A Comprehensive Monograph on Metolazone (DB00524)

I. Executive Summary & Drug Identification

1.1. Overview

Metolazone is a quinazoline-sulfonamide derivative classified pharmacologically as a thiazide-like diuretic.[1] It is a small molecule drug primarily indicated for the management of hypertension and for the treatment of salt and water retention (edema) associated with congestive heart failure and various renal diseases.[1] While sharing a primary mechanism of action with thiazide diuretics, Metolazone possesses two distinct characteristics that define its unique and critical niche in clinical practice. First, it maintains significant diuretic efficacy in patients with advanced renal impairment, a condition where traditional thiazide diuretics are largely ineffective.[4] Second, it exhibits a potent synergistic effect when co-administered with loop diuretics, a combination therapy known as sequential nephron blockade, which is employed to overcome diuretic resistance in patients with severe, refractory edema.[4] These properties establish Metolazone as a vital therapeutic agent, particularly in complex cardiovascular and renal patient populations.

1.2. Chemical and Physical Properties

A precise understanding of Metolazone's chemical and physical nature is fundamental to its pharmacological profile and formulation characteristics.

1.2.1. Chemical Structure and Nomenclature

Metolazone is a synthetic small molecule belonging to the quinazoline class.[1] Its structure consists of a 1,2,3,4-tetrahydroquinazolin-4-one core with methyl, 2-tolyl, sulfamyl, and chloro substituents at positions 2, 3, 6, and 7, respectively.[2] The formal International Union of Pure and Applied Chemistry (IUPAC) name for the compound is 7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2-dihydroquinazoline-6-sulfonamide.[2]

1.2.2. Molecular Formula and Weight

The molecular formula of Metolazone is C16​H16​ClN3​O3​S.[1] It has a calculated average molecular weight of 365.835 g/mol and a monoisotopic weight of 365.06008979 g/mol.[1]

1.2.3. Physical Description

In its solid state, Metolazone is described as an odorless and tasteless substance that forms crystals when recrystallized from ethanol.[2] It is sparingly soluble in water but demonstrates greater solubility in plasma, blood, alkaline solutions, and various organic solvents.[5]

1.2.4. Synonyms and Related Compounds

Metolazone is known by numerous synonyms and chemical identifiers, including Metolazon, Metolazona, Métolazone, Metolazonum, and SR 720-22.[1] Additionally, related chemical entities have been identified, such as Metolazone Sodium (PubChem CID 4170), a monosodium salt form of the drug, and Metolazone Lasix (PubChem CID 68666232), a compound that includes both Metolazone and the loop diuretic Furosemide.[8]

Table 1: Comprehensive Drug Identifiers for Metolazone

Identifier Type	Identifier Code	Source Database / Authority
DrugBank ID	DB00524	DrugBank 1
CAS Number	17560-51-9	Chemical Abstracts Service 1
PubChem CID	4170	PubChem 2
IUPAC Name	7-chloro-2-methyl-3-(2-methylphenyl)-4-oxo-1,2-dihydroquinazoline-6-sulfonamide	IUPAC 2
InChI Key	AQCHWTWZEMGIFD-UHFFFAOYSA-N	InChI Trust 2
SMILES	CC1NC2=CC(=C(C=C2C(=O)N1C3=CC=CC=C3C)S(=O)(=O)N)Cl	PubChem 2
Molecular Formula	C16​H16​ClN3​O3​S	PubChem 2
UNII	NM7V2Y3G0U	FDA Global Substance Registration System 2
ChEBI ID	CHEBI:64354	Chemical Entities of Biological Interest 2
ChEMBL ID	CHEMBL878	ChEMBL 2
KEGG ID	D00431	Kyoto Encyclopedia of Genes and Genomes 2
ATC Codes	C03BA08, C03EA12, G01AE10	WHO Collaborating Centre for Drug Statistics 10
RxCUI	6916	NLM RxNorm 2

II. Comprehensive Pharmacological Profile

2.1. Mechanism of Action: A Dual-Site Model

Metolazone's diuretic and antihypertensive effects stem from its interference with electrolyte reabsorption in the renal tubules. Although commonly categorized as "thiazide-like," this functional label belies a more complex, dual-site mechanism of action that is central to its unique clinical utility, particularly in patients with renal dysfunction.

