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Pronunciation
(in DAP a mide)
Generic Available (U.S.)
Yes
Brand Names: Canada
Pharmacologic Category
Pharmacologic Category Synonyms
Use: Labeled Indications
Management of mild-to-moderate hypertension; treatment of edema in heart failure
Use: Unlabeled/Investigational
Nephrotic syndrome (Tanaka, 2005)
Pregnancy Risk Factor
B
Pregnancy Considerations
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
Excretion in breast milk unknown/not recommended
Contraindications
Hypersensitivity to indapamide or any component of the formulation or sulfonamide-derived drugs; anuria
Canadian labeling: Additional contraindications (not in U.S. labeling): Severe renal failure (Clcr <30 mL/minute); hepatic encephalopathy; severe hepatic impairment; hypokalemia; concomitant use with nonantiarrhythmic agents causing torsade de pointes; breast-feeding
Warnings/Precautions
Concerns related to adverse effects:
• 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.
• Sulfa allergy: Chemical similarities are present among sulfonamides, sulfonylureas, carbonic anhydrase inhibitors, thiazides, and loop diuretics (except ethacrynic acid). Use in patients with sulfonamide allergy is specifically contraindicated in product labeling, however, a risk of cross-reaction exists in patients with allergy to any of these compounds; avoid use when previous reaction has been severe. Discontinue if signs of hypersensitivity are noted.
Disease-related concerns:
• 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. Canadian labeling contraindicates use in severe hepatic impairment or 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. Canadian labeling contraindicates use in hypokalemia.
• Renal impairment: Use with caution in severe renal disease. Canadian labeling contraindicates use in severe renal failure (Clcr <30 mL/minute).
• Systemic lupus erythematosus (SLE): Can cause SLE exacerbation or activation.
Dosage forms specific issues:
• Lactose: Formulation may contain lactose; Canadian labeling recommends avoiding use in patients with hereditary conditions of galactose intolerance, glucose-galactose malabsorption, or lactase deficiency.
Adverse Reactions
≥5%:
Central nervous system: Agitation, anxiety, dizziness, fatigue, headache, irritability, lethargy, malaise, nervousness (dose dependent), pain, tension, tiredness
Endocrine & metabolic: Hypokalemia (<3.5 mEq/L: 20% to 72%, dose dependent)
Neuromuscular & skeletal: Back pain, muscle cramps/spasm, paresthesia, weakness
Respiratory: Rhinitis
Miscellaneous: Infection
≥1% to <5%:
Cardiovascular: Arrhythmia, chest pain, flushing, orthostatic hypotension, palpitation, peripheral edema, PVC, vasculitis
Central nervous system: Depression, drowsiness, insomnia, lightheadedness, vertigo
Dermatologic: Hives, pruritus, rash
Endocrine & metabolic: Hyperglycemia, hyperuricemia, hypochloremia, hyponatremia, libido decreased
Gastrointestinal: Abdominal pain, anorexia, constipation, cramping, diarrhea, dyspepsia, gastric irritation, nausea, vomiting, weight loss, xerostomia
Genitourinary: Nocturia, polyuria
Neuromuscular & skeletal: Hypertonia
Ocular: Blurred vision, conjunctivitis
Renal: BUN increased, creatinine increased, glycosuria
Respiratory: Cough, pharyngitis, rhinorrhea, sinusitis
Miscellaneous: Flu-like syndrome
<1%, postmarketing, and/or case reports (limited to important or life-threatening): Agranulocytosis, anaphylactic reaction, aplastic anemia, bullous eruptions, erythema multiforme, fever, hepatitis, hypercalcemia, jaundice (cholestatic jaundice), leukopenia, liver function test abnormality, pancreatitis, photosensitivity, pneumonitis, purpura, Stevens-Johnson syndrome, thrombocytopenia, torsade de pointes
Metabolism/Transport Effects
None known.
