Like other potassium-conserving agents, amiloride may cause hyperkalemia (serum potassium levels greater than 5.5 mEq per liter) which, if uncorrected, is potentially fatal. Hyperkalemia occurs commonly (about 10%) when amiloride is used without a kaliuretic diuretic. This incidence is greater in patients with renal impairment, diabetes mellitus (with or without recognized renal insufficiency), and in the elderly. When amiloride is used concomitantly with a thiazide diuretic in patients without these complications, the risk of hyperkalemia is reduced to about 1% to 2%. It is thus essential to monitor serum potassium levels carefully in any patient receiving amiloride, particularly when it is first introduced, at the time of diuretic dosage adjustments, and during any illness that could affect renal function.
Hypertension, chronic (alternative agent):
Note: Not recommended for initial management but may be considered as additional therapy in patients with resistant hypertension who do not respond adequately to optimal combination therapy with preferred agents. An aldosterone receptor antagonist (eg, spironolactone) is typically preferred for resistant hypertension that does not respond to preferred agents; amiloride is an alternative. May be used in patients who develop hypokalemia due to other diuretics (Ref).
Oral: Initial: 5 mg once daily; evaluate response after ~2 to 4 weeks and increase dose as needed to 10 mg daily in 1 or 2 divided doses (Ref).
Hypokalemia due to chronic stable renal potassium wasting (eg, certain tubulopathies, chronic kaliuretic diuretic use), treatment (off-label use):
Note: In patients with renal potassium wasting, amiloride may be more effective and better tolerated than oral potassium supplementation (Ref).
Oral: Initial: 5 to 10 mg once daily; if needed, may gradually increase dose (eg, every 1 to 2 weeks based on serum potassium monitoring) in 5 mg/day increments based on response and tolerability up to 40 mg/day (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Manufacturer's labeling: Use of amiloride in patients with diabetes mellitus, SCr >1.5 mg/dL, or BUN >30 mg/dL should be done with caution and careful monitoring; use is contraindicated in patients with anuria, acute or chronic renal insufficiency, or evidence of diabetic nephropathy.
Alternate recommendations:
CrCl 10 to 50 mL/minute: Administer at 50% of normal dose (Ref). The Beers Criteria recommends avoiding use in older adults ≥65 years of age with a CrCl <30 mL/minute due to the risk of hyperkalemia and hyponatremia (Ref). The 2017 guideline for the prevention, detection, evaluation, and management of high blood pressure in adults recommends avoiding use in patients with significant chronic kidney disease (eg, GFR <45 mL/minute) (Ref).
CrCl <10 mL/minute: Avoid use (Ref).
There are no dosage adjustments provided in the manufacturer’s labeling; use with caution.
Older adults also show decreased clearance of amiloride; avoid use in patients with CrCl <30 mL/minute. If being treated for hypertension, avoid in those with CrCl <45 mL/minute. Refer to adult dosing (Ref).
(For additional information see "Amiloride: Pediatric drug information")
Hypertension: Limited data available: Children and Adolescents: Oral: Initial: 0.4 to 0.625 mg/kg/dose once daily; maximum daily dose: 20 mg/day (Ref).
Edema: Limited data available: Children and Adolescents: Oral: 0.625 mg/kg/day divided every 12 to 24 hours; maximum daily dose: 20 mg/day (Ref).
Nephrogenic diabetes insipidus, congenital: Limited data available: Infants, Children, and Adolescents: Oral: 0.3 mg/kg/day in divided doses 3 times daily or 20 mg/1.73 m2/day in combination with hydrochlorothiazide; dosing based on a retrospective descriptive analysis (n=30, age range: 1 month to 40 years), two pediatric case series (n=4 and n=5), and a case report (Ref).
Dosage adjustment for concomitant therapy: Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
There are no dosage adjustments provided in the manufacturer's labeling; use with caution.
The following adverse drug reactions and incidences are derived from product labeling unless otherwise specified.