2.1.1. Primary Target: The Distal Convoluted Tubule

The primary molecular target of Metolazone is the Solute carrier family 12 member 3, more commonly known as the thiazide-sensitive Na+-Cl− cotransporter (NCC).[1] This transporter is located on the apical membrane of epithelial cells in the distal convoluted tubule (DCT) of the nephron. Metolazone functions as a potent inhibitor of the NCC.[1] By binding to and blocking this cotransporter, Metolazone prevents the reabsorption of sodium (

Na+) and chloride (Cl−) ions from the tubular fluid back into the bloodstream.[3] This inhibition results in increased urinary excretion of sodium and chloride (saluresis), with the two ions being excreted in approximately equivalent amounts.[5] The increased solute concentration in the tubular fluid creates an osmotic gradient that drives the excretion of water, leading to diuresis.[4] Furthermore, the increased delivery of sodium to the more distal segments of the nephron, specifically the collecting duct's tubular exchange site, enhances the secretion and subsequent loss of potassium (

K+).[1]

2.1.2. Secondary Action: The Proximal Convoluted Tubule

A key feature that distinguishes Metolazone from classic thiazide diuretics is its secondary, albeit lesser, inhibitory action on sodium reabsorption in the proximal convoluted tubule.[1] This proximal effect has been demonstrated in human studies through the observation of increased urinary excretion of phosphate and magnesium ions, which are primarily reabsorbed in this segment of the nephron.[1] Unlike some other diuretics that act proximally, Metolazone does not inhibit the enzyme carbonic anhydrase.[1]

This dual-site mechanism is of profound clinical importance. The term "thiazide-like" is a functional oversimplification based on its primary action at the DCT. However, its chemical structure (a quinazoline-sulfonamide) and, more importantly, its secondary proximal action, are what grant it efficacy in settings of advanced renal disease. In chronic kidney disease (CKD), as the glomerular filtration rate (GFR) declines, the proximal tubule undergoes compensatory hypertrophy and increases its fractional reabsorption of sodium. This adaptive response significantly reduces the amount of sodium delivered downstream to the DCT, thereby rendering diuretics that act exclusively at the DCT, such as hydrochlorothiazide, less effective. This phenomenon is a primary driver of diuretic resistance in CKD. Metolazone's ability to inhibit sodium reabsorption at both the proximal and distal sites allows it to circumvent this compensatory mechanism. By partially blocking sodium uptake proximally, it ensures a greater sodium load reaches its primary site of action in the DCT, thus preserving its diuretic effect even when GFR is severely compromised (e.g., below 20 mL/min).[5] Therefore, Metolazone should be understood not merely as a thiazide alternative but as a diuretic with a distinct pharmacological profile that makes it uniquely suited for managing fluid overload in patients with advanced renal disease and diuretic resistance.

2.2. Pharmacodynamics

2.2.1. Onset and Duration of Action

Following oral administration, the onset of diuresis and saluresis is typically observed within one hour.[5] Metolazone is characterized by a long duration of action, with effects persisting for 24 hours or more, a feature that supports convenient once-daily dosing regimens.[1] The duration of effect can be modulated by dose adjustments, with higher doses potentially prolonging the therapeutic action.[5]

2.2.2. Antihypertensive Effect

The precise mechanism underlying Metolazone's antihypertensive effect is not fully elucidated but is largely attributed to its diuretic and saluretic properties.[1] The initial reduction in blood pressure is associated with a decrease in plasma volume, extracellular fluid, and cardiac output.[4] With chronic administration, plasma volume and cardiac output tend to return toward baseline levels, while a reduction in peripheral vascular resistance is maintained, which is believed to be the primary mechanism for the sustained antihypertensive effect.[4]

2.2.3. Potency in Renal Impairment

In patients with normal renal function, the diuretic potency of Metolazone at maximum therapeutic doses is approximately equivalent to that of standard thiazide diuretics.[5] Its most significant pharmacodynamic characteristic, however, is its retained efficacy in patients with impaired renal function. Metolazone can induce a clinically meaningful diuresis in individuals with GFRs below 20 mL/min, a level of renal dysfunction at which thiazide diuretics are generally considered ineffective.[4]

2.3. Pharmacokinetics: Absorption, Distribution, Metabolism, and Excretion (ADME)

The clinical behavior of Metolazone is governed by its distinct pharmacokinetic profile, which is characterized by formulation-dependent absorption, extensive protein binding, minimal metabolism, and renal elimination.