Drug Interactions
ACE Inhibitors: Thiazide Diuretics may enhance the hypotensive effect of ACE Inhibitors. Specifically, postural hypotension which can accompany ACE Inhibitor initiation. Thiazide Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Risk C: Monitor therapy
Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy
Alfuzosin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Allopurinol: Thiazide Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Risk C: Monitor therapy
Amifostine: Antihypertensives may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, antihypertensive medications should be withheld for 24 hours prior to amifostine administration. If antihypertensive therapy can not be withheld, amifostine should not be administered. Risk D: Consider therapy modification
Analgesics (Opioid): May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy
Antidiabetic Agents: Thiazide Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Risk C: Monitor therapy
Antihypertensives: May enhance the hypotensive effect of other Antihypertensives. Risk C: Monitor therapy
Artemether: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Barbiturates: May enhance the orthostatic hypotensive effect of Thiazide Diuretics. Risk C: Monitor therapy
Beta2-Agonists: May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Bile Acid Sequestrants: May decrease the absorption of Thiazide Diuretics. The diuretic response is likewise decreased. Risk D: Consider therapy modification
Calcium Salts: Thiazide Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Risk C: Monitor therapy
CarBAMazepine: Thiazide Diuretics may enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy
Chloroquine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Ciprofloxacin (Systemic): May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Dofetilide: Thiazide Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide Diuretics may increase the serum concentration of Dofetilide. Risk X: Avoid combination
Dronedarone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Dronedarone. Risk X: Avoid combination
Gadobutrol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk D: Consider therapy modification
Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Herbs (Hypotensive Properties): May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Hypotensive Agents: May enhance the adverse/toxic effect of other Hypotensive Agents. Risk C: Monitor therapy
Indacaterol: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk C: Monitor therapy
Licorice: May enhance the hypokalemic effect of Thiazide Diuretics. Risk C: Monitor therapy
Lithium: Thiazide Diuretics may decrease the excretion of Lithium. Risk D: Consider therapy modification
Lumefantrine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
MAO Inhibitors: May enhance the orthostatic hypotensive effect of Orthostatic Hypotension Producing Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Nilotinib: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
Nonsteroidal Anti-Inflammatory Agents: May diminish the therapeutic effect of Thiazide Diuretics. Risk C: Monitor therapy
OXcarbazepine: Thiazide Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Pimozide: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Pimozide. Risk X: Avoid combination
Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Antihypertensives. Risk C: Monitor therapy
QTc-Prolonging Agents: May enhance the adverse/toxic effect of other QTc-Prolonging Agents. Their effects can be additive, causing life-threatening ventricular arrhythmias. Risk D: Consider therapy modification
QUEtiapine: May enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
QuiNINE: QTc-Prolonging Agents may enhance the QTc-prolonging effect of QuiNINE. QuiNINE may enhance the QTc-prolonging effect of QTc-Prolonging Agents. Risk X: Avoid combination
RiTUXimab: Antihypertensives may enhance the hypotensive effect of RiTUXimab. Risk D: Consider therapy modification
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Risk D: Consider therapy modification
Tetrabenazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Tetrabenazine. Risk X: Avoid combination
Thioridazine: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Thioridazine. Risk X: Avoid combination
Topiramate: Thiazide Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide Diuretics may increase the serum concentration of Topiramate. Management: Monitor for increased topiramate levels/adverse effects (e.g., hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary. Risk D: Consider therapy modification
Toremifene: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Toremifene. The risk for potentially dangerous arrhythmias may be increased. Risk X: Avoid combination
Toremifene: Thiazide Diuretics may enhance the hypercalcemic effect of Toremifene. Risk C: Monitor therapy
Vandetanib: QTc-Prolonging Agents may enhance the arrhythmogenic effect of Vandetanib. Risk X: Avoid combination
Vemurafenib: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Vemurafenib. Risk X: Avoid combination
Vitamin D Analogs: Thiazide Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Risk C: Monitor therapy
Yohimbine: May diminish the antihypertensive effect of Antihypertensives. Risk C: Monitor therapy
Ziprasidone: QTc-Prolonging Agents may enhance the QTc-prolonging effect of Ziprasidone. The risk of a severe arrhythmia may be increased. Risk X: Avoid combination
Ethanol/Nutrition/Herb Interactions
Herb/Nutraceutical: Avoid herbs with hypertensive properties (bayberry, blue cohosh, cayenne, ephedra, ginger, ginseng [American], kola, licorice); may diminish the antihypertensive effect of indapamide. Avoid herbs with hypotensive properties (black cohosh, California poppy, coleus, golden seal, hawthorn, mistletoe, periwinkle, quinine, shepherd's purse); may enhance the hypotensive effect of indapamide.
