Indapamide hemihydrate. Chemical Name: Indapamide hemihydrate is 4-chloro-N-(2-methyl-1-indolinyl)-3-sulfamoyl benzamide hemihydrate. Chemical Structure:
. 1/2 H2O Molecular Formula: C16H16CIN3O3S, 1/2 H2O Molecular weight: 374.85. CAS Registry Number: 26807-65-8.
Indapamide hemihydrate is a nonthiazide indole derivative of chlorosulfonamide. It 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. Melting point: approximately 185degC.
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 2.5 mg 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 in 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 than 2.5 mg/day is an appreciable increase in urinary volume observed in humans. No significant changes in plasma sodium levels have been observed in clinical studies. Significant hypokalaemia (plasma potassium < 3.2 mmol/L has been reported in some 10% of patients. Indapamide (2.5 mg daily) does not adversely affect serum triglycerides, LDL cholesterol, the LDL-HDL cholesterol ratio or glucose tolerance.
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. 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 60 L) and 40% of the dose is located in the blood one hour after administration. After a single oral dose of 2.5 mg, as well as after repeated administration of 2.5 mg 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, mainly by CYP2C9 and CYP3A4 isozymes and by cytosolic hydrolysis enzymes. Care should be taken when administering indapamide in combination with drugs that alter the activity of these enzymes (see also Interactions with other Medicines under PRECAUTIONS). 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.
Management of essential hypertension. It may be tried as a sole therapeutic agent in the treatment of mild to moderate hypertension. Normally indapamide is used as the initial agent in multiple drug regimens.
Anuria Progressive and severe oliguria Hepatic encephalopathy or coma Severe hepatic impairment Hypokalaemia Concomitant administration with non-anti-arrhythmic agents causing torsades de pointes Known hypersensitivity to indapamide, other sulphonamide derivatives, or to any of the excipient ingredients in indapamide tablets.
Electrolyte changes observed with indapamide become more prominent at doses above 2.5 mg/day. The daily maximum recommended dose of indapamide is 2.5 mg administered as one tablet, since doses above 2.5 mg 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 2.5 mg daily can be safely administered to hypertensive patients with impaired renal function, the treatment should be discontinued if increasing azotaemia and oliguria occur. 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. Studies in functionally anephric patients on indapamide monotherapy for one month undergoing chronic haemodialysis have not shown evidence of drug accumulation, despite the fact that indapamide is not dialysable. Hyperuricaemia may occur during administration of indapamide. Rarely gout has been reported.
In general, diuretics should not be given with lithium because they reduce its renal clearance and add a high risk of lithium toxicity.
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 be assessed during therapy. Hypokalaemia will be more common in association with concomitant steroid or ACTH therapy and with inadequate electrolyte intake. 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.
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. When liver function is impaired, thiazide and thiazide-related diuretics may cause hepatic encephalopathy.
Orthostatic hypotension may occur and may be potentiated by alcohol, barbiturates, narcotics or concurrent therapy with other antihypertensives. When indapamide 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 to be associated with sulphonamides. These possibilities should be kept in mind with the use of indapamide.
Very rare cases of photosensitivity reactions have been reported. If photosensitivity reaction occurs during treatment, it is recommended to stop the treatment. If a re-administration of the diuretic is deemed necessary, it is recommended to protect exposed areas to the sun or to artificial UVA.
Studies in rats showed no impairment of male or female fertility at oral indapamide doses up to 25 mg/kg/day.
Indapamide or its metabolites have been shown to cross the placenta and distribute in the foetus in pregnant animals. Thiazides, related diuretics and loop diuretics enter the foetal circulation and may cause electrolyte disturbances. Neonatal thrombocytopenia 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. There is no information on the use of indapamide in pregnancy. Whilst animal studies have not suggested any teratogenic effect, indapamide is not recommended for administration to pregnant women unless the expected benefit outweighs the potential risk. In animals treated with oral doses of indapamide, a reduction in the number of implantation sites was seen at 25 mg/kg/day and decreases were seen in weight gain of the F1 generation from rats treated at doses >= 2.5 mg/kg/day. Galactopoiesis was reduced in the F1 generation from rats treated orally at 0.5 mg/kg/day and this led to increased mortality of the F2 generation during the first 48 hours of life. No embryotoxicity or teratogenic potential was seen in rats (up to 150 mg/kg/day) or rabbits (up to 180 mg/kg/day).