1% to 10%:
Central nervous system: Dizziness, fatigue, headache
Endocrine & metabolic: Hyperkalemia (up to 10%; risk reduced in patients receiving kaliuretic diuretics), dehydration, gynecomastia, hyperchloremic metabolic acidosis, hyponatremia
Gastrointestinal: Abdominal pain, change in appetite, constipation, diarrhea, gas pain, nausea, vomiting
Genitourinary: Impotence
Neuromuscular & skeletal: Muscle cramps, weakness
Respiratory: Cough, dyspnea
<1%, postmarketing, and/or case reports: Alopecia, bladder spasm, cardiac arrhythmia, chest pain, dysuria, gastrointestinal hemorrhage, increased intraocular pressure, jaundice, orthostatic hypotension, palpitations, polyuria
Hypersensitivity to amiloride or any component of the formulation; presence of elevated serum potassium levels (>5.5 mEq/L); if patient is receiving other potassium-conserving agents (eg, spironolactone, triamterene) or potassium supplementation (medicine, potassium-containing salt substitutes, potassium-rich diet) except in severe and/or refractory cases of hypokalemia; anuria; acute or chronic renal insufficiency; evidence of diabetic nephropathy. Patients with evidence of renal impairment (blood urea nitrogen [BUN] >30 mg/dL or serum creatinine >1.5 mg/dL) or diabetes mellitus should not receive amiloride without close, frequent monitoring of serum electrolytes and renal function.
Significant drug interactions exist, requiring dose/frequency adjustment or avoidance. Consult drug interactions database for more information.
Concerns related to adverse effects:
• Fluid/electrolyte changes: May decrease sodium and chloride and increase BUN, especially with concomitant diuretic therapy; close medical supervision and dose evaluation are required. Watch for and correct electrolyte disturbances; adjust dose to avoid dehydration.
• Hyperkalemia: [US Boxed Warning]: Hyperkalemia (serum potassium levels >5.5 mEq/L) may occur, which can be fatal if not corrected; patients at higher risk include those with renal impairment, diabetes, and the elderly. Serum potassium levels must be monitored at frequent intervals especially when therapy is initiated, when dosages are changed or with any illness that may cause renal dysfunction. Risk of hyperkalemia may be increased when used concomitantly with other medications that may increase potassium (eg, angiotensin agents). Signs/symptoms of hyperkalemia include paresthesias, muscle weakness, fatigue, flaccid paralysis of limbs, bradycardia, shock, and ECG abnormalities. If hyperkalemia occurs, discontinue amiloride immediately and manage hyperkalemia as clinically appropriate.
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).
• Cirrhosis: In cirrhosis, avoid electrolyte and acid/base imbalances that might lead to hepatic encephalopathy.
• Diabetes: If possible, avoid use in patients with diabetes mellitus; if cannot be avoided, use with extreme caution and monitor electrolytes and renal function closely. Discontinue amiloride at least 3 days prior to glucose tolerance testing.
• Metabolic/respiratory acidosis: Use with caution in patients who are at risk for metabolic or respiratory acidosis (eg, cardiopulmonary disease, poorly controlled diabetes); monitor acid base balance frequently.
• Renal impairment: Amiloride is primarily eliminated renally; patients with renal impairment are at greater risk for toxicities.
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Generic: 5 mg
Yes
Tablets (aMILoride HCl Oral)
5 mg (per each): $0.23 - $1.29
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Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Tablet, Oral, as hydrochloride:
Midamor: 5 mg
Oral: Administer with food or meals to avoid GI upset.
Oral: Administer with food or milk
Hypertension, chronic: Counteracts potassium loss induced by other diuretics in the treatment of hypertension or heart failure; usually used in conjunction with more potent diuretics such as thiazides or loop diuretics.
Note: Potassium-sparing diuretics are not recommended for the initial treatment of hypertension (ACC/AHA [Whelton 2018]).
Ascites; Hypokalemia due to chronic stable renal potassium wasting (eg, certain tubulopathies, chronic kaliuretic diuretic use), treatment
AMILoride may be confused with amiodarone, amLODIPine, inamrinone
Beers Criteria: Diuretics are identified in the Beers Criteria as potentially inappropriate medications to be used with caution in patients 65 years and older due to the potential to cause or exacerbate syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia; monitor sodium concentration closely when initiating or adjusting the dose in older adults (Beers Criteria [AGS 2023]).