2.3.1. Absorption

Metolazone is rapidly absorbed from the gastrointestinal tract following oral administration. However, both the rate and extent of absorption are highly dependent on the specific pharmaceutical formulation.[1] The time to reach peak plasma concentration (Tmax) generally occurs within 2 to 4 hours, although some data suggest it can be as long as 8 hours, possibly reflecting enterohepatic recycling.[1] The presence of food, particularly high-fat meals, can delay the rate of absorption and prolong Tmax, but it does not appear to significantly affect the overall extent of drug exposure as measured by Cmax and the area under the curve (AUC).[4]

2.3.2. Distribution

Metolazone is extensively distributed throughout the body, with a large volume of distribution (Vd) reported to be approximately 113 L or within the range of 108.7 to 126.3 L.[4] It exhibits a high degree of binding to both plasma proteins (up to 33%) and, notably, to erythrocytes (50-70%).[1] This extensive binding leaves only a small fraction (2-5%) of the drug in its unbound, pharmacologically active form in the circulation.[1] This high affinity for plasma proteins and red blood cells is a key contributor to its prolonged duration of action.[12] Metolazone is also known to cross the placental barrier and is distributed into breast milk.[12]

2.3.3. Metabolism

Metolazone undergoes minimal metabolism in the body.[1] It is estimated that less than 20% of an administered dose is biotransformed, and the resulting metabolites are considered to be devoid of any significant pharmacological or toxicological activity.[15] The drug undergoes enterohepatic recycling, a process where it is excreted in the bile, reabsorbed in the intestine, and returned to the systemic circulation, which contributes to its sustained plasma levels and long half-life.[1] There is some evidence to suggest that Metolazone may influence the expression and activity of the cytochrome P450 enzyme CYP3A4 and the drug transporter P-glycoprotein (MDR1).[4]

2.3.4. Excretion

The primary route of elimination for Metolazone is via the kidneys.[1] Approximately 70-95% of the drug is excreted unchanged in the urine through a combination of glomerular filtration and active tubular secretion.[1] The elimination half-life (

t1/2​) is approximately 14 hours, though some sources report a range of 8 to 10 hours.[1]

Table 2: Key Pharmacokinetic Parameters of Metolazone

Parameter	Value / Description	Clinical Relevance
Bioavailability	~65% 16; highly formulation-dependent 1	Different brands (e.g., Zaroxolyn, Mykrox) are not bioequivalent and cannot be interchanged.
Time to Peak (Tmax)	2-4 hours 1; up to 8 hours reported 5	Onset of action is rapid, but peak effect may be delayed.
Effect of Food	Delays absorption (prolongs Tmax) but does not significantly alter total exposure (AUC) 4	Can be taken with or without food, but consistency is recommended to minimize variability.
Protein Binding	High: 50-70% to erythrocytes, up to 33% to plasma proteins 1	Contributes to long duration of action; not effectively removed by dialysis.
Volume of Distribution (Vd)	~113 L 15	Indicates extensive distribution into tissues.
Metabolism	Minimal; <20% biotransformed to inactive metabolites 1	Low potential for metabolic drug interactions; primarily eliminated as unchanged drug.
Elimination Half-life (t1/2​)	8-14 hours 1	Supports once-daily dosing regimen.
Route of Excretion	Primarily renal; 70-95% excreted unchanged in urine 1	Accumulation is possible in severe renal failure; dose adjustments are generally not required.

III. Clinical Applications and Therapeutic Guidelines

3.1. FDA-Approved Indications

Metolazone is approved by the U.S. Food and Drug Administration (FDA) for the following conditions:

• Hypertension: For the management of high blood pressure, either as a monotherapy or in combination with other antihypertensive drugs from different classes.[1]
• Edema: For the treatment of salt and water retention (edema) associated with congestive heart failure (CHF).[4]
• Edema in Renal Diseases: For the management of edema accompanying various renal diseases, including the nephrotic syndrome and states of diminished renal function.[4]
• Edema in Pregnancy: The use of Metolazone during pregnancy is indicated only when edema is due to pathological causes. It is not intended for the treatment of physiologic dependent edema resulting from the mechanical consequences of pregnancy.[5]

3.2. Dosing and Administration

The administration of Metolazone requires careful individualization of dosage based on the patient's clinical condition and response to therapy. A single daily dose is recommended and should be taken at approximately the same time each day to ensure consistent therapeutic effect.[5] Treatment should be initiated at the lower end of the dosing range and titrated upwards as needed.[19]

