NATRILIX(r) Indapamide hemihydrate 2.5mg Chemical structure: C16H16ClN3O3S, 1/2 H2O
CAS Registry Number
: 26 807-65-8
, 1/2
H O
Indapamide (4-chloro-N(2-methyl-1-indolinyl)-3-sulphamoyl benzamide hemihydrate) is a non- thiazide indole derivative of chlorosulphonamide. Indapamide is a white crystalline lipophilic powder, soluble in methanol, ethanol, acetic acid and ethyl acetate, very slightly soluble in ether, chloroform and benzene and practically insoluble in water.
Molecular Weight
: 374.85 (Indapamide hemihydrate)
Melting point:
approximately 185degC
Excipients
Maize starch, lactose, povidone, magnesium stearate, talc, beeswax-white, titanium dioxide, glycerol, sodium lauryl sulfate, hypromellose, macrogol 6000.
Indapamide is an oral antihypertensive agent. The mechanism whereby indapamide exerts its antihypertensive action has not been completely elucidated; both vascular and renal actions have been implicated. At a dose of 2.5mg the renal effects of indapamide are minimal and the antihypertensive effect of indapamide has been attributed to a reduction in vascular reactivity to pressor amines. The finding that indapamide retains its antihypertensive activity to functionally anephric patients lends support to the hypothesis. The renal site of action of indapamide is the proximal segment of the distal tubule. Indapamide appears to have natriuretic properties (sodium and chloride being excreted in equivalent amounts) with less effect on kaliuresis or uric acid excretion. Only at doses greater that 2.5mg/day is an appreciable increase in urinary volume observed in man. No significant changes in plasma sodium levels have been observed in clinical studies. Significant hypokalaemia (plasma potassium <3.2mmol/l) has been reported in some 10% of patients. Indapamide (2.5mg daily) does not adversely affect serum triglycerides, LDL cholesterol, the LDL- HDL cholesterol ratio, or glucose tolerance.
Absorption
Possibly related to its high lipid solubility, absorption of indapamide from the gastrointestinal tract is rapid (within 0.5 to 1 hour after an oral dose) and complete. Bioavailability of the tablet formulation is 100% and is virtually unchanged with food or antacids.
Distribution
Indapamide is widely distributed throughout the body, with extensive binding to some specific sites. In blood, it is highly bound to red blood cells (80%) and, more specifically, to carbonic acid anhydrase (98%) without having any significant inhibiting activity on this enzyme. In plasma, it is relatively highly bound to plasma proteins (79%). It is also taken up to a significant degree in the vascular compartment, the drug has a relatively low apparent volume of distribution (approximately 60L) and 40% of the dose is located in the blood one hour after administration.
Metabolism and Elimination
After a single dose of 2.5mg, as well as after repeated administration of 2.5mg daily for 15 days, plasma elimination half life of unchanged indapamide is biphasic with half lives of 14 and 25 hours, indicating that once daily dosing is possible and that no change in kinetics occurs after repeated dosing. Both single and multiple dose data indicate that indapamide's kinetics are linear. Steady state plasma levels are reached within three to four days after starting treatment and the drug does not accumulate in hypertensive patients with various degrees of renal insufficiency. Indapamide is extensively metabolised in the liver. Following radioactivity studies using carbon-14, the main route of elimination is the urine, but only 5 to 7% of the dose is excreted into the urine as unchanged drug; 20 to 23% of total radioactivity is eliminated into the faeces. Renal clearance of indapamide (as unchanged drug) is approximately 5 mL/minute, representing less than 10% of systemic clearance. The high lipid solubility of the indoline moiety confers to indapamide its highly localised binding to structures in the cardiovascular system.
Treatment of hypertension. It may be tried as a sole therapeutic agent in the treatment of hypertension. Normally NATRILIX is used as the initial agent in multiple drug regimes.
Severe renal failure, anuria, progressive and severe oliguria, Hepatic coma, hepatic encephalopathy or severe impairement of liver function, Known hypersensitivity to indapamide or to other sulphonamide derivatives, or to any of the excipients, Hypokalaemia.
