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Zaroxolyn

Pronunciation

Generic Name: Metolazone
Class: Thiazide-like Diuretics
VA Class: CV701
CAS Number: 17560-51-9

Introduction

Diuretic and antihypertensive agent; structurally and pharmacologically similar to thiazide diuretics.a e

Uses for Zaroxolyn

Hypertension

Zaroxolyn tablets used alone or in combination with other antihypertensive agents for all stages of hypertension.a b c e

Mykrox tablets (no longer commercially available in the US) were indicated for the management of hypertension and were recommended by the manufacturer for hypertensive patients in whom metolazone therapy was being initiated.a e

Zaroxolyn tablets have 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); monotherapy may be effective in some patients who are unresponsive to a loop diuretic.a

JNC 7 classifies metolazone as a thiazide-like drug with regard to management of hypertension.a c

Thiazide-like drugs have well-established benefits, can be useful in achieving goal BP alone or combined with other antihypertensive drugs, enhance the antihypertensive efficacy of multidrug regimens, and are more affordable than other agents.a b c

JNC 7 recommends that thiazide-like drugs be used as initial therapy for the treatment of uncomplicated hypertension in most patients, either alone or combined with other classes of antihypertensive drugs with demonstrated benefit (e.g., ACE inhibitors, angiotensin II receptor antagonists, β-adrenergic blocking agents, calcium-channel blocking agents).c 111

Most hypertension outcome studies have involved thiazide-like drugs, which generally have been unsurpassed in preventing cardiovascular complications of hypertension and are relatively inexpensive and well tolerated.c 111

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The principal goal of preventing and treating hypertension is to reduce the risk of cardiovascular and renal morbidity and mortality, including target organ damage.c 111 113 The higher the baseline BP, the more likely the development of MI, heart failure, stroke, and renal disease.c 111 113

Effective antihypertensive therapy reduces the risk of stroke by about 34–40%, MI by about 20–25%, and heart failure by >50%.c 111

Antihypertensive drug therapy is recommended for all patients with SBP/DBP ≥140/90 mm Hg who fail to respond to life-style/behavioral modifications.c 111

Initial antihypertensive therapy with drugs generally is recommended for anyone with diabetes mellitus, chronic renal impairment, or heart failure having SBP ≥130 mm Hg or DBP ≥80 mm Hg.c 111

Black hypertensive patients generally tend to respond better to monotherapy with diuretics or calcium-channel blocking agents than to monotherapy with ACE inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.c 101 111 113

Diuretics largely eliminate the diminished response in blacks to ACE inhibitors, angiotensin II receptor antagonists, or β-adrenergic blocking agents.c 111

Thiazide-like drugs are preferred in hypertensive patients with osteoporosis. Secondary beneficial effect in hypertensive geriatric patients of reducing the risk of osteoporosis secondary to effect on calcium homeostasis and bone mineralization.

Diuretics will not prevent the development of toxemia, nor is there evidence that diuretics have a beneficial effect on the overall course of established toxemia.e

Although hypertension during pregnancy responds well to thiazide-like drugs, and the drugs had been used widely in the past for preeclampsia and eclampsia,b d such use no longer is recommended and other antihypertensives (e.g., methyldopa, hydralazine, labetalol) currently are preferred.c

Diuretics generally are not recommended for pregnancy-induced hypertension because of the maternal hypovolemia associated with this form of hypertension; decreased placental perfusion is possible.d

Diuretics are not considered first-line agents for control of chronic hypertension in pregnant women.c

Edema in CHF

Zaroxolyn tablets used in management of edema and salt retention associated with CHF.a b e

Mykrox tablets (no longer commercially available in US) not evaluated for management of CHF; appropriate safe and effective dosage not established.a Do not use when diuresis is desired therapeutic effect.a

Zaroxolyn tablets used in conjunction with moderate sodium restriction (≤3 g of sodium daily), an ACE inhibitor, and usually a β-adrenergic blocking agent, with or without a cardiac glycoside.111

Diuretics produce rapid symptomatic benefits, relieving pulmonary and peripheral edema more rapidly (within hours or days) than cardiac glycosides, ACE inhibitors, or β-adrenergic blocking agents (in weeks or months).