Category C: Drugs which, owing to their pharmacological effects, have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations.
These effects may be reversible. Accompanying texts should be consulted for further details.
Indapamide is excreted in human milk during lactation. Other antihypertensive diuretics have been associated during breast-feeding, with decrease or even suppression of milk lactation. Serious adverse reactions might occur in nursing infants such as hypersensitivity to sulfonamide-derived drugs, hypokalaemia and nuclear icterus.
Safety and effectiveness have not been established. Genotoxicity Indapamide was negative in mutagenicity tests in bacteria and in a bone marrow micronucleus test in mice.
Potential interactions may occur with lithium, digoxin, alcohol, narcotics and barbiturates; refer to
section for further information.
No interactions have been reported between indapamide and anticoagulants or uricosurics. It is recommended that the drug not be used in combination with a diuretic agent since the combination may produce hypokalaemia and hyperuricaemia. When indapamide is given with other nondiuretic antihypertensive agents, the effects on blood pressure are additive.
Combinations which are NOT RECOMMENDED:
Non-Antiarrhythmic Drugs which Lengthen the QT Interval or Cause Torsades de Pointes, such as:
Some antipsychotics:
Chlorpromazine, thioridazine, trifluoperazine, amisulpiride, droperidol, haloperidol, pimozide
Others:
Astemizole, erythromycin IV, pentamidine, terfenadine, moxifloxacin, diphemanil, methadone.
Torsades de pointes (low potassium levels are a risk, as are bradycardia and pre-existing long QT interval). Substances which do not have the unwanted effect of causing torsades de pointes should be used in cases of low potassium levels.
Combinations which require special care:
Antiarrhythmic Drugs Which Produce Torsades de Pointes: Class IA Antiarrhythmic Agents (e.g. quinidine, disopyramide); Class III Antiarrhythmic agents (e.g. amiodarone, sotalol)
Torsades de pointes (low potassium levels are a risk factor, as are bradycardia and a pre-existing long QT interval). Prevention of low potassium levels and correction if necessary: monitoring of the QT interval. Antiarrhythmics should not be administered in cases of torsades de pointes (management by pacemaker).
Potassium Lowering Drugs: amphotericin B (IV Route), glucocorticoids and mineralocorticoids (systemic route), tetracosactide, stimulant laxatives
Increased risk of low potassium levels (additive effects). Monitoring of potassium levels, and correction if necessary; particular consideration required in cases of treatment with cardiac glycosides. Non-stimulant laxatives should be used.
NSAID (Systemic Route), High-Dose Salicylates
Possible reduction in the antihypertensive effect of indapamide. Acute renal insufficiency in dehydrated patients (reduction in glomerular filtration). Hydrate the patient; monitor renal function at the start of treatment.
Cardiac Glycosides
Low potassium levels favour the toxic effects of cardiac glycosides. Potassium levels and ECG should be monitored and treatment reconsidered if necessary.
Combinations which require some care:
Potassium Sparing Diuretics (Amiloride, Spironolactone, Triamterene)
The rationale combination, which is useful for some patients, does not exclude the onset of low potassium levels or, particularly in patients with renal insufficiency, raised potassium levels. Potassium levels and ECG should be monitored and treatment reconsidered if necessary.
Metformin
Lactic acidosis due to metformin caused by possible functional renal insufficiency linked to diuretics and in particular to loop diuretics. Do not use metformin when plasma creatinine levels exceed 15 mg/L (135 umol/L) in men and 12 mg/L (110 mmol/L) in women.
