Metolazone
Regulatory sources consulted
Approved indications
- Treatment of edema due to congestive heart failure or renal disease, including nephrotic syndrome and diminished renal function.
- Treatment of hypertension, alone or with antihypertensive drugs of a different class.
Contraindications
Absolute
- Anuria.
- Hepatic coma or precoma.
- Known allergy or hypersensitivity to metolazone.
Clinical warnings
- Major warning · Severe, rapidly developing hyponatremia or hypokalemia may occur; measure electrolytes and discontinue promptly if severe symptoms develop. — DailyMed setid 27ab833e-b809-4a80-b7fc-b3599f1751d3
- Major warning · Hypokalemia increases arrhythmia risk and digitalis toxicity; monitor especially with high doses, brisk diuresis, liver disease, or corticosteroids. — DailyMed setid 27ab833e-b809-4a80-b7fc-b3599f1751d3
- Major warning · Combination with furosemide may cause unusually large or prolonged fluid and electrolyte losses. — DailyMed setid 27ab833e-b809-4a80-b7fc-b3599f1751d3
- Major warning · Cross-allergy may occur in patients allergic to sulfonamide-derived drugs, thiazides or quinethazone. Sensitivity reactions such as angioedema or bronchospasm may occur even with the first dose and without a history of allergy or bronchial asthma. — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27ab833e-b809-4a80-b7fc-b3599f1751d3
- Major warning · In all patients, measure serum electrolytes periodically and monitor for clinical signs of fluid or electrolyte imbalance, including hyponatremia, hypochloremic alkalosis and hypokalemia. — https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27ab833e-b809-4a80-b7fc-b3599f1751d3
Drug interactions
- HighLithium
Mechanism: Diuretics reduce renal lithium clearance and increase its toxicity.
Recommendation: Avoid the combination; if essential, monitor lithium closely.
DailyMed setid 27ab833e-b809-4a80-b7fc-b3599f1751d3
- HighFurosemideC03CA01
Mechanism: The combination may cause large or prolonged fluid and electrolyte losses.
Recommendation: Use only with close monitoring of volume status, electrolytes, and renal function.
DailyMed setid 27ab833e-b809-4a80-b7fc-b3599f1751d3
- HighDigitalis glycosides
Mechanism: Diuretic-induced hypokalemia increases myocardial sensitivity to digitalis and may cause serious arrhythmias.
Recommendation: Monitor potassium, ECG, and signs of digitalis toxicity; correct hypokalemia.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27ab833e-b809-4a80-b7fc-b3599f1751d3
- HighCurariform drugs such as tubocurarine
Mechanism: Hypokalemia may enhance neuromuscular blockade and cause respiratory depression or apnea.
Recommendation: Consider discontinuing metolazone three days before elective surgery and monitor neuromuscular blockade.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27ab833e-b809-4a80-b7fc-b3599f1751d3
- ModerateAnticoagulants
Mechanism: Metolazone may alter the hypoprothrombinemic response to anticoagulants.
Recommendation: Monitor anticoagulant response and adjust the dose if needed.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27ab833e-b809-4a80-b7fc-b3599f1751d3
- ModerateAlcohol, barbiturates, narcotics, and other antihypertensive drugs
Mechanism: Volume contraction may potentiate orthostatic hypotension or the antihypertensive effect.
Recommendation: Monitor blood pressure, especially at initiation, and adjust concomitant treatments if needed.
https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=27ab833e-b809-4a80-b7fc-b3599f1751d3
Adverse events
Common (≥1%)
Orthostatic hypotension · Hypokalemia · Hyponatremia · Hypomagnesemia · Azotemia · Increased creatinine · Nausea · Headache
Rare but serious
Stevens-Johnson syndrome or toxic epidermal necrolysis · Hepatitis or cholestatic jaundice · Pancreatitis · Aplastic anemia or agranulocytosis
Pregnancy and lactation
Use during pregnancy only if clearly needed; metolazone crosses the placenta and may cause fetal or neonatal jaundice and thrombocytopenia. Metolazone appears in breast milk; because of the potential for serious adverse reactions in the nursing infant, decide whether to discontinue nursing or discontinue the drug, taking into account the importance of treatment to the mother.