Substrate of OCT2
Note: Interacting drugs may not be individually listed below if they are part of a group interaction (eg, individual drugs within “CYP3A4 Inducers [Strong]” are NOT listed). For a complete list of drug interactions by individual drug name and detailed management recommendations, use the Lexicomp drug interactions program by clicking on the “Launch drug interactions program” link above.
Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When used at chemotherapy doses, hold blood pressure lowering medications for 24 hours before amifostine administration. If blood pressure lowering therapy cannot be held, do not administer amifostine. Use caution with radiotherapy doses of amifostine. Risk D: Consider therapy modification
Ammonium Chloride: Potassium-Sparing Diuretics may enhance the adverse/toxic effect of Ammonium Chloride. Specifically the risk of systemic acidosis. Risk C: Monitor therapy
Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Angiotensin II Receptor Blockers: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Angiotensin-Converting Enzyme Inhibitors: Potassium-Sparing Diuretics may enhance the hyperkalemic effect of Angiotensin-Converting Enzyme Inhibitors. Risk C: Monitor therapy
Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Risk C: Monitor therapy
Arginine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Benperidol: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Brigatinib: May diminish the antihypertensive effect of Antihypertensive Agents. Brigatinib may enhance the bradycardic effect of Antihypertensive Agents. Risk C: Monitor therapy
Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Bromperidol: May diminish the hypotensive effect of Blood Pressure Lowering Agents. Blood Pressure Lowering Agents may enhance the hypotensive effect of Bromperidol. Risk X: Avoid combination
CycloSPORINE (Systemic): Potassium-Sparing Diuretics may enhance the hyperkalemic effect of CycloSPORINE (Systemic). Risk X: Avoid combination
Desmopressin: Hyponatremia-Associated Agents may enhance the hyponatremic effect of Desmopressin. Risk C: Monitor therapy
Dexmethylphenidate: May diminish the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Diacerein: May enhance the therapeutic effect of Diuretics. Specifically, the risk for dehydration or hypokalemia may be increased. Risk C: Monitor therapy
Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Dofetilide: AMILoride may increase the serum concentration of Dofetilide. Risk C: Monitor therapy
Drospirenone-Containing Products: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Risk C: Monitor therapy
Finerenone: Potassium-Sparing Diuretics may enhance the hyperkalemic effect of Finerenone. Risk C: Monitor therapy
Flunarizine: May enhance the therapeutic effect of Antihypertensive Agents. Risk C: Monitor therapy
Heparin: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Risk C: Monitor therapy
Heparins (Low Molecular Weight): May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Management: Monitor serum potassium concentrations closely. The spironolactone Canadian product monograph lists its combination with heparin or low molecular weight heparins as contraindicated. Risk C: Monitor therapy
Herbal Products with Blood Pressure Increasing Effects: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Herbal Products with Blood Pressure Lowering Effects: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Risk C: Monitor therapy
Indoramin: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Levodopa-Foslevodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa-Foslevodopa. Risk C: Monitor therapy
Lithium: Potassium-Sparing Diuretics may increase the serum concentration of Lithium. Potassium-Sparing Diuretics may decrease the serum concentration of Lithium. Risk C: Monitor therapy
Loop Diuretics: May enhance the hypotensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Lormetazepam: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Risk C: Monitor therapy
Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nicorandil: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Risk C: Monitor therapy
Nonsteroidal Anti-Inflammatory Agents: May diminish the antihypertensive effect of Potassium-Sparing Diuretics. Nonsteroidal Anti-Inflammatory Agents may enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Obinutuzumab: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Management: Consider temporarily withholding blood pressure lowering medications beginning 12 hours prior to obinutuzumab infusion and continuing until 1 hour after the end of the infusion. Risk D: Consider therapy modification
Opioid Agonists: May enhance the adverse/toxic effect of Diuretics. Opioid Agonists may diminish the therapeutic effect of Diuretics. Risk C: Monitor therapy
Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Pholcodine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Pholcodine. Risk C: Monitor therapy
Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Polyethylene Glycol-Electrolyte Solution: Diuretics may enhance the nephrotoxic effect of Polyethylene Glycol-Electrolyte Solution. Risk C: Monitor therapy
Potassium Salts: May enhance the hyperkalemic effect of AMILoride. Management: Amiloride and potassium supplements should not be used except in severe or refractory cases of hypokalemia. If coadministered, monitor serum potassium closely as rapid increases in potassium are possible. Risk D: Consider therapy modification
Potassium-Sparing Diuretics: May enhance the hyperkalemic effect of other Potassium-Sparing Diuretics. Risk X: Avoid combination
Prazosin: Antihypertensive Agents may enhance the hypotensive effect of Prazosin. Risk C: Monitor therapy
Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
QuiNIDine: AMILoride may enhance the adverse/toxic effect of QuiNIDine. AMILoride may diminish the therapeutic effect of QuiNIDine. Risk C: Monitor therapy
Silodosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Risk C: Monitor therapy
Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Risk C: Monitor therapy
Tacrolimus (Systemic): Potassium-Sparing Diuretics may enhance the hyperkalemic effect of Tacrolimus (Systemic). Risk C: Monitor therapy
Terazosin: Antihypertensive Agents may enhance the hypotensive effect of Terazosin. Risk C: Monitor therapy
Tolvaptan: May enhance the hyperkalemic effect of Potassium-Sparing Diuretics. Risk C: Monitor therapy
Urapidil: Antihypertensive Agents may enhance the hypotensive effect of Urapidil. Risk C: Monitor therapy
Medications considered acceptable for the treatment of chronic hypertension during pregnancy may generally be continued in patients trying to conceive. Diuretics are second-line agents for the treatment of hypertension in pregnant patients (ACC/AHA [Whelton 2018]; ACOG 2019; NICE 2019; SOGC [Magee 2022]).
Chronic maternal hypertension is associated with adverse events in the fetus/infant. Chronic maternal hypertension may increase the risk of birth defects, low birth weight, premature delivery, stillbirth, and neonatal death. Actual fetal/neonatal risks may be related to the duration and severity of maternal hypertension. Untreated chronic hypertension may also increase the risks of adverse maternal outcomes, including gestational diabetes, preeclampsia, delivery complications, stroke, and myocardial infarction (ACOG 2019; SOGC [Magee 2022]); however, data related to the use of amiloride during pregnancy are insufficient and other agents may be preferred (ESC [Regitz-Zagrosek 2018]).
Case reports describe the use of potassium-sparing diuretics such as amiloride for the adjunctive treatment of Gitleman syndrome during pregnancy (Calò 2012; Moustakakis 2012; Shahzad 2019). Use of amiloride may be considered in some pregnant patients for the treatment of primary aldosteronism (PA). Although data specific to the treatment of PA in pregnancy are limited, adjunctive therapy with amiloride may be initiated in the second or third trimester (ES [Funder 2016]; Forestiero 2022; Sanga 2022).
It is not known if amiloride is present in breast milk.
In general, diuretics have the potential to decrease milk volume and suppress lactation; use should be avoided when possible (ACOG 2019; WHO 2002). Due to the potential for serious adverse reactions in the breastfeeding infant, a decision should be made to discontinue breastfeeding or to discontinue the drug, taking into account the importance of treatment to the mother.
Do not use potassium-containing salt substitutes.
BP, serum electrolytes (especially potassium), kidney function.
Blocks epithelial sodium channels in the late distal convoluted tubule (DCT), and collecting duct which inhibits sodium reabsorption from the lumen. This effectively reduces intracellular sodium, decreasing the function of Na+/K+ATPase, leading to potassium retention and decreased calcium, magnesium, and hydrogen excretion. As sodium uptake capacity in the DCT/collecting duct is limited, the natriuretic, diuretic, and antihypertensive effects are generally considered weak.
Onset of action: Within 2 hours; Peak effect: 6 to 10 hours
Duration: ~24 hours
Absorption: 30% to 90% (Macfie 1981)
Distribution: Vd: 350 to 380 L (Macfie 1981)
Protein binding: Minimal (Macfie 1981)
Metabolism: Does not undergo hepatic metabolism
Half-life elimination: Normal renal function: 6 to 9 hours; Renal impairment (CrCl <50 mL/minute): 21 to 144 hours (George 1980)
Time to peak, serum: 3 to 4 hours
Excretion: Urine (~50%; as unchanged drug); feces (~40%)
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