FLUMIDE LP

The most significant modifiable risk factor for cardiovascular disease and the most prominent contributor to all-cause mortality is hypertension.

Characterized by an office blood pressure of ≥140/90, hypertension is pervasive and impacts an estimated 25% of adults globally.

Treatment for hypertension should include a number of lifestyle changes (ie. reduced sodium intake) along with pharmacotherapy.

• it should be noted that treatment with several antihypertensive agents may be required in order to achieve blood pressure targets.

Thiazide-like diuretics such as indapamide are a valuable tool for the treatment of hypertension and continue to grow in popularity, falling behind only ACE inhibitors in terms of prescription frequency.

When compared to hydrochlorothiazide (another commonly prescribed diuretic), indapamide has been shown to be superior at lowering systolic blood pressure, reducing left ventricular mass index, lowering oxidative stress, inhibiting platelet aggregation, and reducing microalbuminuria associated with diabetes.

Interestingly, unlike thiazide diuretics, several sources suggest that indapamide is not associated with glucose or lipid disturbances. 16, 19 Indapamide is characterized by both a methylindoline and a sulfamoyl chlorobenzamide functional group, with the former being largely responsible for the molecule's lipid solubility.

Indapamide is a diuretic indicated for use as monotherapy or in combination with other blood pressure-lowering agents to treat hypertension.

It may also be used to treat fluid and salt retention associated with congestive heart failure.

Classified as a sulfonamide diuretic, indapamide is an effective antihypertensive agent and by extension, has shown efficacy in the prevention of target organ damage. 2, 3 Administration of indapamide produces water and electrolyte loss, with higher doses associated with increased diuresis. 2, 10 Severe and clinically significant electrolyte disturbances may occur with indapamide use.

• for example, hypokalemia resulting from renal potassium loss may lead to QTc prolongation. 2, 9 Further electrolyte imbalances may occur due to renal excretion of sodium, chloride, and magnesium. 2, 9, 10 Other indapamide induced changes include increases in plasma renin and aldosterone, and reduced calcium excretion in the urine. 2, 11, 15 In many studies investigating the effects of indapamide in both non-diabetic and diabetic hypertensive patients, glucose tolerance was not significantly altered.

However, additional studies are necessary to assess the long term metabolic impacts of indapamide, since thiazide related impaired glucose tolerance can take several years to develop in non-diabetic patients.

The bioavailability of indapamide is virtually complete after an oral dose and is unaffected by food or antacids. 6, 4 Indapamide is highly lipid-soluble due to its indoline moiety.

• a characteristic that likely explains why indapamide's renal clearance makes up less than 10% of its total systemic clearance. 2, 6, 4 The Tmax occurs approximately 2.3 hours after oral administration.

The Cmax and

AUC 0-24 values are 263 ng/mL and 2.95 ug/hr/mL, respectively.

Some sources report an apparent volume of distribution of 25 L for indapamide, while others report a value of approximately 60 L. 6, 4, 13.

As a result of extensive metabolism in the liver, the majority of indapamide excreted is metabolized, with only 7% remaining unchanged.

In humans, as many as 19 distinct indapamide metabolites may be produced, although not all have been identified. 2, 6 There are several metabolic routes through which indapamide may be metabolized, and CYP3A4 is the main enzyme involved in the corresponding hydroxylation, carboxylation, and dehydrogenation reactions.

Indapamide can undergo dehydrogenation to form

M5, then oxidation to form M4, then further hydroxylation at the indole moiety to form M2.

These reactions are facilitated by

Another route of metabolism occurs when indapamide is first hydroxylated to M1 by CYP3A4.

M1 then undergoes dehydrogenation to form M3 and is further oxidized to form M2.

Hydroxylation of indapamide's indole moiety is thought to form the major metabolite (M1), which is less pharmacologically active compared to its parent compound according to animal studies.

Indapamide may also undergo epoxidation via

CYP3A4 to form a reactive epoxide intermediate.

The unstable epoxide intermediate may then undergo dihydroxylation via microsomal epoxide hydrolase to form M6, or glutathione conjugation to form M7.

Hover over products below to view reaction partners Indapamide Indapamide metabolite M5 Indapamide metabolite M4 Indapamide metabolite M2 Indapamide metabolite M1 Indapamide metabolite M3 Indapamide metabolite M2 Indapamide epoxide intermediate Indapamide glutathione conjugate M7 Indapamide metabolite M6.

An estimated 60-70% of indapamide is eliminated in the urine, while 16-23% is eliminated in the feces.