Recent literature (PubMed)
To examine the decongestive effect of the sodium-glucose cotransporter 2 inhibitor dapagliflozin compared to the thiazide-like diuretic metolazone in patients hospitalized for heart failure and resistant to treatment with intravenous furosemide. A multi-centre, open-label, randomized, and active-comparator trial. Patients were randomized to dapagliflozin 10 mg once daily or metolazone 5-10 mg once daily for a 3-day treatment period, with follow-up for primary and secondary endpoints until day 5 (96 h). The primary endpoint was a diuretic effect, assessed by change in weight (kg). Secondary endpoints included a change in pulmonary congestion (lung ultrasound), loop diuretic efficiency (weight change per 40 mg of furosemide), and a volume assessment score. 61 patients were randomized. The mean (±standard deviation) cumulative dose of furosemide at 96 h was 977 (±492) mg in the dapagliflozin group and 704 (±428) mg in patients assigned to metolazone. The mean (±standard deviation) decrease in weight at 96 h was 3.0 (2.5) kg with dapagliflozin compared to 3.6 (2.0) kg with metolazone [mean difference 0.65, 95% confidence interval (CI) -0.12,1.41 kg; P = 0.11]. Loop diuretic efficiency was less with dapagliflozin than with metolazone [mean 0.15 (0.12) vs. 0.25 (0.19); difference -0.08, 95% CI -0.17,0.01 kg; P = 0.10]. Changes in pulmonary congestion and volume assessment score were similar between treatments. Decreases in plasma sodium and potassium and increases in urea and creatinine were smaller with dapagliflozin than with metolazone. Serious adverse events were similar between treatments. In patients with heart failure and loop diuretic resistance, dapagliflozin was not more effective at relieving congestion than metolazone. Patients assigned to dapagliflozin received a larger cumulative dose of furosemide but experienced less biochemical upset than those assigned to metolazone. ClinicalTrials.gov Identifier: NCT04860011.
Heart failure is a common condition with considerable associated costs, morbidity, and mortality. Patients often present to hospital with dyspnea and edema. Inadequate inpatient decongestion is an important contributor to high readmission rates. There is little evidence concerning diuresis to guide clinicians in caring for patients with acute decompensated heart failure. Contemporary diuretic strategies have been defined by expert opinion and older landmark clinical trials. To present a narrative review of contemporary recommendations, along with their underlying evidence and pharmacologic rationale, for diuretic strategies in inpatients with acute decompensated heart failure. PubMed, OVID, and Embase databases were searched from inception to December 22, 2022, with the following search terms: heart failure, acute heart failure, decompensated heart failure, furosemide, bumetanide, ethacrynic acid, hydrochlorothiazide, indapamide, metolazone, chlorthalidone, spironolactone, eplerenone, and acetazolamide. Randomized controlled trials and systematic reviews involving at least 100 adult patients (> 18 years) were included. Trials involving torsemide, chlorothiazide, and tolvaptan were excluded. Early, aggressive administration of a loop diuretic has been associated with expedited symptom resolution, shorter length of stay, and possibly reduced mortality. Guidelines make recommendations about dose and frequency but do not recommend any particular loop diuretic over another; however, furosemide is most commonly used. Guidelines recommend that the initial furosemide dose (on admission) be 2-2.5 times the patient's home dose. A satisfactory diuretic response can be defined as spot urine sodium content greater than 50-70 mmol/L at 2 hours; urine output greater than 100-150 mL/h in the first 6 hours or 3-5 L in 24 hours; or a change in weight of 0.5-1.5 kg in 24 hours. If congestion persists after the maximization of loop diuretic therapy over the first 24-48 hours, an adjunc