Electrolyte changes observed with indapamide become more prominent at doses above 2.5mg/day. The daily maximum recommended dose of indapamide is 2.5mg administered as one tablet, since doses above 2.5mg only increase the diuretic effect and electrolyte disturbances consequent to diuresis without any further appreciable antihypertensive effect. Hypokalaemia may occur at all doses. (Symptoms of hypokalaemia include weakness, cramps, and cardiac dysrrhythmias. Hypokalaemia is a particular hazard in digitalised patients; dangerous or fatal arrhythmias may be precipitated). Although indapamide 2.5mg daily can be safely administered to hypertensive patients with impaired renal function caution should be observed when the drug is administered to patients with severe renal impairment since the unchanged drug is excreted primarily by the renal route.and plasma concentrations are elevated in these patients (see Pharmacokinetics and PRECAUTIONS sections).
Hyperuricaemia may occur during administration of indapamide. Rarely gout has been reported but in patients with hyperuricaemia tendency to gout attacks may be increased.
In general, diuretics should not be given with lithium because they reduce its renal clearance and add a high risk of lithium toxicity (see INTERACTIONS section).
Cases of photosensitivity reactions have been reported with thiazides and thiazide-related diuretics. It is recommended to stop treatment if a photosensitivity reaction occurs during treatment. If re-administration of the diuretic is deemed necessary, it is recommended that areas exposed to the sun or to artificial UVA are protected.
NATRILIX tablets contain lactose. Patients with an intolerance to lactose, rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Patients receiving indapamide should be monitored for signs and symptoms of fluid or electrolyte imbalance; namely hyponatraemia, hypochloraemia and hypokalaemia. Blood urea, nitrogen and uric acid should also be assessed during therapy. The signs of electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, gastrointestinal disturbances such as nausea and vomiting, tachycardia and ECG changes.
Plasma sodium
This must be measured before starting treatment, then at regular intervals subsequently as any diuretic treatment may cause hyponatraemia, sometimes with very serious consequences. The decrease in plasma sodium may be asymptomatic initially and regular monitoring is therefore essential, and should be even more frequent in the elderly and patients with cirrhosis (see ADVERSE EFFECTS and OVERDOSAGE sections).
Plasma potassium
Potassium depletion with hypokalaemia is the major risk of thiazide and related diuretics. The risk of onset of hypokalaemia (<3.4 mmol/L) must be prevented in certain high risk populations, i.e. the elderly, malnourished and/or polymedicated, cirrhotic patients with oedema and ascites, and patients with coronary artery disease and/or heart failure. In these patient groups, hypokalaemia increases the cardiac toxicity of digitalis preparations and increases the risk of arrhythmias. Hypokalaemia will be more common in association with concomitant steroid or ACTH therapy and with inadequate electrolyte intake. Individuals with a long QT interval, whether the origin is congenital or iatrogenic, are also at increased risk as hypokalaemia and bradycardia, are predisposing factors 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. Hypokalaemia, if detected, should be corrected.
Plasma calcium
Thiazide and related diuretics may decrease urinary calcium excretion and cause a slight and transitory rise in calcium. Frank hypercalcaemia may be due to previously unrecognised hyperparathyroidism. Diuretic treatment should be withdrawn before the investigation of parathyroid function. Special caution should be used in treating patients with severe hepatic disease to avoid metabolic alkalosis in cases of potassium depletion which may precipitate episodes of hepatic encephalopathy. Administration of the diuretic must be stopped immediately if this occurs. Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates, narcotics or concurrent therapy with other antihypertensives. When NATRILIX is given with other non diuretic antihypertensive agents, the effects on blood pressure are additive. Sulphonamide derivatives have been reported to exacerbate or activate systemic lupus erythematosus. Serious allergic skin reactions (such as Stevens-Johnson syndrome) have also occasionally been reported associated with sulphonamides. These possibilities should be kept in mind with the use of indapamide. Although indapamide 2.5mg daily can safely be administered to hypertensive patients with impaired renal function, the treatment should be discontinued if increasing azotaemia and oliguria occur. Studies in functionally anephric patients for one month undergoing chronic haemodialysis have not shown evidence of drug accumulation, despite the fact that indapamide is not dialysable. A study in patients with impaired renal function demonstrated that patients with severe renal impairment (creatinine clearance 11-35mL/min) had impaired clearance of indapamide and elevated plasma levels of the drug.
Monitoring of blood glucose is important in diabetics, in particular in the presence of hypokalaemia.
This medicinal product contains a drug substance which may give a positive reaction in doping tests.
Safety and effectiveness have not been established.