Indapamide is characterized by biphasic elimination.

In healthy subjects, indapamide's elimination half-life can range from 13.9-18 hours. 2, 4 The long half-life is conducive to once-daily dosing.

Indapamide's renal and hepatic clearance values are reported to be 1.71 mL/min and 20-23.4 mL/min, respectively.

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Indapamide overdose symptoms may include but are not limited to nausea, vomiting, gastrointestinal disorders, electrolyte disturbances and weakness.

Other signs of overdose include respiratory depression and severe hypotension.

In cases of overdose, supportive care interventions may be necessary to manage symptoms.

Emesis and gastric lavage may be recommended to empty the stomach; however, patients should be monitored closely for any electrolyte or fluid imbalances.

Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of indapamide.

This occurred primarily in elderly females.

This appears to be dose related.

Also, a large case-controlled pharmacoepidemiology study indicates that there is an increased risk of hyponatremia with indapamide 2.5 mg and 5 mg doses.

Hyponatremia considered possibly clinically significant (< 125 mEq/L) has not been observed in clinical trials with the 1.25 mg dosage.

Thus, patients should be started at the 1.25 mg dose and maintained at the lowest possible dose. See DOSAGE AND ADMINISTRATION. Hypokalemia occurs commonly with diuretics See ADVERSE REACTIONS, hypokalemia, and electrolyte monitoring is essential, particularly in patients who would be at increased risk from hypokalemia, such as those with cardiac arrhythmias or who are receiving concomitant cardiac glycosides.

In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity.

Read prescribing information for lithium preparations before use of such concomitant therapy.

Known hypersensitivity to indapamide or to other sulfonamide-derived drugs.

The adult starting indapamide dose for hypertension is 1.25 mg as a single daily dose taken in the morning.

If the response to 1.25 mg is not satisfactory after 4 weeks, the daily dose may be increased to 2.5 mg taken once daily.

If the response to 2.5 mg is not satisfactory after 4 weeks, the daily dose may be increased to 5.0 mg taken once daily, but adding another antihypertensive should be considered.

The adult starting indapamide dose for edema of congestive heart failure is 2.5 mg as a single daily dose taken in the morning.

If the response to 2.5 mg is not satisfactory after one week, the daily dose may be increased to 5.0 mg taken once daily.

If the antihypertensive response to indapamide is insufficient, indapamide may be combined with other antihypertensive drugs, with careful monitoring of blood pressure.

It is recommended that the usual dose of other agents be reduced by 50% during initial combination therapy.

As the blood pressure response becomes evident, further dosage adjustments may be necessary.

In general, doses of 5.0 mg and larger have not appeared to provide additional effects on blood pressure or heart failure, but are associated with a greater degree of hypokalemia.

There is minimal clinical trial experience in patients with doses greater than 5.0 mg once a day.

Tablets, USP are available containing 1.25 mg or 2.5 mg of indapamide, USP.

The 1.25 mg tablets are pink, film coated, round, biconvex, beveled edge tablet debossed with “875” on one side of the tablet and plain on the other side.

They are available as follows

NDC 16571-875-01 bottles of 100 tablets The 2.5 mg tablets are white, film coated, round, biconvex, beveled edge tablet debossed with “876” on one side of the tablet and plain on the other side.

NDC 16571-876-01 bottles of 100 tablets Store at 20° to 25°C (68° to 77°F).

Avoid excessive heat.

Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

Manufactured for

Brunswick, NJ 08816 Revised: 04/2023 200653 PIR87610-01.

Reproduction studies have been performed in rats, mice and rabbits at doses up to 6,250 times the therapeutic human dose and have revealed no evidence of impaired fertility or harm to the fetus due to indapamide.

Postnatal development in rats and mice was unaffected by pretreatment of parent animals during gestation.

There are, however, no adequate and well-controlled studies in pregnant women.

Moreover, diuretics are known to cross the placental barrier and appear in cord blood.

Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.

There may be hazards associated with this use such as fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions that have occurred in the adult.

It is not known whether this drug is excreted in human milk.

Because most drugs are excreted in human milk, if use of this drug is deemed essential, the patient should stop nursing.

Safety and effectiveness of indapamide in pediatric patients have not been established.

Clinical studies of indapamide did not include sufficient numbers of subjects aged and over to determine whether they respond differently from younger subjects.

Other reported clinical experience has not identified differences in responses between the elderly and younger patients.

In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Severe cases of hyponatremia, accompanied by hypokalemia have been reported with recommended doses of indapamide in elderly females See WARNINGS.