Iodinated Contrast Media
In cases of dehydration caused by diuretics, there is an increased risk of acute renal insufficiency, particularly when high doses of iodinated contrast media are used. Rehydration should be carried out before the iodinated compound is administered.
Calcium (Salts)
Risk of increased levels of calcium due to reduced elimination of calcium in the urine.
Cyclosporin
Risk of increased creatinine levels with no change in circulating levels of cyclosporin, even when there is no salt and water depletion.
Baclofen
Concomitant treatment with baclofen and antihypertensive agents may potentiate the fall in blood pressure.
Indapamide does not affect alertness but reactions related to low blood pressure may occur in some patients, particularly at the start of treatment or in combination with another antihypertensive medication. As a result the ability to drive or operate machinery may be impaired.
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. Other adverse reactions have been non-specific. Cutaneous rash and impotence have been occasionally reported. Percentages shown below indicate the incidence in clinical trials. The most severe and common adverse effect is the electrolyte imbalance. Electrolyte changes reported include:
hypokalaemia: serum potassium < 3.4 mmol - 25%
serum potassium <3.2 mmol - 10% (potassium supplementation may be required in up to 25% of cases) hypochloraemia: 9.4% hyponatraemia: 3.1%.
Central Nervous System: (8.1%)
Incidence > 1% < 3%: asthenia, headache, dizziness, vertigo. Incidence < 1%: drowsiness, sleepiness, insomnia, weakness, lethargy, visual disturbance.
Gastrointestinal: (2.6%)
Incidence < 1%: nausea/anorexia, dryness of mouth, gastralgia, vomiting, diarrhoea, constipation.
Musculoskeletal: (1.4%)
Incidence > 1% < 3%: muscle cramps. Incidence < 1%: joint pain, back pain, weakness of legs.
Cardiovascular: (1%)
Incidence < 1%: orthostatic hypotension, tachycardia, ECG changes (nonspecific ST-T changes, U waves, left ventricular strain).
Urogenital: (0.5%)
Incidence < 1%: impotence, modification of libido, polyuria.
Dermatological: (0.5%)
Incidence < 1%: rash, pruritus.
Endocrine: (0.2%)
Incidence < 1%: gout.
Other: (0.5%)
Incidence < 1%: tinnitus, malaise/fainting, sweat.
Effect on laboratory tests
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%.
One tablet (indapamide 2.5 mg) daily to be taken in the morning. The action of indapamide 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 one tablet (2.5 mg) of indapamide daily is not recommended as there is little additional antihypertensive effect, whilst the diuretic effect becomes more prominent. A single tablet of indapamide may effectively be combined with the following antihypertensive agents: b-blockers, methyldopa, clonidine, prazosin and angiotensin converting enzyme 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 one to two weeks after the cessation of therapy.
There have been no reports of overdosage. Based on the pharmacological activities of indapamide, overdosage may lead to excessive diuresis with electrolyte depletion. In cirrhotic patients, overdosage might precipitate hepatic coma.
There is no specific antidote. Treatment is symptomatic and supportive. Discontinue drug; induce emesis or perform gastric lavage; correct dehydration, electrolyte imbalance, hepatic coma and hypotension by established procedures.
White, biconvex, sugar coated tablets. AUST R 167028.
Blister packs of 90 tablets.
are intended for oral administration. Each tablet contains 2.5 mg of indapamide.
In addition, each tablet contains the following inactive ingredients: lactose monohydrate, povidone, maize starch, magnesium stearate, Opaseal clear P-2-0300G (ethyl acetate, stearic acid, polyvinyl acetate phthalate, industrial methylated spirit 74 OP), purified talc, calcium carbonate, acacia, titanium dioxide, sucrose, Opaglos 6000P off-white (shellac, industrial methylated spirit 74 OP, beeswax white, carnauba wax).
Apotex Pty Ltd 16 Giffnock Avenue Macquarie Park NSW 2113 Chemmart is a registered trade mark of Symbion Pty Ltd.
S4: Prescription Only Medicine.
11 January 2010