Storage
Store at 20°C to 25°C (68°F to 77°F).
Mechanism of Action
Diuretic effect is localized at the proximal segment of the distal tubule of the nephron; it does not appear to have significant effect on glomerular filtration rate nor renal blood flow; like other diuretics, it enhances sodium, chloride, and water excretion by interfering with the transport of sodium ions across the renal tubular epithelium
Pharmacodynamics/Kinetics
Absorption: Rapid and complete
Distribution: Vd: 25 L (Grebow, 1982)
Protein binding, plasma: 71% to 79%
Metabolism: Extensively hepatic
Bioavailability: 93% (Ernst, 2009)
Half-life elimination: Biphasic: 14 and 25 hours
Time to peak: 2 hours
Excretion: Urine (~70%; 7% as unchanged drug within 48 hours); feces (23%)
Dosage
Adults: Oral:
Edema: Initial: 2.5 mg/day; if inadequate response after 1 week, may increase dose to 5 mg/day. Note: There is little therapeutic benefit to increasing the dose >5 mg/day; there is, however, an increased risk of electrolyte disturbances
Hypertension: Initial: 1.25 mg/day; if inadequate response, may increase dose once every 4 weeks to 2.5 mg/day and then to 5 mg/day if needed. Consider adding another antihypertensive and decreasing the dose if response is not adequate. Note: Canadian labeling recommends a maximum dose of 2.5 mg/day.
Administration: Oral
May be administered without regard to meals (Caruso, 1983); however, administration with food or milk may to decrease GI adverse effects. Administer early in day to avoid nocturia.
Monitoring Parameters
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
Dietary Considerations
May be taken without regard to meals (Caruso, 1983); however, administration with food or milk may to decrease GI adverse effects.
Patient Education
Take early in the day. Follow prescriber's instructions for diet and lifestyle changes. Monitor weight on a regular basis. Report weight gain, swelling of ankles or hands, or respiratory difficulty. You may experience dizziness, weakness, sensitivity to sunlight, or dry mouth.
Geriatric Considerations
Indapamide has the advantage over other related thiazide diuretics in that it may be effective when Clcr is <30 mL/minute.
Cardiovascular Considerations
In general, indapamide may be used to treat hypertension but offers no compelling advantages over thiazide diuretics in this setting.
Hypertension in octogenarians: The HYVET trial which included patients ≥80 years of age with hypertension (sustained SBP ≥160 mm Hg; target blood pressure: 150/80 mm Hg) demonstrated that the use of a sustained release formulation of indapamide (not available in the U.S.) at a fixed dose of 1.5 mg, with or without the concomitant use of perindopril, is beneficial in reducing the risk of death from cardiovascular causes, stroke, or any other cause, and reducing the rate of heart failure. Important limitations of the study included exclusion of stage 1 hypertensives, follow-up was short (median 1.8 years), and only a small number of patients over the age of 85 years were enrolled (Beckett, 2008). This trial led to an AHA consensus statement recommending treatment of hypertension in octogenarians with SBP >150 mm Hg to a target SBP of 140-145 mm Hg if tolerated (Aronow, 2011).
Dental Health: Effects on Dental Treatment
Key adverse event(s) related to dental treatment: Orthostatic hypotension, palpitations, flushing, xerostomia (normal salivary flow resumes upon discontinuation), and rhinorrhea.