Indapamide should be avoided in pregnant women and should never be used to treat physiological oedema of pregnancy. Whilst animal studies have not suggested any teratogenic effect, there is no information on the use of indapamide in pregnancy. Diuretics can cause foetoplacental ischaemia, with a risk of impaired foetal growth. Thiazides, related diuretics and loop diuretics enter the foetal circulation and may cause electrolyte disturbances. Neonatal thrombocytopaenia has been reported with thiazides and related diuretics. Loop diuretics like frusemide and bumetanide are probably also associated with this risk. During the latter part of pregnancy products of this type should only be given on sound indications, and then in the lowest effective dose.
Breast-feeding is not recommended as indapamide is excreted in human breast milk and the possible effect on the newborn is unknown.
A reproduction study in rats showed no impairment of male or female fertility at oral indapamide doses up to 25mg/kg/day, however, the number of implantation sites was reduced at the highest dose.
Carcinogenicity studies in mice and rats showed no evidence of tumourigenicity when indapamide was administered in the diet at levels up to 100mg/kg/day.
Indapamide was negative in mutagenicity tests in bacteria and in a bone marrow micronucleus test in mice. There was a decrease in weight gain of the F1 generation from rats treated orally at 2.5mg/kg/day. Galactopoiesis was affected in the F1 generation from rats treated orally at 0.5mg/kg/day and this led to increased mortality of the F2 generation during the first 48 hours of life. No embryo-foetal toxicity or teratogenic potential were seen in rats (up to 150mg/kg/day) and in rabbits (up to 180mg/kg/day).
No interactions have been reported between indapamide and anticoagulants, uricosurics agents. It is recommended that the drug not be used in combination with a diuretic agent since the combination may produce hypokalaemia and hyperuricaemia.
Combinations that are not recommended:
Lithium:
Co-administration of NATRILIX and lithium may result in increased plasma lithium levels and produce symptoms of overdosage (due to decreased urinary lithium excretion. However, if the use of diuretics is necessary, careful monitoring of plasma lithium and dose adjustment are required.
Torsades de pointes-inducing drugs:
Co-administration of NATRILIX and Torsades de pointes-inducing drugs, including the following, is not recommended due to the increased risk of ventricular arrhythmias, particularly torsades de pointes (hypokalaemia is a risk factor):
class Ia antiarrhythmics (e.g. disopyramide)
class III antiarrhythmics (e.g. amiodarone, sotalol)
some antipsychotics : phenothiazines (e.g. trifluoperazine), benzamides (e.g. amisulpride, sulpiride) and butyrophenones (e.g. droperidol, haloperidol)
others: diphemanil, erythromycin IV, pentamidine, moxifloxacin.
Monitor (using plasma electrolytes and ECG) for hypokalaemia and correct, if required, before concomitant administration of NATRILIX and a Torsades de pointes-inducing drug. Co-administration of NATRILIX and drugs that cause Torsades de pointes in the presence of hypokalaemia is not recommended.
NSAIDs (systemic route) including COX-2 selective inhibitors, high dose salicylic acid (>= 3 g/day):
Due to the risk of acute renal failure in dehydrated patients as a result of decreased glomerular filtration, it is recommended that adequate hydration and renal function be monitored at the start of treatment.
Co-administration with NSAIDs may also result in a reduction in the antihypertensive effect of NATRILIX.
Angiotensin converting enzyme (ACE) inhibitors: Co-administration with ACE inhibitors in the presence of pre-existing sodium depletion (particularly in patients with renal artery stenosis) may increase the risk of sudden hypotension and/or acute renal failure when treatment with an ACE inhibitor is initiated. In patients with hypertension when prior diuretic treatment may have caused sodium depletion, it is necessary to either:
stop the diuretic three days before starting treatment with the ACE inhibitor, and restart a hypokalaemic diuretic if necessary; or
give low initial doses of the ACE inhibitor and increase the dose gradually.
In patients with congestive heart failure, initiation with a very low dose of ACE inhibitor, possibly after a reduction in the dose of the concomitant hypokalaemic diuretic, is recommended. The monitoring of renal function (plasma creatinine) during the first weeks of treatment with an ACE inhibitor is recommended in all patients.