A critical aspect of Metolazone prescribing is the recognition that different formulations are not therapeutically interchangeable. The two primary formulations historically available in the U.S., Zaroxolyn and Mykrox, exhibit different pharmacokinetic profiles, particularly in their rate and extent of absorption.[1] Mykrox was designed as a more rapidly available and more bioavailable formulation, allowing for the use of lower doses to achieve a therapeutic effect compared to Zaroxolyn.[5] This non-bioequivalence represents a significant potential for medication errors. Substituting one brand for another on a milligram-for-milligram basis without appropriate dose conversion can lead to either a dangerous overdose (e.g., switching from a higher dose of Zaroxolyn to the same milligram dose of Mykrox) or a loss of therapeutic efficacy. This distinction must be a paramount consideration for all prescribers and pharmacists to ensure patient safety.[19]

Table 3: Dosing Guidelines for Metolazone Formulations (Zaroxolyn vs. Mykrox)

Indication	Formulation	Initial Daily Dose	Titration / Maximum Daily Dose
Hypertension	Zaroxolyn	2.5 - 5 mg once daily 22	Maximum recommended dose is 5 mg/day.23
	Mykrox	0.5 mg once daily 23	May be increased to 1 mg/day if needed. Maximum recommended dose is 1 mg/day.23
Edema	Zaroxolyn	5 - 10 mg once daily 23	May be gradually increased up to 20 mg/day for severe refractory edema.22
	Mykrox	0.5 mg once daily 23	May be increased to 1 mg/day if needed.23

3.3. Synergistic Combination Therapy with Loop Diuretics

Metolazone is frequently employed as an adjunctive agent with loop diuretics (e.g., furosemide, bumetanide) to manage severe, refractory edema, particularly in patients with advanced congestive heart failure or chronic kidney disease who have developed diuretic resistance.[4] This powerful combination therapy relies on the principle of

sequential nephron blockade.

The mechanism of this synergy is pharmacologically elegant. Loop diuretics act by inhibiting the Na-K-2Cl cotransporter in the thick ascending limb of the loop of Henle, a site responsible for reabsorbing approximately 25% of filtered sodium. This action delivers a massive load of sodium to the distal nephron. In diuretic resistance, the distal convoluted tubule undergoes hypertrophy and increases its reabsorptive capacity, effectively reclaiming much of the sodium that escaped the loop of Henle and blunting the diuretic effect. By adding Metolazone, which blocks sodium reabsorption at this distal site, this compensatory mechanism is overcome, leading to a profound and often dramatic increase in sodium and water excretion.[4]

However, this therapeutic strategy represents a double-edged sword. While highly effective, the combination can produce a "marked diuresis" that may overwhelm the body's homeostatic controls, leading to "excessive or prolonged fluid and electrolyte depletion".[5] This can manifest as severe hypokalemia, hyponatremia, hypovolemia, and pre-renal azotemia, which can precipitate life-threatening cardiac arrhythmias and acute kidney injury. Recent evidence has even suggested a potential association with increased mortality when this combination is used, highlighting the significant risks involved.[25] Therefore, this combination should be considered a high-risk, high-reward intervention, typically reserved for inpatient settings where patients can be intensively monitored for weight, urine output, blood pressure, electrolytes, and renal function.

3.4. Clinical Trial Landscape

Metolazone has been the subject of numerous clinical investigations over its long history. Clinical trials have explored its use in various cardiovascular conditions. For instance, it has been studied in patients with heart failure and diuretic resistance (NCT04860011) and in acute decompensated heart failure (NCT02620384, NCT00904488).[26] It has also been included in trials investigating antihypertensive strategies, such as the Coronavirus (COVID-19) ACEi/ARB Investigation (NCT04330300).[29] The history of these trials, which includes studies that were terminated or suspended, provides a broad perspective on the evolving research interests and challenges associated with the drug's use.[27]

IV. Safety, Tolerability, and Risk Management

4.1. Adverse Drug Reactions

While generally well-tolerated, Metolazone can cause a range of adverse reactions, many of which are extensions of its primary pharmacological activity.[5]

• Common Reactions: The most frequently encountered adverse effects are related to its renal and metabolic actions. These include electrolyte imbalances such as hypokalemia (low potassium), hyponatremia (low sodium), hypochloremia (low chloride), and hypomagnesemia (low magnesium).[4] Metabolic disturbances like hyperuricemia (which can precipitate gout), hyperglycemia (impaired glucose tolerance), and hypercalcemia (high calcium) are also common.[4] Other relatively common effects are dizziness, lightheadedness, headache, fatigue, weakness, muscle cramps, and orthostatic hypotension.[5]
• Serious Reactions: Although less frequent, Metolazone has been associated with severe and potentially life-threatening adverse events. These include profound electrolyte derangements leading to cardiac arrhythmias, pancreatitis, and intrahepatic cholestatic jaundice.[5] Severe hypersensitivity reactions can manifest as necrotizing angiitis (vasculitis) or severe dermatologic conditions like Stevens-Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN).[5] Hematologic toxicities, though rare, include aplastic anemia, agranulocytosis, leukopenia, and thrombocytopenia.[11]

