PHARMACOLOGICAL ACTION: Indapamide, an indole derivative of chlorosulphonamide, has an anti-hypertensive action causing a drop in systolic, diastolic and mean blood pressure. This anti-hypertensive action is maximal at a dose of 2,5 mg per day and the diuretic effect is slight, usually without clinical manifestation. At higher doses, the diuretic effect becomes more prominent. The extra-renal antiaction of 2,5 mg per day is demonstrated as a decrease in vascular hyperactivity and a reduction in total peripheral and arteriolar resistance. The extra-renal mechanism of action has also been demonstrated by the maintenance of anti-hypertensive effect in functionally anephric patients. The extra-renal action is thought to be due to the inhibition of transmembrane ionic influx, essentially calcium, and the stimulation of synthesis of the vasodilatory hypotensive prostaglandin PGE2. Pharmacokinetics: Indapamide is rapidly and completely absorbed from the gastro-intestinal tract. Elimination is biphasic with a terminal half-life of 14 to 18 hours. Indapamide is strongly bound to plasma proteins (79% ). It is extensively metabolised; approximately 60 to 70% of the dose has been reported to be excreted in the urine with approximately 5% excreted unchanged. Approximately 16 to 23% of the administered dose is excreted in the faeces. In a comparative single dose two way crossover bioavailability study it was established that Cmax is 91,84 ng/mL and tmax is 1,73 hours. The methyl-indoline portion of the molecule gives indapamide its lipophilic character; indapamides lipid solubility being 5 to 8 times that of the thiazides.
INDICATIONS: INDALIX is indicated in the management of mild to moderate hypertension.
CONTRA-INDICATIONS: Hypersensitivity to any of the ingredients. Severe hepatic insufficiency. Safety in pregnancy and lactation has not been established.
DOSAGE AND DIRECTIONS FOR USE:
The usual dose is 2,5 mg once daily, either alone, or in conjunction with other anti-hypertensive agents to be taken in the morning with breakfast.
There is no experience of the use of this medicine in children.
SIDE-EFFECTS AND SPECIAL PRECAUTIONS:
Side-effects: The most frequent reported side-effects include dizziness and headaches. Indapamide may cause a number of metabolic disturbances e.g. hyperglycemia and glycosuria in diabetics and other susceptible patients and hyperuricaemia and precipitation of gout attacks in some patients.
The administration of indapamide may be associated with electrolyte imbalances including hypochloraemic alkalosis, hyponatraemia, and hypokalaemia. The urinary excretion of calcium is reduced. Hypomagnesaemia has also occurred. Adverse changes in plasma lipids have also been noted but their clinical significance is unclear. Signs of electrolyte imbalance include dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain and cramps and gastro-intestinal disturbances.
Other side-effects include anorexia, gastric irritation, nausea, vomiting, constipation, diarrhoea and photosensitivity reactions. Postural hypotension, paraesthesia, impotence and yellow vision.
Hypersensitivity reactions include skin rashes, photosensitivity, pulmonary oedema and pneumonitis.
Cholestatic jaundice, pancreatitis, and blood dyscrasias including thrombocytopenia and less frequently granulocytopenia, leucopenia and aplastic haemolytic anaemia have been reported. Special Precautions: Indapamide should be used with caution in patients with impaired hepatic function since it may increase the risk of hepatic encephalopathy. It should also be given with caution to patients with renal impairment since it can reduce renal function further.
Indapamide may provoke hyperglycaemia and glycosuria in diabetics and other susceptible patients and aggravate or unmask diabetes mellitus. Indapamide should not be given to patients with Addison's disease.
All patients should be carefully observed for signs of fluid and electrolyte imbalance, especially in the presence of vomiting or during parenteral fluid therapy.
Hyponatraemia may occur in patients with severe congestive heart failure who are very oedematous, particularly with large doses in conjunction with restricted salt in the diet.
The use of indapamide may exacerbate or activate systemic lupus erythematosus in susceptible patients.
The use of indapamide may cause hypokalaemia which intensifies the effect of digitalis on cardiac muscle and administration of digitalis or its glycosides may have to be temporarily suspended. Patients with severe coronary artery disease and cirrhosis of the liver are particularly at risk from hypokalaemia and potassium serum levels should be monitored.
Indapamide crosses the placenta and there have been reports of neonatal jaundice, thrombocytopenia, and electrolyte imbalances following maternal treatment. Indapamide is excreted in the breast milk. Interactions: The concomitant use of indapamide may enhance the toxicity of digitalis glycosides by depleting serum-potassium concentrations.
Indapamide may enhance the neuromuscular blocking action of competitive muscle relaxants such as tubocurarine when administered concomitantly.
Indapamide may enhance the effect of antihypertensive agents.
Blood glucose concentrations should be monitored in patients taking anti-diabetic agents, since requirements may change.
Indapamide may interfere with a number of diagnostic tests, including tests for parathyroid function; serum concentrations of protein-bound iodine may increase without signs of thyroid disturbances.
Concomitant use of disopyramide may cause cardiac arrhythmias due to the hypokalaemic action of indapamide.
KNOWN SYMPTOMS OF OVERDOSAGE AND PARTICULARS OF ITS TREATMENT: See SIDE-EFFECTS AND SPECIAL PRECAUTIONS.
Treatment is supportive and symptomatic and directed at fluid and electrolyte replacement. In case of recent ingestion gastric lavage should be carried out.
IDENTIFICATION: White, biconvex, coated tablet.
PRESENTATION: INDALIX is available in packs of 30 and 600 tablets.
STORAGE CONDITIONS: Store in a well closed container, below 25°C in a dry place.
KEEP OUT OF REACH OF CHILDREN
REGISTRATION NUMBER: 31/7.1/0670
NAME AND BUSINESS ADDRESS OF THE APPLICANT: TRIOMED (Pty) Ltd
Montrose Place, 2 BeIlaRosa Street, Bellville 7530
DATE OF PUBLICATION OF THIS PACKAGE INSERT: 14 April 1998