Indapamide

C03B - Low-ceiling diuretics, excl. thiazides ATC C03BA11 Small molecule approved 1983 Oral Natural product

JFDA label: Natrilix SR Tab

Mechanism of Action

Inhibitor of Solute carrier family 12 member 3 — Thiazide-sensitive sodium-chloride cotransporter inhibitor

Target	Action	Gene / class
Solute carrier family 12 member 3 efficacy	INHIBITOR	SLC12A3

Indications

Approved

Chronic kidney disease (CKD) and hypertension
Coronary artery disease (CAD) and hypertension
Diabetes and hypertension
Heart failure
Hypertension

Off-label

Calcium nephrolithiasis

Contraindications

Source: Lexicomp

Additional contraindications (not in U.S. labeling): Severe renal failure (CrCl Absolute
Hypersensitivity to indapamide or any component of the formulation or sulfonamide-derived drugs Absolute
anuria Note: Although the FDA approved product labeling states this medication is contraindicated with other sulfonamide-containing drug classes, the scientific basis of this statement has been challenged. See “Warnings/Precautions” for more detail Absolute

Adverse Reactions

Very Common >10%Common 1–10%Uncommon 0.1–1% Rare 0.01–0.1%Very Rare <0.01%Not Known

Nervous system disorders (17)

Common Agitation · anxiety · Depression · dizziness · drowsiness · fatigue · headache · hypertonia · insomnia · irritability · lethargy · malaise · nervousness (dose-dependent) · pain · paresthesia · tension · vertigo

Renal and urinary disorders (4)

Common Increased blood urea nitrogen · increased serum creatinine · Nocturia · polyuria

Metabolism and nutrition disorders (8)

Common Decreased libido · glycosuria · hyperglycemia · hyperuricemia · hypochloremia · Hypokalemia (Infection: Infection · hyponatremia · weight loss

Gastrointestinal disorders (10)

Common Abdominal cramps · abdominal pain · anorexia · constipation · diarrhea · dyspepsia · gastric irritation · nausea · vomiting · xerostomia

Skin and subcutaneous tissue disorders (3)

Common Pruritus · skin rash · urticaria

Musculoskeletal and connective tissue disorders (4)

Common Back pain · muscle cramps · muscle spasm · weakness

Eye disorders (2)

Common Blurred vision · conjunctivitis

Respiratory, thoracic and mediastinal disorders (6)

Common Cough · flu-like symptoms · pharyngitis · Rhinitis · rhinorrhea · sinusitis

Other (8)

Common Cardiac arrhythmia · chest pain · flushing · orthostatic hypotension · palpitations · peripheral edema · vasculitis · ventricular premature contractions

Dosing

Source: Lexicomp

Edema: Oral: Initial: 2.5 mg daily; if inadequate response after 1 week, may increase dose to 5 mg daily. Note: There is little therapeutic benefit to increasing the dose >5 mg daily; there is, however, an increased risk of electrolyte disturbances Hypertension: Oral: Initial: 1.25 mg daily; if inadequate response, may increase dose once every 4 weeks to 2.5 mg daily and then to 5 mg daily if needed. Consider adding another antihypertensive and decreasing the dose if response is not adequate. Usual dosage range (ASH/ISH [Weber 2014]): 1.25 to 2.5 mg daily. Calcium nephrolithiasis (off-label use): Oral: 2.5 mg once daily (AUA [Pearle 2014])

Use with caution (Beers Criteria [AGS 2015]). Refer to adult dosing.

There are no dosage adjustments provided in the manufacturer's labeling; however, the following adjustments have been recommended: GFR 10 to 50 mL/minute: 1.25 to 2.5 mg once daily (Golightly 2013) GFR Hemodialysis: 1.25 to 2.5 mg once daily (limited data); not dialyzable (Golightly 2013; Acchiardo 1983)

There are no dosage adjustments provided in manufacturer’s labeling; use with caution.

Warnings & Precautions

Source: Lexicomp

Electrolyte disturbances

Severe hyponatremia with hypokalemia has been reported at recommended doses (particularly in elderly women); risk may be dose dependent, therefore, use lowest dose possible. Hypochloremic alkalosis, hypomagnesemia, or hypercalcemia can also occur; monitor electrolytes periodically during therapy.

Photosensitivity

Photosensitization may occur.

Sulfonamide (“sulfa”) allergy

The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes. Disease-related concerns:

Adrenal insufficiency

Avoid use of diuretics for treatment of elevated blood pressure in patients with primary adrenal insufficiency (Addison disease). Adjustment of glucocorticoid/mineralocorticoid therapy and/or use of other antihypertensive agents is preferred to treat hypertension (Bornstein 2016; Inder 2015).

Diabetes

Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.

Gout

In certain patients with a history of gout, a familial predisposition to gout, or chronic renal failure, gout can be precipitated.

Hepatic impairment

Use with caution in patients with severe hepatic dysfunction; in cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.

Hypercholesterolemia

Use with caution in patients with moderate or high cholesterol concentrations; thiazide diuretics have been shown to increase cholesterol concentrations; however, indapamide (a thiazide-like diuretic) has not been shown to adversely affected lipids.

Hypokalemia

Use with caution in patients with hypokalemia; correct before initiating therapy.

Renal impairment

Use with caution in severe renal disease.

Systemic lupus erythematosus (SLE)

Can cause SLE exacerbation or activation. Dosage forms specific issues:

Lactose

Formulation may contain lactose.