4.2. Contraindications and Precautions

• Absolute Contraindications: Metolazone is strictly contraindicated in patients with:
• Anuria (inability to produce urine).[6]
• Hepatic coma or pre-coma states.[6]
• Known hypersensitivity to Metolazone or other sulfonamide-derived drugs, due to the risk of cross-sensitivity.[6]
• Warnings and Precautions: Caution should be exercised when prescribing Metolazone to patients with severe renal or hepatic disease, diabetes mellitus, hyperuricemia or gout, and systemic lupus erythematosus (SLE), as the drug can exacerbate these conditions.[4] Due to the risk of fluid and electrolyte imbalance, periodic monitoring of serum electrolytes (sodium, potassium, chloride), blood urea nitrogen (BUN), uric acid, and glucose levels is essential for all patients on therapy.[4] The risk of developing hypokalemia is significantly increased with the use of larger doses, during rapid diuresis, in the presence of severe liver disease, with inadequate oral potassium intake, or with concomitant use of corticosteroids.[5]

4.3. Drug-Drug Interactions

Metolazone is subject to numerous clinically significant drug-drug interactions that can alter its efficacy and increase the risk of toxicity.

Table 4: Clinically Significant Drug-Drug Interactions with Metolazone

Interacting Agent(s)	Effect of Interaction	Mechanism	Clinical Management
Lithium	Increased risk of lithium toxicity 6	Metolazone reduces the renal clearance of lithium.	Concomitant use should generally be avoided. If necessary, reduce lithium dose and monitor serum lithium levels frequently.5
Loop Diuretics (e.g., Furosemide)	Potent synergistic diuretic effect; high risk of severe fluid and electrolyte depletion 5	Sequential nephron blockade.	Use with extreme caution, preferably in a monitored setting. Closely monitor fluid status, electrolytes, and renal function.6
Cardiac Glycosides (e.g., Digoxin)	Increased risk of digitalis toxicity (e.g., arrhythmias) 6	Diuretic-induced hypokalemia sensitizes the myocardium to the effects of digoxin.	Monitor serum potassium levels closely and correct any deficits before and during therapy.6
Antihypertensive Agents	Additive hypotensive effects; increased risk of orthostatic hypotension 5	Pharmacodynamic synergism.	Use with caution, especially during initial therapy. Dosage adjustments of the other antihypertensive may be necessary.5
Alcohol, Barbiturates, Opiates	Potentiated orthostatic hypotension 6	Additive hypotensive effects, potentiated by volume contraction.	Advise patients to rise slowly from sitting or lying positions.
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)	May reduce the diuretic and antihypertensive effects of Metolazone 6	NSAIDs can cause sodium and water retention by inhibiting prostaglandin synthesis.	Monitor blood pressure and for signs of fluid retention.
Antidiabetic Agents (Insulin, Sulfonylureas)	May impair glucose tolerance, leading to hyperglycemia 4	Metolazone can decrease insulin sensitivity.	Monitor blood glucose levels in diabetic patients. Adjustment of the antidiabetic medication dose may be required.6
Corticosteroids, ACTH	Increased risk of hypokalemia 5	Additive potassium-wasting effects.	Monitor serum potassium levels closely.
Neuromuscular Blocking Agents (e.g., Tubocurarine)	Enhanced neuromuscular blockade, potential for respiratory depression 6	Diuretic-induced hypokalemia can potentiate the effects of these agents.	It is advisable to discontinue Metolazone 3 days prior to elective surgery.6

V. Use in Special Populations

5.1. Renal Impairment

Metolazone's utility in patients with renal impairment is one of its defining features. Unlike traditional thiazide diuretics, it retains its efficacy even in patients with a GFR as low as 20 mL/min.[5] For adults, no specific dosage adjustment is typically required, even for those with an eGFR <30 mL/minute/1.73 m2 or those with end-stage renal disease.[11] However, as the drug is primarily excreted by the kidneys, accumulation can occur in patients with severe renal disease, warranting cautious use and monitoring.[12] If azotemia and oliguria worsen during therapy, discontinuation of the drug should be considered.[16] Due to its high degree of protein binding (90-95%), Metolazone is not significantly removed by hemodialysis or peritoneal dialysis, and supplemental dosing is not necessary.[16]