Other compounds causing hypokalaemia: amphotericin B (IV), gluco- and mineralo-corticoids (systemic route), stimulant laxatives: Due to the increased risk of hypokalaemia (additive effect):
monitoring, and correction if required, of plasma potassium (especially during digitalis treatment) is recommended
the use of non-stimulant laxatives is recommended.
Baclofen:
Due to the increased risk of antihypertensive effects, it is recommended that adequate hydration and renal function be monitored at the start of treatment.
Digitalis preparations:
Monitoring of plasma potassium and ECG is recommended due to the increased risk of hypokalaemia following co-administration of NATRILIX and digitalis preparations.
Potassium-sparing diuretics (amiloride, spironolactone, triamterene):
Due to the increased risk of either hyperkalaemia or hypokalaemia (particularly in patients with renal failure or diabetes), care should be taken when co-administering potassium-sparing diuretics. Plasma potassium and ECG should be monitored and, if necessary, treatment reviewed.
Metformin:
Do not co-administer with metformin when plasma creatinine exceeds 15 mg/L (135 mmol/L) in men and 12 mg/L (110 mmol/L) in women due to the increased risk of metformin induced lactic acidosis as a result of the possibility of functional renal failure associated with diuretics and more particularly with loop diuretics.
Iodinated contrast media:
Adequate hydration before administration of the iodinated compound is recommended due to an increased risk of acute renal failure resulting from dehydration, particularly when large doses of iodinated contrast media are used.
Imipramine-like antidepressants, neuroleptics:
Caution is recommended with these combinations due to an increased antihypertensive effect and increased risk of orthostatic hypotension.
Calcium (salts):
Caution is recommended with this combination due to the risk of hypercalcaemia resulting from decreased urinary elimination of calcium.
Cyclosporin, tacrolimus:
Caution is recommended with this combination due to the risk of increased plasma creatinine without any change in circulating cyclosporin levels, even in the absence of water/sodium depletion.
Corticosteroids, (systemic route):
Caution is recommended with this combination due to the risk of decreased antihypertensive effect (water/sodium retention due to corticosteroids).
Hyperuricaemia (0.4%). Hyperglycaemia (0.4%) (see ADVERSE EFFECTS section) The following values represent the maximum variations from pre-treatment values in occasional patients at some stage during, but not necessarily throughout treatment. Blood uric acid up 8.6%, blood glucose up 6%, BUN up 5.7%, blood creatinine up 3.6%.
Indapamide does not affect vigilance but different reactions related to a decrease in blood pressure may occur in individual cases, especially at the start of treatment or when another antihypertensive agent is added. Treatment with any blood pressure lowering agent may, therefore, affect the ability to drive, cross the road safely or operate machinery.
In general, most adverse effects are mild and transient with the most frequently reported being asthenia, dizziness, headache, fatigue, muscle cramps and gastrointestinal disturbances usually occurring within the first month of treatment. The majority of adverse reactions concerning clinical or laboratory parameters are dose-dependent. Other adverse reactions have been nonspecific. Cutaneous rash and impotence have been occasionally reported. Percentages shown below indicate the incidence in clinical trials. Thiazide-related diuretics, including indapamide, may cause the following undesirable effects ranked according to the following frequencies: Very common (>= 1/10); common (>= 1/100, < 1/10); uncommon (>= 1/1.000, < 1/100); rare (>= 1/10.000); very rare (<1/10.000); not known (cannot be estimated from the available data):
Blood and the lymphatic system disorders:
Very rare
: thrombocytopaenia, leucopaenia, agranulocytosis, aplastic anaemia, haemolytic anaemia
Metabolism and nutrition disorders:
For indapamide 2.5 mg, 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 (Potassium supplementation may be required in up to 25% of cases), after 4 to 6 weeks treatment. After 12 weeks treatment, the mean fall in plasma potassium was 0.23 mmol/L. Hypochloraemia 9.4%; hyponatraemia 3.1%
Very rare
: Hypercalcaemia
Nervous system disorders:
Common:
dizziness, headache, fatigue, asthenia
Uncommon:
drowsiness, sleepiness, insomnia, weakness, anxiety, visual disturbance
Rare:
vertigo, paresthesia
Cardiac disorders:
Very rare
: arrhythmia, hypotension, palpitations, chest pain
Gastrointestinal disorders:
Uncommon
: vomiting, dyspepsia, abdominal pain
Rare
: nausea, constipation, dry mouth
Very rare:
pancreatitis
Hepato-biliary disorders:
Very rare:
abnormal hepatic function
Skin and subcutaneous tissue disorders:
Hypersensitivity reactions, mainly dermatological, in subjects with a predisposition to allergic and asthmatic reactions:
Common:
maculopapular rashes
Uncommon:
purpura, pruritus
Very rare:angioneurotic oedema and/or urticaria, toxic epidermic necrolysis, Steven Johnson syndrome (see PRECAUTIONS section)
Musculoskeletal disorders:
Common:muscle cramps
Renal and urinary disorders:
Uncommon:cystitis
Very rare
: renal failure
Other adverse reactions, reported in clinical studies with the immediate release formulation of indapamide include the following:
Central Nervous System: lethargy. Gastrointestinal: anorexia, gastralgia, diarrhoea.
