest it is worth knowing: in patients with hyperuricaemia attacks of gout become more frequent; cases of photosensitivity have been described, and if it appears the medicine is withdrawn, while if a diuretic is nonetheless needed the skin is protected from the sun and from artificial UVA; the product may produce a positive result in athletes' doping tests; and the fall in blood pressure, especially at the start of treatment or when a second antihypertensive is added, can impair the ability to drive.
Interaction with other medicines
Indapamide's interactions almost all grow from a single root — from the hypokalaemia the medicine can cause. It is what turns combinations that would be harmless on their own into dangerous ones.
- agents causing torsade de pointes: class Ia and III antiarrhythmics, phenothiazines, benzamides, butyrophenones, and also bepridil, cisapride, diphemanil, intravenous erythromycin, halofantrine, mizolastine, pentamidine, sparfloxacin, moxifloxacin and intravenous vincamine — the risk of ventricular arrhythmias rises and hypokalaemia predisposes to them; electrolyte monitoring and an ECG are needed, and where there is hypokalaemia one switches to agents without that risk;
- lithium: the plasma lithium concentration rises with signs of overdose, as it does on a low-sodium diet — lithium monitoring and dose adjustment are needed;
- digitalis preparations: hypokalaemia predisposes to the toxic manifestations of the glycosides, so potassium and the ECG are monitored and, if necessary, the treatment is changed;
- ACE inhibitors: in patients with sodium deficiency, especially with renal artery stenosis, starting treatment threatens sudden hypotension and acute renal failure — the diuretic is stopped 3 days beforehand, or the ACE inhibitor is begun at low doses with creatinine monitored for the first weeks;
- other diuretics capable of lowering potassium: the risk of hypokalaemia adds up, and potassium is monitored especially carefully where digitalis is taken at the same time;
- metformin: the risk of lactic acidosis rises because of possible functional renal impairment; metformin is not used where creatinine is above 15 mg/l in men and 12 mg/l in women;
- iodinated contrast media: with dehydration caused by diuretics the risk of acute renal failure rises, so the patient is well hydrated before the examination;
- corticosteroids weaken the hypotensive effect through sodium and water retention, and ciclosporin may raise plasma creatinine without changing its own concentration.
One everyday detail that also made it into the product information is worth remembering separately: laxatives should be chosen from among those that do not stimulate peristalsis. The reason is the same one — loss of potassium.
Pregnancy and breastfeeding
The rule is put as a general principle: the use of diuretics in pregnant women should be avoided. And separately, with emphasis, the thing they are sometimes asked for is ruled out: they should never be used to treat the physiological oedema that occurs during pregnancy.
The reason lies not in indapamide itself but in the class: diuretics can cause fetoplacental ischaemia with a risk of impaired fetal growth. During breastfeeding the medicine is not recommended — it passes into human milk.
Adverse effects
Most of the clinical and laboratory unwanted effects are dose-dependent, and at the end of the section the product information gives figures that show that dependence better than any words could. In phase two and three studies indapamide 1.5 mg and 2.5 mg were compared. On the 1.5 mg dose a potassium below 3.4 mmol/l was seen in 10% of patients and below 3.2 in 4%, after 4–6 weeks of treatment; the mean fall in potassium at 12 weeks was 0.23 mmol/l. On the 2.5 mg dose the same figures were 25% and 10%, and the mean fall 0.41 mmol/l. Moving from 1.5 to 2.5 mg therefore more than doubles the rate of hypokalaemia.
The list of reactions itself is short. Commonly there are hypokalaemia and a maculopapular rash. Uncommonly — hyponatraemia, vomiting, purpura. Rarely — hypochloraemia and hypomagnesaemia, dizziness, a feeling of tiredness, headache, paraesthesia, nausea, constipation, dry mouth. Very rarely — hypercalcaemia, cardiac rhythm disturbances and a fall in blood pressure, thrombocytopenia, leucopenia, agranulocytosis, aplastic and haemolytic anaemia, pancreatitis, renal failure, impaired liver function, angioedema and urticaria, toxic epidermal necrolysis, Stevens-Johnson syndrome. With unknown frequency, syncope, torsade de pointes, hepatitis and the possibility of hepatic encephalopathy developing in the course of liver failure, worsening of systemic lupus erythematosus, a prolonged QT interval on the electrocardiogram, raised glucose and uric acid, and increased liver enzyme activity have been described. Skin reactions, incidentally, occur more often in patients prone to allergy and asthmatic reactions.
Overdose
No toxic effect of indapamide has been established at doses of up to 40 mg, roughly 16 times the therapeutic dose. Manifestations of acute poisoning nonetheless exist, and they follow from the disturbance of the water and electrolyte balance, that is, from hyponatraemia and hypokalaemia.
It may look like this: nausea, vomiting, a fall in blood pressure, muscle cramps, dizziness, drowsiness, confusion, polyuria or, on the contrary, oliguria going as far as anuria because of hypovolaemia. In overdose, gastric lavage is performed or activated charcoal given as soon as possible, and the water and electrolyte balance is restored in hospital.
How to get a prescription for Indapen® online
Indapamide has one figure that explains why the dose must not be changed on one's own: moving from 1.5 mg to 2.5 mg raises the rate of hypokalaemia from 10% to 25%, while the blood pressure does not go any lower — at 2.5 mg the hypotensive effect is already at its maximum. Treatment here, therefore, is not about choosing a dose but about regular monitoring of potassium and sodium. On e-zdrowie.com you fill in a medical questionnaire, the doctor reviews the answers and, if the medicine is suitable, issues an electronic prescription: the code arrives by message, and any Polish pharmacy will dispense the tablets against it.
Begin the questionnaire with electrolytes and kidneys: give your latest potassium and sodium, your creatinine or creatinine clearance, and the date of the test. A low potassium is a direct contraindication, and below a clearance of 30 ml/min the medicine is not used. Report liver disease: severe impairment and hepatic encephalopathy are also on the list of prohibitions, and cirrhosis with oedema and ascites calls for more frequent monitoring. Name separately any medicines affecting heart rhythm, digitalis preparations, lithium, other diuretics, ACE inhibitors and metformin — all of them change either the risk or the schedule. Say whether you have diabetes, gout, a prolonged QT interval, or a tendency to allergy or asthma. And state your age: in the elderly creatinine is assessed with a correction for age, body weight and sex, and they need sodium monitoring more often.