Loop diuretics (e.g., bumetanide, ethacrynic acid, furosemide, torsemide) are diuretics of choice for most patients with CHF.

Edema in Renal Diseases

Zaroxolyn tablets used in management of edema and salt retention associated with renal diseases (e.g., nephrotic syndrome, impaired renal function).a e

Mykrox tablets (no longer commercially available in US) not evaluated for management of fluid retention caused by renal or hepatic disease; appropriate safe and effective dosage not established.a Do not use when diuresis is desired therapeutic effect.a

May be more effective than other thiazide-like diuretics in management of edema in patients with impaired renal function.a b

Use in diabetes insipidus, in renal tubular acidosis, or in prophylaxis of renal calculus formation associated with hypercalciuria not established.a

Edema in Pregnancy

Do not use thiazides as routine therapy in pregnant women with mild edema who are otherwise healthy.b

Use of thiazide-like diuretics may be appropriate in the management of edema of pathologic origin during pregnancy when clearly needed; routine use of diuretics in otherwise healthy pregnant women is irrational and exposes the woman and fetus to unnecessary hazard.e

Dependent edema secondary to restriction of venous return by the expanded uterus should be managed by elevating the lower extremities and/or by wearing support hose; use of diuretics in these pregnant women is inappropriate.e

In rare cases when the hypervolemia associated with normal pregnancy results in edema that produces extreme discomfort, a short course of diuretic therapy may provide relief and may be considered when other methods (e.g., increased recumbency, rest) are ineffective.e

Edema associated with pregnancy generally responds well to thiazides except when caused by renal disease.b

Zaroxolyn Dosage and Administration

General

Formulation Considerations

  • Do not interchange Mykrox and bioequivalent formulations with Zaroxolyn and bioequivalent formulations.a e Mykrox tablets (no longer commercially available in US) are more rapidly and extensively absorbed than other metolazone formulations; not therapeutically equivalent to Zaroxolyn or other formulations of drug that share the latter’s slower and incomplete absorption.a e

BP Monitoring and Antihypertensive Treatment Goals

  • Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.111

  • Avoid large or abrupt reductions in BP.

  • Adjust dosage at approximately monthly intervals (more aggressively in high-risk patients [stage 2 hypertension, comorbid conditions]) if BP control is inadequate at a given dosage; it may take months to control hypertension adequately while avoiding adverse effects of therapy.111

  • SBP is the principal clinical end point, especially in middle-aged and geriatric patients.103 104 111 Once the goal SBP is attained, the goal DBP usually is achieved.111

  • The goal is to achieve and maintain a lifelong SBP <140 mm Hg and a DBP <90 mm Hg if tolerated.111 113

  • The goal in hypertensive patients with diabetes mellitus or renal impairment is to achieve and maintain a SBP <130 mm Hg and a DBP <80 mm Hg.111 113

Administration

Administer orally as a single daily dose.a e

Dosage

Dosage depends on specific formulation used and condition being treated.a

Individualize dosage according to individual requirements and response.a e

Adjust dosage to achieve an initial therapeutic response and to determine minimal dose necessary to maintain desired therapeutic response.e

More careful dosage adjustment may be necessary in patients receiving concomitant therapy with other antihypertensive agents or diuretics.e (See Specific Drugs under Interactions.)

Pediatric Patients

CHF, Hypertension, Bronchopulmonary Dysplasia, Nephrotic Syndrome, Nephrogenic Diabetes Insipidus

0.05–0.1 mg/kg once daily has been given.e (See Pediatric Use under Cautions.)