5.2. Hepatic Impairment

Metolazone should be used with caution in patients with severe hepatic disease. In this population, even minor drug-induced alterations in fluid and electrolyte balance can precipitate hepatic encephalopathy or coma.[11] While no specific dose adjustments are recommended, close clinical and laboratory monitoring is critical.[11]

5.3. Geriatric Population

Elderly patients may be more sensitive to the effects of Metolazone and are at a greater risk for adverse events, including electrolyte disturbances and renal dysfunction.[31] Therefore, dose selection in this population should be cautious, typically starting at the low end of the dosing range (e.g., 2.5 mg once daily or every other day).[5] Metolazone is included in the American Geriatrics Society Beers Criteria as a medication to be used with caution in adults 65 years and older due to its potential to cause or exacerbate the syndrome of inappropriate antidiuretic hormone secretion (SIADH) or hyponatremia. Close monitoring of serum sodium is recommended when initiating or adjusting the dose in older adults.[16]

5.4. Pregnancy and Lactation

• Pregnancy: Metolazone crosses the placenta and can be found in cord blood.[16] While animal reproduction studies have not shown evidence of harm to the fetus, potential complications associated with thiazide-like diuretics in human newborns include jaundice, thrombocytopenia, hypoglycemia, and electrolyte imbalances.[16] Its use is not considered appropriate for managing physiologic edema of pregnancy but may be considered for pathologic causes when the potential benefit justifies the potential risk to the fetus.[5]
• Lactation: Metolazone is excreted into breast milk.[12] Due to the potential for serious adverse reactions in a nursing infant, the manufacturer recommends that a decision be made whether to discontinue breastfeeding or to discontinue the drug, taking into account the importance of the medication to the mother.[12]

5.5. Pediatric Use

The use of Metolazone in the pediatric population is considered off-label.[21] The generally accepted dosage for edema in children is 0.2-0.4 mg/kg/day administered orally, either as a single daily dose or divided every 12 hours.[11] Clinical studies, including a retrospective analysis in infants in a cardiac intensive care unit, have demonstrated its efficacy, often in combination with furosemide, for treating resistant edema.[33] However, careful monitoring of fluid balance, electrolytes, and renal function is essential in this vulnerable population.

VI. Regulatory and Historical Context

6.1. Regulatory Milestones and Approval History

Metolazone was first patented in 1966 and received its initial approval for medical use from the FDA in 1974.[13] The original brand name, Zaroxolyn, was approved under New Drug Application (NDA) 17-386 prior to January 1, 1982.[20]

The regulatory history of Metolazone provides a compelling case study in the lifecycle management of a legacy drug, reflecting the evolution of scientific and regulatory standards over several decades. For example, a 1986 review of a supplemental NDA noted that the original carcinogenicity studies conducted in the 1970s were considered inadequate by the more rigorous standards of the time, although the drug's long-standing clinical benefit supported its continued approval.[20] This demonstrates the FDA's process of continuous risk-benefit re-evaluation as scientific methodologies advance. Over the years, numerous supplemental NDAs have been approved to update the product's labeling, such as the addition of a formal Geriatric Use section to the precautions in 2002.[31] More recently, in 2015, a supplement was approved to modernize manufacturing controls by updating the dissolution testing methods.[14] This latter focus highlights the agency's contemporary emphasis on ensuring consistent product quality and performance, a particularly salient issue for a drug like Metolazone with known formulation-dependent bioavailability. This ongoing process of regulatory oversight ensures that even decades-old drugs continue to meet modern standards for safety, efficacy, and quality.