Dental Health: Vasoconstrictor/Local Anesthetic Precautions
Indapamide is one of the drugs confirmed to prolong the QT interval and is accepted as having a risk of causing torsade de pointes. The risk of drug-induced torsade de pointes is extremely low when a single QT interval prolonging drug is prescribed. In terms of epinephrine, it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval. Until more information is obtained, it is suggested that the clinician consult with the physician prior to the use of a vasoconstrictor in suspected patients, and that the vasoconstrictor (epinephrine, mepivacaine and levonordefrin [Carbocaine® 2% with Neo-Cobefrin®]) be used with caution.
Dental Comment
Indapamide is known to prolong the QT interval. The QT interval is measured as the time and distance between the Q point of the QRS complex and the end of the T wave in the ECG tracing. After adjustment for heart rate, the QT interval is defined as prolonged if it is more than 450 msec in men and 460 msec in women. A long QT syndrome was first described in the 1950s and 60s as a congenital syndrome involving QT interval prolongation and syncope and sudden death. Some of the congenital long QT syndromes were characterized by a peculiar electrocardiographic appearance of the QRS complex involving a premature atria beat followed by a pause, then a subsequent sinus beat showing marked QT prolongation and deformity. This type of cardiac arrhythmia was originally termed “torsade de pointes” (translated from the French as “twisting of the points”). Indapamide is considered as having a risk of causing torsade de pointes. Since it is not known what effect vasoconstrictors in the local anesthetic regimen will have in patients with a known history of congenital prolonged QT interval or in patients taking any medication that prolongs the QT interval, a medical consult is suggested.
Mental Health: Effects on Mental Status
May rarely cause mood changes
Mental Health: Effects on Psychiatric Treatment
May decrease lithium clearance resulting in an increase in serum lithium levels and potential lithium toxicity; monitor serum lithium levels
Nursing: Physical Assessment/Monitoring
Assess allergy history prior to beginning therapy (sulfonamides, thiazides). Monitor for hypotension, hypokalemia, and photosensitivity at regular intervals during therapy.
Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, oral: 1.25 mg, 2.5 mg
Pricing: U.S. (www.drugstore.com)
Tablets (Indapamide)
1.25 mg (90): $15.99
2.5 mg (30): $13.99
References
Acchiardo SR and Skoutakis VA, “Clinical Efficacy, Safety, and Pharmacokinetics of Indapamide in Renal Impairment,” Am Heart J, 1983, 106(1 Pt 2):237-44.
Aronow WS, Fleg JL, Pepine CJ, et al, “ACCF/AHA 2011 Expert Consensus Document on Hypertension in the Elderly: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents,” Circulation, 2011, 123(21):2434-506.
Beckett NS, Peters R, Fletcher AE, et al, “Treatment of Hypertension in Patients 80 Years of Age or Older,” N Engl J Med, 2008, 358(18):1887-98.
Caruso FS, Szabadi RR, and Vukovich RA, “Pharmacokinetics and Clinical Pharmacology of Indapamide,” Am Heart J, 1983, 106(1 Pt 2):212-20.
Ernst ME and Moser M, “Use of Diuretics in Patients With Hypertension,” N Engl J Med, 2009, 361(22):2153-64; published erratum appears in N Engl J Med, 2010, 363(19):1877.
Grebow PE, Treitman JA, Barry EP, et al, “Pharmacokinetics and Bioavailability of Indapamide -- A New Antihypertensive Drug,” Eur J Clin Pharmacol, 1982, 22(4):295-9.
Letsas KP, Alexanian IP, Pappas LK, et al, “QT Interval Prolongation and Torsade de Pointes Associated With Indapamide,” Int J Cardiol, 2006, 112(3):373-4.
Lindenfeld J, Albert NM, Boehmer JP, et al, “HFSA 2010 Comprehensive Heart Failure Practice Guideline,” J Card Fail, 2010, 16(6):e1-194.
Tanaka M, Oida E, Nomura K, et al, “The Na+-Excreting Efficacy of Indapamide in Combination With Furosemide in Massive Edema,” Clin Exp Nephrol, 2005, 9(2):122-6.
International Brand Names
Lexi-Comp.com
Last full review/revision December 2011
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