Prolonged use (beyond a few days) not recommended.e (See Pediatric Use under Cautions.)

Adults

Hypertension
Monotherapy
Oral (Zaroxolyn or another bioequivalent formulation)

Usual initial dosage range is 2.5–5 mg once daily for mild to moderate essential hypertension.109 111 c e

Adjust dosage at appropriate intervals to attain maximum therapeutic response.e (See BP Monitoring and Antihypertensive Treatment Goals under Dosage and Administration.)

If an adequate response is not achieved with this dosage, another hypotensive agent may be added or substituted.a c

Oral (Mykrox [no longer commercially available in US])

When this formulation was available, initial dosage of 0.5 mg once daily (usually in the morning) was used for mild to moderate hypertension.a

If BP was inadequately controlled at this dosage, dosage was increased to 1 mg once daily; an increase in hypokalemia may occur at this dosage.a

Dosages >1 mg daily do not provide increased efficacy.a

If Mykrox tablets were substituted for another metolazone formulation in the management of hypertension, the recommended dosage titration was to be followed.a

If BP was inadequately controlled using Mykrox alone at a dosage of 1 mg daily, dosage of Mykrox was not to be increased; another hypotensive agent with a different mechanism of action was to be added.a

Combination Therapy
Oral

To avoid possibility of hypotension, initially reduce dosage of concomitant hypotensive agent if metolazone is added to regimen of a patient stabilized on a potent hypotensive agent.a

Edema in CHF
Monotherapy
Oral (Zaroxolyn or another bioequivalent formulation)

Manufacturer recommends a usual initial dosage range of 5–20 mg once daily.109 e

Some experts recommend an initial dosage of 2.5 mg once daily up to a maximum total daily dosage of 20 mg.f

Has been administered every other day after response of patient was stabilized.28

Daily dosage depends on severity of patient’s condition, sodium intake, and responsiveness.e Adjust daily dosage based on results of thorough clinical and laboratory evaluations.e

Reduction of dosage to a lower maintenance level may be possible if desired therapeutic response attained.e

High doses may prolong diuresis and saluresis; single daily dose is recommended.e (See Absorption under Pharmacokinetics.)

Combination Therapy
Oral (Zaroxolyn or another bioequivalent formulation)

For sequential nephron blockade in the management of edema in CHF, some experts recommend an initial dosage of 2.5–10 mg once daily in combination with a loop diuretic.f

For sequential nephron blockade in the management of severe CHF, some experts recommend an initial dosage of 2.5–5 mg once or twice daily in combination with a loop diuretic.f

Edema in Renal Diseases
Oral (Zaroxolyn or another bioequivalent formulation)

Usual initial dosage range is 5–20 mg once daily.109 e

Daily dosage depends on severity of patient’s condition, sodium intake, and responsiveness.e Adjust daily dosage based on results of thorough clinical and laboratory evaluations.e

Reduction of dosage to a lower maintenance level may be possible if desired therapeutic response attained.e

High doses may prolong diuresis and saluresis; single daily dose is recommended.e (See Absorption under Pharmacokinetics.)

Prescribing Limits

Adults

Edema in CHF
Monotherapy
Oral (Zaroxolyn or another bioequivalent formulation)

Maximum total daily dose: 20 mg.f

Special Populations

Hepatic Impairment

No specific dosage recommendations.e (See Hepatic Impairment under Cautions.)

Renal Impairment

No specific dosage recommendations.e (See Renal Impairment under Cautions.)

Geriatric Patients

Select dosage with caution, usually initiating therapy at the low end of the dosing range, because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.e (See Geriatric Use under Cautions.)

Paroxysmal Nocturnal Dyspnea Patients

May be advisable to administer an increased dosage in the management of edematous conditions to ensure prolongation of diuresis and saluresis for a full 24-hour period.e

Cautions for Zaroxolyn

Contraindications

  • Anuria.e

  • Hepatic coma or pre-coma.a e

  • Known hypersensitivity to metolazone or any ingredient in the formulation.a e (See Hypersensitivity under Cautions.)