6.2. Commercial Landscape and Brand Names

• Brand Names (U.S.): In the United States, Metolazone has been marketed primarily under the brand names Zaroxolyn and Mykrox.[1] The Mykrox brand is no longer actively marketed, though generic alternatives may be available.[19]
• Generic Availability: The first Abbreviated New Drug Application (ANDA) for a generic version of Metolazone tablets was approved by the FDA for Mylan Laboratories in December 2003.[38] Since then, several other pharmaceutical companies, such as Alembic Pharmaceuticals in 2020, have received ANDA approvals to market generic Metolazone.[17] The brand name product Zaroxolyn serves as the Reference Listed Drug (RLD), the standard against which generic versions must demonstrate bioequivalence.[35]
• International Brand Names: Metolazone is used worldwide and is available under a wide array of international brand names, including Zytanix, Metoz, Diulo, Metenix, Xaqua, Xuret, Normelan, and Pavedal, among many others.[7]

VII. Conclusion

Metolazone is a well-established quinazoline-sulfonamide diuretic with a long history of clinical use in the management of hypertension and edema. Its pharmacological profile is distinguished by a dual-site mechanism of action, inhibiting sodium reabsorption in both the distal and proximal renal tubules. This unique characteristic underpins its most significant clinical advantage: the ability to maintain diuretic efficacy in patients with severe renal impairment, a setting where traditional thiazide diuretics fail. Furthermore, its potent synergy with loop diuretics provides a critical therapeutic option for overcoming diuretic resistance in patients with refractory fluid overload. However, this potency necessitates careful clinical management, as the risk of profound fluid and electrolyte disturbances is substantial, particularly with combination therapy and in vulnerable populations such as the elderly. The existence of non-bioequivalent oral formulations also demands heightened vigilance from clinicians and pharmacists to prevent medication errors. As a legacy drug that has been adapted to meet evolving regulatory standards for over four decades, Metolazone remains an indispensable tool in the cardiovascular and nephrology armamentarium, offering unique benefits for complex patient populations when used with appropriate caution and diligent monitoring.

