Metolazone shares the uses of the thiazide diuretics; however, there is some evidence that metolazone may be more effective than other thiazide-like diuretics in the management of edema in patients with impaired renal function.
Metolazone is used in the management of edema associated with heart failure and renal diseases (e.g., nephrotic syndrome, impaired renal function).
Metolazone has been used concomitantly with a loop diuretic to manage hypertension and/or induce diuresis in patients who did not respond to either diuretic alone (e.g., in those with advanced renal insufficiency), and metolazone alone may be effective in some patients who are unresponsive to a loop diuretic. For further information on the role of diuretics in antihypertensive therapy and information on overall principles and expert recommendations for treatment of hypertension,
Studies have not been performed to determine if metolazone is effective in the treatment of diabetes insipidus or renal tubular acidosis or in the prophylaxis of renal calculus formation associated with hypercalciuria.
Dosage and Administration
Metolazone is administered orally.
Dosage of metolazone depends on the specific formulation used and condition being treated and should be individualized according to the patient's requirements and response. Mykrox® tablets (no longer commercially available in the US) were more rapidly and extensively absorbed than other metolazone formulations and were not therapeutically equivalent to Zaroxolyn® or other formulations of the drug that share the latter's slower and incomplete absorption. Mykrox® and bioequivalent formulations should not be interchanged with Zaroxolyn® and bioequivalent formulations. If metolazone is added to the regimen of a patient stabilized on a potent hypotensive agent, the dosage of the hypotensive agent should initially be reduced to avoid the possibility of severe hypotension.
For the management of edema associated with heart failure or renal disease, the usual initial adult dosage of metolazone (as Zaroxolyn or another bioequivalent formulation) is 5-10 mg once daily in the morning. Metolazone dosage (as Zaroxolyn or another bioequivalent formulation) of up to 20 mg once daily may be required in some patients. After several days or when nonedematous weight is attained, reduction of dosage to a lower maintenance level may be possible. Metolazone has been administered every other day after the response of the patient was stabilized.
For the management of fluid retention (e.g., edema) associated with heart failure, some experts recommend initiating metolazone (as Zaroxolyn or another bioequivalent formulation) at a low dosage (e.g., 2.5 mg once daily) and increasing the dosage (maximum of 20 mg daily) until urine output increases and weight decreases, generally by 0.5-1 kg daily. When metolazone (as Zaroxolyn or another bioequivalent formulation) is used for sequential nephron blockade in the management of fluid retention in heart failure, some experts recommend an initial dosage of 2.5-10 mg once daily in combination with a loop diuretic. Experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.
For the management of hypertension using Zaroxolyn or another bioequivalent formulation, an initial adult dosage of 1.25-2.5 mg once daily in the morning has been suggested. The usual adult dosage of metolazone (using Zaroxolyn or another bioequivalent formulation) is 2.5-5 mg daily, and the usual maximum adult dosage is 5 mg daily. The panel members appointed to the Eighth Joint National Committee on the Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC8 expert panel) state that evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) should be used when available to determine target dosages of antihypertensive agents. Target dosages generally can be achieved within 2-4 weeks, but it may take up to several months. Antihypertensive therapy should be titrated until goal blood pressure is achieved.
If an adequate blood pressure response is not achieved with metolazone monotherapy, another antihypertensive agent with demonstrated benefit may be added; if goal blood pressure is still not achieved with the use of 2 antihypertensive agents at optimal dosages, a third drug may be added.
Careful monitoring of blood pressure during initial titration or subsequent upward adjustment in dosage of metolazone is recommended. The goal of hypertension management and prevention is to achieve and maintain optimal control of blood pressure; specific target levels of blood pressure should be individualized based on consideration of multiple factors, including patient age and comorbidities, and the currently available evidence from clinical studies.
In patients who experience intolerable adverse effects with metolazone, dosage reduction should be considered; if adverse effects worsen or fail to resolve, it may be necessary to discontinue the diuretic and switch to another class of antihypertensive agent.
Adverse reactions that have been reported with metolazone, but not with thiazides, include abdominal bloating, palpitation, chest pain, and chills. In a study on the use of metolazone in patients with ascites caused by liver disease, metolazone appeared to produce a greater incidence of electrolyte disturbances and encephalopathy, but a lower incidence of azotemia, than did the thiazides.
Precautions and Contraindications
Although experience with metolazone is limited, the drug appears to share the toxic potentials of the thiazides, and the usual precautions of thiazide administration should be observed.
Concurrent administration of metolazone and furosemide may occasionally cause excessive volume and electrolyte depletion, and caution should be used when administering these drugs together.
In addition to sharing the contraindications of the thiazide diuretics, metolazone is contraindicated in patients with hepatic coma or pre-coma and in patients with known allergy or hypersensitivity to metolazone.
Safety and efficacy of metolazone in children have not been established.
The rate and extent of absorption of commercially available metolazone tablets vary depending on the preparation. Mykrox 0.5-mg tablets are more rapidly and extensively absorbed than Zaroxolyn tablets and other formulations of metolazone with dissolution and absorption characteristics similar to the latter. The rate and extent of absorption of metolazone from Mykrox tablets reportedly are equivalent to those of an oral solution of the drug. Following oral administration of Mykrox, peak blood metolazone concentrations are attained within 2-4 hours. Blood concentrations of the drug are proportional to dose at Mykrox doses of 0.5-2 mg, and steady-state blood concentrations are usually attained within 4-5 days. Zaroxolyn and other similar metolazone formulations are slowly and incompletely absorbed from the GI tract, with peak blood concentrations occurring about 8 hours after administration and absorption continuing for an additional 12 hours. An average of 65% of a dose of such a metolazone formulation has been reported to be absorbed following oral administration in healthy individuals, and an average of about 40% of a dose of such a formulation is absorbed in patients with cardiac disease.
Metolazone has a steady-state apparent volume of distribution of about 113 L. About 50-70% of the drug in the blood is bound to erythrocytes, and up to 33% is bound to plasma proteins. Only 2-5% of the drug in the circulation is unbound. Metolazone crosses the placenta and is distributed into milk.
Plasma concentrations of metolazone decrease in a biphasic manner. The elimination half-life of the drug has been reported to be approximately 14 hours.
Metolazone is not metabolized to a substantial extent. From 70-95% of the drug is excreted unchanged in urine by glomerular filtration and active tubular secretion. The rate of clearance of metolazone is proportional to the creatinine clearance. The remainder of the drug is eliminated by nonrenal routes, mainly in bile, and is reported to undergo enterohepatic recycling.