Pregnancy & Lactation

Pregnancy

FDA category B

Adverse events were not observed in animal reproduction studies. Diuretics cross the placenta and are found in cord blood. Maternal use may cause may cause fetal or neonatal jaundice, thrombocytopenia, or other adverse events observed in adults. Use of diuretics during normal pregnancies is not appropriate; use may be considered when edema is due to pathologic causes (as in the nonpregnant patient); monitor.

Lactation

It is not known if indapamide is excreted in breast milk. If therapy is needed, the manufacturer recommends that nursing be discontinued.

Monitoring

Clinical pearl	Blood pressure (both standing and sitting/supine); serum electrolytes, hepatic function, renal function, uric acid; assess weight, I & O reports daily to determine fluid loss

Chemistry & Properties

Formula	C16H16ClN3O3S
Molecular weight	365.84 g/mol
IUPAC name	4-chloro-N-(2-methyl-2,3-dihydroindol-1-yl)-3-sulfamoylbenzamide
CAS	26807-65-8
PubChem CID	3702
InChIKey	`NDDAHWYSQHTHNT-UHFFFAOYSA-N`
logP	2.08 (XLogP 2.9)
Polar surface area	92.5 Å²
H-bond acceptors / donors	4 / 2
Drug-likeness (QED)	0.87
Lipinski violations	0

SMILES

CC1Cc2ccccc2N1NC(=O)c1ccc(Cl)c(S(N)(=O)=O)c1

Biology & Pharmacokinetics

Pharmacokinetics

BBB penetrant	No

Enzyme interactions

Enzyme	Role	Detail
CYP2C8	Inhibitor	—

Receptor binding (top 1)

Target	Action	Affinity
N-Acylphosphatidylethanolamine-phospholipase D (NAPEPLD)	Allosteric modulator	pKd 6.2

Transporters

ASBT (Inhibitor)BCRP (Inhibitor)BSEP (Inhibitor)BSEP (Inhibitor)MRP1 (Inhibitor)MRP2 (Inhibitor)MRP3 (Inhibitor)MRP4 (Inhibitor)OAT3 (Inhibitor)OATP1B1 (Inhibitor)OATP1B1 (Inhibitor)OATP1B3 (Inhibitor)OATP1B3 (Inhibitor)P-gp (Inhibitor)P-gp (Substrate)

Drug–drug interactions (100+, DDInter)

Interacting drug	Severity	Management
Aminolevulinic acid	major
Arsenic trioxide	major
Cisapride	major
Dolasetron	major
Acarbose	moderate
Acetohexamide	moderate
Albiglutide	moderate
Aldesleukin	moderate
Alimemazine	moderate
Alogliptin	moderate
Amifostine	moderate
Aminolevulinic acid (topical)	moderate
Amphotericin B	moderate
Amphotericin B (cholesteryl sulfate)	moderate
Amphotericin B (lipid complex)	moderate
Amphotericin B (liposomal)	moderate
Beclomethasone dipropionate	moderate
Betamethasone	moderate
Bisacodyl	moderate
Brimonidine (ophthalmic)	moderate
Brimonidine (topical)	moderate
Bupropion	moderate
Calcifediol	moderate
Calcipotriol (topical)	moderate
Calcitriol	moderate
Calcitriol (topical)	moderate
Calcium Phosphate	moderate
Calcium acetate	moderate
Calcium carbonate	moderate
Calcium chloride	moderate
Calcium citrate	moderate
Calcium glubionate anhydrous	moderate
Calcium glucoheptonate	moderate
Calcium gluconate	moderate
Calcium lactate	moderate
Canagliflozin	moderate
Capecitabine	moderate
Castor oil	moderate
Celecoxib	moderate
Chlorpropamide	moderate

Showing 40 of 100+.

Registered Products (13)

Brand	Form / strength	Pack	Agent	Citizen (JOD)
Dapamix S.R	Tablet 1.5 mg	30 tab pack varies	Al-Taqqadom Pharmaceutical Industries	3.550
Inzide	Tablet 1.5 mg	30 tab	United Pharmaceutical	3.550
Pharmalix SR	Tablet 1.5 mg	30 tab	Pharma International Company/ Jordan	3.550
Bi-Preterax Arginine	Tablet 1.25 mg, 5 mg	30 tab	The Jordan Drugstore Co	3.930
Natrilix SR Tab	Tablet 1.5 mg	30 tab	The Jordan Drugstore Co	3.980
Bi-Preterax Arginine 10mg/2.5mg	Tablet 2.5 mg, 10 mg	30 tab	The Jordan Drugstore Co	6.450
Triplixam 5mg/1.25mg/5mg	Tablet 1.25 mg, 5 mg, 5 mg	30 tab	The Jordan Drugstore Co	7.030
Triplixam 5mg /1.25mg /10 mg	Film-Coated Tablet 1.25 mg, 10 mg, 5 mg	30 Film	The Jordan Drugstore Co	7.100
Natrixam 1.5mg/10mg	Tablet 1.5 mg, 10 mg	30 tab	The Jordan Drugstore Co	7.990
Natrixam 1.5mg/5mg	Tablet 1.5 mg, 5 mg	30 tab	The Jordan Drugstore Co	7.990
Triplixam 10mg/2.5mg/10mg	Tablet 2.5 mg, 10 mg, 10 mg	30 tab	The Jordan Drugstore Co	13.930
Triplixam 10mg/2.5mg/5mg	Tablet 2.5 mg, 5 mg, 10 mg	30 tab	The Jordan Drugstore Co	13.930
Dapamix S.R	Tablet 1.5 mg	1000 tab pack varies	Al-Taqqadom Pharmaceutical Industries	100.580