Works cited

1. Metolazone: Uses, Interactions, Mechanism of Action | DrugBank ..., accessed September 12, 2025, https://go.drugbank.com/drugs/DB00524
2. Metolazone | C16H16ClN3O3S | CID 4170 - PubChem, accessed September 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Metolazone
3. www.ncbi.nlm.nih.gov, accessed September 12, 2025, https://www.ncbi.nlm.nih.gov/books/NBK534203/#:~:text=Metolazone%20is%20a%20cardiovascular%20agent,%2C%20chloride%2C%20and%20water%20excretion.
4. Metolazone - StatPearls - NCBI Bookshelf, accessed September 12, 2025, https://www.ncbi.nlm.nih.gov/books/NBK534203/
5. Metolazone Tablets, USP Rx Only - accessdata.fda.gov, accessed September 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/label/2019/017386s043lbl.pdf
6. Metolazone Monograph for Professionals - Drugs.com, accessed September 12, 2025, https://www.drugs.com/monograph/metolazone.html
7. Metolazone [USAN:USP:INN:BAN:JAN] - PubChem, accessed September 12, 2025, https://pubchem.ncbi.nlm.nih.gov/substance/134993048
8. Metolazone sodium | C16H15ClN3NaO3S | CID 91667967 - PubChem, accessed September 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/Metolazone-sodium
9. Metolazone Lasix | C28H27Cl2N5O8S2 | CID 68666232 - PubChem, accessed September 12, 2025, https://pubchem.ncbi.nlm.nih.gov/compound/68666232
10. Metolazone - brand name list from Drugs.com, accessed September 12, 2025, https://www.drugs.com/ingredient/metolazone.html
11. Metolazone - Mechanism, Indication, Contraindications, Dosing, Adverse Effect, Interaction, Renal Dose, Hepatic Dose | Drug Index | Pediatric Oncall, accessed September 12, 2025, https://www.pediatriconcall.com/drugs/metolazone/769
12. ZAROXOLYN® (Metolazone) 2.5 mg Tablets Diuretic/Antihypertensive sanofi-aventis Canada Inc., accessed September 12, 2025, https://pdf.hres.ca/dpd_pm/00003343.PDF
13. Metolazone - Wikipedia, accessed September 12, 2025, https://en.wikipedia.org/wiki/Metolazone
14. Zaroxolyn® (metolazone) Tablets and authorized generic metolazone tablets. - accessdata.fda.gov, accessed September 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2015/017386Orig1s040.pdf
15. Module 2 2.5 Clinical overview Metolazone 5 mg tablets Page 1 / WEU VERSION 03 FINAL DEC 2020 CONFIDENTIAL - GOV.UK, accessed September 12, 2025, https://assets.publishing.service.gov.uk/media/61c5f4348fa8f54c0e4571e5/FOI_21-849-1.pdf
16. MetOLazone | Drug Lookup | Pediatric Care Online - AAP Publications, accessed September 12, 2025, https://publications.aap.org/pediatriccare/drug-monograph/18/5737/MetOLazone
17. Alembic Pharma receives USFDA approval for Metolazone tablets - The Economic Times, accessed September 12, 2025, https://m.economictimes.com/industry/healthcare/biotech/pharmaceuticals/alembic-pharma-receives-usfda-approval-for-metolazone-tablets/articleshow/79543801.cms
18. Metolazone - PubMed, accessed September 12, 2025, https://pubmed.ncbi.nlm.nih.gov/30480942/
19. Metolazone: MedlinePlus Drug Information, accessed September 12, 2025, https://medlineplus.gov/druginfo/meds/a682345.html
20. 19532 Microx Pharmacology Review - accessdata.fda.gov, accessed September 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/pre96/19532_MICROX_PHARMR.PDF
21. Metolazone: Side Effects, Uses, Dosage, Interactions, Warnings - Rx List, accessed September 12, 2025, https://www.rxlist.com/metolazone/generic-drug.htm
22. What is the dose of Metolazone? - Dr.Oracle AI, accessed September 12, 2025, https://www.droracle.ai/articles/12878/metolazone-dose-
23. Metolazone Dosage Guide + Max Dose, Adjustments - Drugs.com, accessed September 12, 2025, https://www.drugs.com/dosage/metolazone.html
24. Zaroxolyn (metolazone) dosing, indications, interactions, adverse effects, and more, accessed September 12, 2025, https://reference.medscape.com/drug/zaroxolyn-metolazone-342416
25. What is the recommended dosing for inpatient metolazone (thiazide-like diuretic) therapy?, accessed September 12, 2025, https://www.droracle.ai/articles/312201/inpatient-metolazone-dosing
26. Heart Failure, Unspecified Unknown Status Phase 3 Trials for Metolazone (DB00524), accessed September 12, 2025, https://go.drugbank.com/indications/DBCOND0083328/clinical_trials/DB00524?phase=3&status=unknown_status
27. Acute Decompensated Heart Failure (ADHF) Terminated Phase 3 Trials for Metolazone (DB00524) | DrugBank Online, accessed September 12, 2025, https://go.drugbank.com/indications/DBCOND0054941/clinical_trials/DB00524?phase=3&status=terminated
28. Metolazone Terminated Phase 4 Trials for Acute Decompensated Heart Failure (ADHF) Treatment | DrugBank Online, accessed September 12, 2025, https://go.drugbank.com/drugs/DB00524/clinical_trials?conditions=DBCOND0054941&phase=4&purpose=treatment&status=terminated
29. Hypertensive Diseases Suspended Phase 4 Trials for Metolazone (DB00524) - DrugBank, accessed September 12, 2025, https://go.drugbank.com/indications/DBCOND0084664/clinical_trials/DB00524?phase=4&status=suspended
30. Metolazone Oral Tablets - Cleveland Clinic, accessed September 12, 2025, https://my.clevelandclinic.org/health/drugs/18784-metolazone-tablets
31. NDA 17-386/S-034 - accessdata.fda.gov, accessed September 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2002/17386slr034,19532slr015ltr.pdf
32. www.pediatriconcall.com, accessed September 12, 2025, https://www.pediatriconcall.com/drugs/metolazone/769#:~:text=0.2%2D0.4%20mg%2Fkg%2F,in%201%2D2%20divided%20doses.
33. Efficacy of metolazone and furosemide in children with furosemide-resistant edema - PubMed, accessed September 12, 2025, https://pubmed.ncbi.nlm.nih.gov/6493882/
34. Enhancement of diuresis with metolazone in infant paediatric cardiac intensive care patients, accessed September 12, 2025, https://pubmed.ncbi.nlm.nih.gov/28889825/
35. Generic Zaroxolyn Availability - Drugs.com, accessed September 12, 2025, https://www.drugs.com/availability/generic-zaroxolyn.html
36. Zaroxolyn® (metolazone) Tablets - accessdata.fda.gov, accessed September 12, 2025, https://www.accessdata.fda.gov/drugsatfda_docs/nda/2013/017386Orig1s039.pdf
37. en.wikipedia.org, accessed September 12, 2025, https://en.wikipedia.org/wiki/Metolazone#:~:text=Metolazone%20is%20a%20thiazide%2Dlike,failure%20and%20high%20blood%20pressure.
38. Mylan Receives FDA Approval for Metolazone Tablets, accessed September 12, 2025, https://investor.mylan.com/news-releases/news-release-details/mylan-receives-fda-approval-metolazone-tablets