Warnings/Precautions

Warnings

Rapid-onset Hyponatremia and/or Hypokalemia

Rapid onset of severe hyponatremia and/or hypokalemia reported rarely following initial doses of thiazide and non thiazide diuretics.e

Immediately discontinue drug and initiate supportive measures when symptoms consistent with severe electrolyte imbalance appear rapidly; parenteral electrolytes may be required.e Carefully reevaluate adequacy of therapy.e

Hypokalemia

Dose-related hypokalemia may occur with consequent weakness, cramps, and cardiac dysrhythmias.e

Increased risk of hypokalemia with large doses, rapid diuresis, severe hepatic disease, concomitant corticosteroids, inadequate oral intake, or excessive extrarenal potassium loss (e.g., vomiting, diarrhea).e

Determine serum potassium concentrations at regular and appropriate intervals; initiate dosage reduction, potassium supplementation, or addition of a potassium-sparing diuretic as needed.e

Particular concern in patients who are digitalized or those with ventricular arrhythmias or a history of ventricular arrhythmias; may result in dangerous or fatal arrhythmias.e

Concomitant Therapy

Concomitant use with certain drugs requires particular caution (e.g., furosemide, other antihypertensive drugs).a e (See Specific Drugs under Interactions.)

Generally, do not use with lithium salts.e (See Specific Drugs under Interactions.)

Sensitivity Reactions

Hypersensitivity

Cross-sensitivity may occur when used in patients known to be allergic to sulfonamide-derived drugs, thiazides, or quinethazone.e

Although some thiazide manufacturers state that allergy to other sulfonamide derivatives is a contraindication, evidence to support cross-sensitivity is limited, and history of sensitivity to sulfonamide anti-infectives (“sulfa sensitivity”) should not be considered an absolute contraindication.

Sensitivity reactions (e.g., angioedema, bronchospasm) reported with or without a history of allergy or bronchial asthma; may occur with first dose.e

General Precautions

Fluid and Electrolyte Imbalance

Hyponatremia may occur at any time during long-term therapy; life-threatening rarely.e

Increased urinary excretion of magnesium reported with thiazide-like diuretics; may result in hypomagnesemia.e

Possible low-salt syndrome in patients with severe edema accompanying cardiac failure or renal disease, especially with hot weather and a low-salt diet.e

Observe for signs of fluid or electrolyte imbalance (particularly hyponatremia, hypochloremic alkalosis, and hypokalemia) such as dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains, cramps, fatigue, hypotension, oliguria, tachycardia, GI disturbances (e.g., nausea, vomiting).e e (See Hypokalemia under Cautions.)

Measure serum electrolytes at appropriate intervals.e

Serum and urinary electrolyte measurements are especially important with diabetes mellitus, vomiting, diarrhea, or expectations of excessive diuresis.b

Glucose Tolerance

May increase blood glucose concentrations and possibly cause hyperglycemia and glycosuria in patients with diabetes or latent diabetes.e

Hyperuricemia

Regularly increases serum uric acid concentrations; occasionally precipitates gouty attacks, including in patients without a prior history.e

Azotemia

Azotemia, presumably prerenal azotemia, may occur.e

Discontinue drug if azotemia and oliguria worsen during treatment in patients with severe renal disease.e

Orthostatic Hypotension

Orthostatic hypotension reported; may be potentiated by alcohol, barbiturates, narcotics, or concomitant therapy with other antihypertensive drugs.e (See Specific Drugs under Interactions.)