Musculoskeletal
: joint pain, back pain, weakness of legs.
Cardiovascular
: orthostatic hypotension, tachycardia, ECG changes (non specific ST-T changes, U waves, left ventricular strain).
Urogenital: modification of libido, polyuria. Endocrine: gout.
Other:
tinnitus, malaise/fainting, sweat.
Laboratory abnormalities:
BUN increase, blood creatinine increase
Post-Marketing experience
Metabolism and nutrition disorder:
Potassium depletion with hypokalaemia, particularly serious in certain high risk populations (see CONTRAINDICATIONS and PRECAUTIONS sections). 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.
Nervous system disorders:
Syncope.
Cardiac disorders:
Torsade de pointes (potentially fatal) (see CONTRAINDICATIONS and INTERACTIONS WITH OTHER MEDICINES sections).
Hepato-biliary disorders:
Possibility of onset of hepatic encephalopathy in case of hepatic insufficiency (see PRECAUTIONS section), hepatitis.
Skin and subcutaneous tissue disorders:
Possible worsening of pre-existing acute disseminated lupus erythematosus. Cases of photosensitivity reactions have been reported (see PRECAUTIONS section).
Investigations:
Electrocardiogram QT prolonged. Elevated liver enzyme levels. 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
One tablet (2.5mg indapamide) to be taken daily, by oral route, in the morning. The action of NATRILIX is progressive and whilst the optimum reduction in blood pressure is usually seen after four weeks, a further small but useful reduction in blood pressure may be observed over the following four to six weeks. A larger dose than 1 tablet (2.5mg) of NATRILIX daily is not recommended as there is little additional antihypertensive effect, whilst the diuretic effect becomes more prominent. A single daily tablet of NATRILIX may effectively be combined with the following antihypertensive agents: beta-blockers, methyldopa, clonidine, prazosin, and ACE inhibitors. Combination with a diuretic agent is not recommended as significant electrolyte disturbances may ensue. Indapamide has a slight but significant carry-over hypotensive effect lasting up to 1 or 2 weeks after the cessation of therapy
For information on the management of overdose, contact the Poison Information Centre on 131126 (Australia) or 0800 764 766 in New Zealand. Signs of acute poisoning at higher dosages take the form of water/electrolyte disturbances (hyponatraemia, hypokalaemia) and may include the possibility of nausea, vomiting, hypotension, cramps, vertigo, drowsiness, confusion, polyuria or oliguria possibly to the point of anuria (by hypovolaemia). In patients with cirrhosis, overdosage might precipitate hepatic coma.
Treatment
There is no specific antidote. Treatment is symptomatic and supportive. Discontinue drug; induce emesis or perform gastric lavage and/or administration of activated charcoal (Activated charcoal may reduce absorption of the medicine if given within one or two hours after ingestion. In patients who are not fully conscious or have impaired gag reflex, consideration should be given to administering activated charcoal via a nasogastric tube, once the airway is protected), correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures.
Presentation
White, film-coated biconvex tablet containing indapamide hemihydrate 2.5mg. NATRILIX is supplied in boxes containing 90 tablets.
Storage conditions
Store in a dry place below 30degC
SERVIER LABORATORIES (AUSTRALIA) PTY. LTD.
8 Cato Street, Hawthorn, Victoria 3122 AUSTRALIA ABN 54 004 838 500 SERVIER LABORATORIES (NEW ZEALAND) LTD Level 4, Zurich House 21 Queen Street Auckland Central Auckland 1010
S4.
13 July,1993
22 February, 2013
28 April, 1983