Hypercalcemia

Hypercalcemia may occur infrequently, particularly in patients receiving high doses of vitamin D or with high bone turnover states; may indicate undetected hyperparathyroidism.e

Discontinue drug before performing parathyroid function tests.e

Lupus Erythematosus

Consider possible exacerbation or activation of systemic lupus erythematosus.e

Fetal/Neonatal Morbidity

Crosses placental barrier and appears in cord blood.a e Use with caution; possible fetal or neonatal jaundice, thrombocytopenia, and other adverse effects reported in adults.e

Specific Populations

Pregnancy

Category B.e

Lactation

Distributed into milk.a e Discontinue nursing or the drug.e

Pediatric Use

Safety and efficacy not established in controlled clinical studies.a e

Limited experience with use in pediatric patients with CHF, hypertension, bronchopulmonary dysplasia, nephrotic syndrome, and nephrogenic diabetes insipidus; dosages used generally ranged from 0.05–0.1 mg/kg once daily, and resulted in a 1- to 2.8-kg weight loss and 150- to 300-mL increase in urine output.e Response was observed in first few days of therapy; not all pediatric patients responded and some gained weight.e Prolonged use (beyond a few days) not recommended; generally associated with no further beneficial effect or a return to baseline status.e

Limited experience with concomitant metolazone and furosemide therapy in pediatric patients with furosemide-resistant edema; exaggerated response with hypovolemia, tachycardia, orthostatic hypotension requiring fluid replacement, severe hypokalemia, hyperbilirubinemia, and persistent diuresis for up to 24 hours after discontinuance reported.e

Perform careful clinical and laboratory monitoring in all pediatric patients receiving diuretic therapy.e

Geriatric Use

Insufficient experience in clinical studies in patients ≥65 years of age to determine whether geriatric patients respond differently than younger patients.e Other reported clinical experience has not identified differences in response between geriatric patients and younger adults.e

Select dosage with caution because of age-related decreases in hepatic, renal, and/or cardiac function and concomitant disease and drug therapy.e (See Geriatric Patients under Dosage and Administration.)

Substantially eliminated by kidneys; risk of toxic reactions may be greater in patients with impaired renal function.e Monitor renal function and adjust dosage accordingly since geriatric patients are more likely to have decreased renal function.e

Hepatic Impairment

Use with caution in patients with hepatic impairment or progressive liver disease (particularly with associated potassium deficiency); electrolyte imbalance may precipitate hepatic coma.b (See Contraindications under Cautions.)

Discontinue immediately if signs of impending hepatic coma appear.b

May produce a greater incidence of electrolyte disturbances and encephalopathy, but a lower incidence of azotemia, than thiazides in patients with ascites caused by liver disease.a

Renal Impairment

Use with caution in patients with severe renal impairment.e (See Elimination Route and also Special Populations, under Pharmacokinetics.)

Common Adverse Effects

Potassium depletion,b e hypochloremic alkalosis in patients at risk (e.g., patients with hypokalemia and loss of chloride),b dilutional hyponatremia,b e hyperuricemia (usually asymptomatic; rarely leading to gout),b e hyperglycemia and glycosuria in diabetic patients.b e Abdominal bloating,a e palpitation,a e chest pain,a e and chills and also reported.a e

Interactions for Zaroxolyn

Specific Drugs

Drug

Interaction

Comments

Alcohol

Hypotensive effect of alcohol may be potentiated by volume contraction associated with metolazonee

May potentiate orthostatic hypotensione

Anticoagulants

Metolazone may affect hypoprothrombinemic response to anticoagulantse

Dosage adjustment may be necessarye

Antidiabetic agents (sulfonylurea)

Metolazone may increase blood glucose concentrations possibly resulting in hyperglycemia and glycosuria in patients with diabetes or latent diabetese

Antihypertensive agents

May potentiate orthostatic hypotensione

Use with caution, particularly during initial therapye

Dosage adjustment of other antihypertensive agent may be necessarye

Barbiturates

Hypotensive effect of barbiturates may be potentiated by volume contraction associated with metolazonee

May potentiate orthostatic hypotensione

Cardiac glycosides

Diuretic-induced hypokalemia may increase myocardium sensitivity to digitalis; possibility of serious arrhythmiase

Corticosteroids

Increased risk of hypokalemia and salt and water retentione

Corticotropin (adrenocorticotropic hormone, ACTH)

Increased risk of hypokalemia and salt and water retentione

Diuretics, loop (e.g., furosemide)

Concomitant therapy with furosemide may cause excessive or prolonged fluid and electrolyte depletiona e

Concomitant therapy with furosemide produced marked diuresis in some patients in whom edema or ascites was refractory to maximum recommended dosages of these or other diuretics alone; mechanism not knowne

Use with cautiona

Insulin

Metolazone may increase blood glucose concentrations possibly resulting in hyperglycemia and glycosuria in patients with diabetes or latent diabetese

Lithium

Reduced renal clearance of lithium, and increased serum lithium concentrations and risk of lithium toxicitye

Generally, do not use with lithium saltse

Methenamine

Urinary alkalizing effect of metolazone may decrease efficacy of methenaminee

Neuromuscular blocking agents (e.g., tubocurarine)

Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (e.g., tubocurarine); possibility of respiratory depression leading to apneae

Advisable to discontinue metolazone 3 days prior to elective surgerye

NSAIAs

NSAIAs and salicylates may decrease antihypertensive effects of metolazonee

Opiates

Hypotensive effect of opiates may be potentiated by volume contraction associated with metolazonee

May potentiate orthostatic hypotensione

Vasopressors (norepinephrine)

Possible decreased arterial responsiveness to norepinephrinee

Decrease in pressor response not sufficient to preclude efficacy of pressor agent for therapeutic usee

Vitamin D

Concomitant therapy may increase risk of hypercalcemiae

Zaroxolyn Pharmacokinetics

Absorption

Bioavailability

Rate and extent of absorption of commercially available tablets vary depending on the preparation.a

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.a e (See Administration under Dosage and Administration.)

Zaroxolyn and other similar metolazone formulations: Slowly and incompletely absorbed from GI tract; peak blood concentrations occur about 8 hours after administration and absorption continues for an additional 12 hours.a e Average of 65 or 40% of a dose of such a metolazone formulation reported to be absorbed following oral administration in healthy individuals or in patients with cardiac disease, respectively.a

Mykrox and other similar metolazone formulations: Rate and extent of absorption reportedly equivalent to those of an oral solution of the drug; peak blood concentrations attained within 2–4 hours following oral administration.a Blood concentrations of drug are proportional to dose at Mykrox doses of 0.5–2 mg; steady-state blood concentrations usually attained within 4–5 days.a

Onset

Zaroxolyn and other similar metolazone formulations: Onset of antihypertensive effect varies from 3–4 days to 3–6 weeks following initial dose.e

Zaroxolyn and other similar metolazone formulations: Diuresis and saluresis usually occur within 1 hour following initial dose.e

Duration

Zaroxolyn and other similar metolazone formulations: Diuresis and saluresis usually persist for ≥24 hours following initial dose; duration of effect may be varied by adjusting daily dosage.e (See Dosage and Administration.)

Distribution

Extent

Crosses placental barrier and appears in cord blood.a e

Distributed into milk.a e

Plasma Protein Binding

Approximately ≤33%.a

Approximately 50–70% bound to erythrocytes and 2–5% circulates unbound.a

Elimination

Metabolism

Not metabolized to a substantial extent.a e

Elimination Route

Excreted principally in urine (70–95%) via glomerular filtration and active tubular secretion as unchanged drug;a e remainder of drug eliminated by nonrenal routes, principally in bile, and reportedly undergoes enterohepatic recycling.a (See Renal Impairment under Cautions and see Special Populations under Pharmacokinetics.)

Half-life

Biphasic; approximately 14 hours.a

Special Populations

Accumulation of drug may occur in patients with severe renal impairment.e (See Renal Impairment under Cautions and see Elimination Route under Pharmacokinetics.)

Stability

Storage

Oral

Tablets

Tight, light-resistant containers at 25°C (may be exposed to 15–30°C).a e

Actions

  • Structurally and pharmacologically similar to thiazide diuretics; quinazoline-derivative diuretic.a e

  • Enhances excretion of sodium, chloride, and water by interfering with transport of sodium ions across renal tubular epithelium.b e

  • Exact mechanism of diuretic action is unclear; principal site of action appears to be the cortical diluting segment of the distal convoluted tubules of the nephron, and to a lesser extent the proximal convoluted tubule.b e

  • Sodium and chloride ions excreted in approximately equivalent amounts.e

  • Enhances urinary excretion of potassium secondary to increased amount of sodium at distal tubular site of sodium-potassium exchange.b e

  • Increases excretion of phosphate and magnesium and markedly increases the fractional excretion of sodium in patients with severely compromised glomerular filtration (as proximal actions).e

  • Diuretic potency at maximum therapeutic dosages approximately equal to that of thiazide diuretics;e however, may produce diuresis in patients with GFR <20 mL/minute, unlike thiazides.a e

  • Unlike thiazides, does not substantially decrease GFR or renal plasma flow.a

  • Does not inhibit carbonic anhydrase.e

  • May alter renal vascular resistance at time of maximal diuresis; exact mechanism unclear.a

  • May increase urinary bicarbonate excretion (although to a lesser extent than chloride excretion) but change in urinary pH is usually minimal; diuretic efficacy not affected by acid-base balance of patient.b

  • Hypocalciuric effect thought to result from a decrease in extracellular fluid (ECF) volume, although calcium reabsorption in the nephron may be increased; also, may cause slight or intermittent elevations in serum calcium concentration.b

  • May decrease rate of uric acid excretion, probably because of competitive inhibition of uric acid secretion or a decrease in ECF volume and a secondary increase in uric acid reabsorption.b

  • Hypotensive activity in hypertensive patients; also augments action of other hypotensive agents.b Precise mechanism of hypotensive action not determined, but postulated that part of effect is caused by direct arteriolar dilation.b

Advice to Patients

  • Importance of informing patients of signs of electrolyte imbalance (e.g., dry mouth, thirst, weakness, lethargy, drowsiness, restlessness, confusion, seizures, oliguria, muscle pain or cramps, muscular fatigue, hypotension, tachycardia, GI disturbances (e.g., nausea and vomiting).b

  • Importance of compliance with scheduled determinations of serum electrolyte concentrations (particularly potassium, sodium, chloride, and bicarbonate).b

  • Advise hypertensive patients to continue lifestyle/behavioral modifications including weight reduction (for those who are overweight or obese), dietary changes to include foods that are rich in potassium and calcium and moderately restricted in sodium (adoption of the Dietary Approaches to Stop Hypertension [DASH] eating plan), increased physical activity, smoking cessation, and moderation of alcohol intake.111

  • Importance of informing hypertensive patients that lifestyle/behavioral modifications reduce BP, enhance antihypertensive drug efficacy, and decrease cardiovascular risk and remain an indispensable part of the management of hypertension.111 113

  • Importance of patients taking medication as prescribed.e

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs, as well as any concomitant illnesses.e

  • Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.e

  • Importance of informing patients of other important precautionary information.e (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Metolazone

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets

2.5 mg*

Zaroxolyn

UCB

5 mg*

Zaroxolyn

UCB

10 mg*

Zaroxolyn

UCB

Comparative Pricing

This pricing information is subject to change at the sole discretion of DS Pharmacy. This pricing information was updated 02/2014. Actual costs to patients will vary depending on the use of specific retail or mail-order locations and health insurance copays.

Metolazone 2.5MG Tablets (MYLAN): 30/$42.99 or 90/$109.97

Metolazone 5MG Tablets (SANDOZ): 30/$42.99 or 90/$121.97

Zaroxolyn 10MG Tablets (UCB PHARMA): 30/$79.99 or 90/$229.97

Zaroxolyn 2.5MG Tablets (UCB PHARMA): 30/$94.99 or 90/$280.96

Zaroxolyn 5MG Tablets (UCB PHARMA): 30/$88.99 or 90/$259.97

AHFS DI Essentials. © Copyright, 2004-2014, Selected Revisions January 1, 2008. American Society of Health-System Pharmacists, Inc., 7272 Wisconsin Avenue, Bethesda, Maryland 20814.

† Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

28. Gelfand ML, Cortega A, Lien A. The use of metolazone in the treatment of congestive heart failure. J Clin Pharmacol. 1974; 14:396-7. Abstract.

100. Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. The 1984 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1984; 144:1045-57. [IDIS 184763] [PubMed 6143542]

101. 1988 Joint National Committee. The 1988 report of the Joint National Committee on Detection, Evaluation, and Treatment of High Blood Pressure. Arch Intern Med. 1988; 148:1023-38. [IDIS 242588] [PubMed 3365073]

102. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI). Bethesda, MD: National Institutes of Health. (NIH publication No. 98-4080.)

103. Izzo JL, Levy D, Black HR. Importance of systolic blood pressure in older Americans. Hypertension. 2000; 35:1021-4. [PubMed 10818056]

104. Frohlich ED. Recognition of systolic hypertension for hypertension. Hypertension. 2000; 35:1019-20. [PubMed 10818055]

105. Bakris GL, Williams M, Dworkin L et al. Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kidney Dis. 2000; 36:646-61. [IDIS 452007] [PubMed 10977801]

106. Associated Press (American Diabetes Association). Diabetics urged: drop blood pressure. Chicago, IL; 2000 Aug 29. Press Release from web site.

107. Appel LJ. The verdict from ALLHAT—thiazide diuretics are the preferred initial therapy for hypertension. JAMA. 2002; 288:3039-42. [IDIS 490723] [PubMed 12479770]

108. The ALLHAT Officers and Coordinators for the ALLHAT Collaborative Research Group. Major outcomes in high-risk hypertensive patients randomized to angiotensin-converting enzyme inhibitor or calcium channel blocker vs diuretic: the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). JAMA. 2002; 288:2981-97. [IDIS 490721] [PubMed 12479763]

109. Celltech Pharmaceuticals Inc. Zaroxolyn (metolazone) tablets prescribing information. Rochester, NY; 2002 Jun.

110. Celltech Pharmaceuticals Inc., Mykrox (metolazone) tablets prescribing information (dated 2001 May). From the Physicians’ desk reference website.

111. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VII) Express. Bethesda, MD: May 14 2003. From NIH website. (Also published in JAMA. 2003; 289.

112. American Diabetes Association. Treatment of hypertension in adults with diabetes. Diabetes Care. 2003; 26(Suppl 1):S80-2.

113. Guidelines Committee. 2003 European Society of Hypertension–European Society of Cardiology guidelines for the management of arterial hypertension. J Hypertension. 2003; 21:1011-53.

a. AHFS drug information 2007. McEvoy GK, ed. Metolazone. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2723-4.

b. AHFS drug information 2007. McEvoy GK, ed. Thiazides general statement. Bethesda, MD: American Society of Health-System Pharmacists; 2007: 2706-15.

c. National Heart, Lung, and Blood Institute National High Blood Pressure Education Program Coordinating Committee. The seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) Complete Version. Bethesda, MD: 2003 Nov 5. Hypertension. 2003; 42:1206-52. [PubMed 14656957]

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f. Hunt SA, Abraham WT, Chin MH et al for the American College of Cardiology and American Heart Association. ACC/AHA 2005 guideline update for the diagnosis and management of chronic heart failure in the adult: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure). American College of Cardiology Website. Available from website.

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