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Metolazone

Pronunciation

Pronunciation

(me TOLE a zone)

Index Terms

  • Zaroxolyn

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling. [DSC] = Discontinued product

Tablet, Oral:

Zaroxolyn: 2.5 mg [DSC], 5 mg [DSC]

Generic: 2.5 mg, 5 mg, 10 mg

Brand Names: U.S.

  • Zaroxolyn [DSC]

Pharmacologic Category

  • Diuretic, Thiazide-Related

Pharmacology

Inhibits sodium reabsorption in the distal tubules causing increased excretion of sodium and water, as well as, potassium and hydrogen ions

Absorption

Incomplete

Excretion

Urine (70% to 95% as unchanged drug)

Onset of Action

Diuresis: ~60 minutes

Time to Peak

~8 hours.

Duration of Action

≥24 hours

Half-Life Elimination

6 to 20 hours

Protein Binding

90% to 95%

Special Populations: Renal Function Impairment

Accumulation may occur in severe renal impairment.

Use: Labeled Indications

Edema: Treatment of edema in congestive heart failure and edema accompanying renal diseases, including the nephrotic syndrome and states of diminished renal function.

Hypertension: Treatment of hypertension.

Guideline recommendations:

Coronary artery disease (CAD) and hypertension: The American Heart Association, American College of Cardiology and American Society of Hypertension (AHA/ACC/ASH) 2015 scientific statement for the treatment of hypertension in patients with coronary artery disease (CAD) recommends the use of a thiazide (or thiazide-like diuretic) as part of a regimen in patients with hypertension and chronic stable angina. A BP target of <140/90 mm Hg is reasonable for the secondary prevention of cardiovascular events. A lower target BP (<130/80 mm Hg) may be appropriate in some individuals with CAD, previous MI, stroke or transient ischemic attack, or CAD risk equivalents (AHA/ACC/ASH [Rosendorff 2015]).

Contraindications

Hypersensitivity to metolazone or any component of the formulation; anuria; hepatic coma or precoma.

Documentation of allergenic cross-reactivity for diuretics is limited. However, because of similarities in chemical structure and/or pharmacologic actions, the possibility of cross-sensitivity cannot be ruled out with certainty.

Dosing: Adult

Edema (renal disease): Oral: Initial: 5-20 mg once daily.

Edema (heart failure) (off-label dose): Oral: Initial: 2.5 mg once daily; maximum daily dose: 20 mg (ACCF/AHA [Yancy, 2013]); Note: Dosing frequency may be adjusted based on patient-specific diuretic needs (eg, administration every other day or weekly) (HFSA [Lindenfeld, 2010]).

Hypertension: Oral: Initial: 2.5-5 mg once daily; adjust dose as necessary to achieve maximum therapeutic effect.

Dosing: Geriatric

Refer to adult dosing.

Dosing: Renal Impairment

There are no dosage adjustments provided in the manufacturer’s labeling; use caution in patients with severe renal impairment, as most of the drug is excreted by the renal route and accumulation may occur.

Dosing: Hepatic Impairment

There are no dosage adjustments provided in manufacturer’s labeling; contraindicated in hepatic coma or precoma.

Extemporaneously Prepared

A 1 mg/mL oral suspension may be made by with tablets and one of three different vehicles (cherry syrup diluted 1:4 with simple syrup; a 1:1 mixture of Ora-Sweet and Ora-Plus; or a 1:1 mixture of Ora-Sweet SF and Ora-Plus). Crush twelve 10 mg tablets in a mortar and reduce to a fine powder. Add small portions of the chosen vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 120 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 120 mL. Label "shake well" and "refrigerate". Stable for 60 days.

A 0.25 mg/mL oral suspension may be made with tablets and a 1:1 mixture of methylcellulose 1% and simple syrup. Crush one 2.5 mg tablet in a mortar and reduce to a fine powder. Add small portions of the vehicle and mix to a uniform paste; mix while adding the vehicle in incremental proportions to almost 10 mL; transfer to a calibrated bottle, rinse mortar with vehicle, and add quantity of vehicle sufficient to make 10 mL. Label "shake well" and "refrigerate". Stable for 91 days refrigerated (preferred), 28 days at room temperature in plastic, and 14 days at room temperature in glass.

Nahata, MC, Pai VB, and Hipple TF, Pediatric Drug Formulations, 5th ed, Cincinnati, OH: Harvey Whitney Books Co, 2004.

Administration

Administer orally as a single daily dose with or without food. Take early in day to avoid nocturia.

Dietary Considerations

May require potassium supplementation

Storage

Store at 25°C (77°F); excursions are permitted between 15°C and 30°C (59°F and 86°F). Protect from light.

Drug Interactions

ACE Inhibitors: Thiazide and Thiazide-Like Diuretics may enhance the hypotensive effect of ACE Inhibitors. Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of ACE Inhibitors. Monitor therapy

Ajmaline: Sulfonamides may enhance the adverse/toxic effect of Ajmaline. Specifically, the risk for cholestasis may be increased. Monitor therapy

Alcohol (Ethyl): May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Alfuzosin: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Allopurinol: Thiazide and Thiazide-Like Diuretics may enhance the potential for allergic or hypersensitivity reactions to Allopurinol. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Allopurinol. Specifically, Thiazide Diuretics may increase the concentration of Oxypurinol, an active metabolite of Allopurinol. Monitor therapy

Amifostine: Blood Pressure Lowering Agents may enhance the hypotensive effect of Amifostine. Management: When amifostine is used at chemotherapy doses, blood pressure lowering medications should be withheld for 24 hours prior to amifostine administration. If blood pressure lowering therapy cannot be withheld, amifostine should not be administered. Consider therapy modification

Aminolevulinic Acid: Photosensitizing Agents may enhance the photosensitizing effect of Aminolevulinic Acid. Monitor therapy

Amphetamines: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Analgesics (Opioid): May enhance the adverse/toxic effect of Diuretics. Analgesics (Opioid) may diminish the therapeutic effect of Diuretics. Monitor therapy

Anticholinergic Agents: May increase the serum concentration of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Antidiabetic Agents: Thiazide and Thiazide-Like Diuretics may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antidiabetic Agents: Hyperglycemia-Associated Agents may diminish the therapeutic effect of Antidiabetic Agents. Monitor therapy

Antipsychotic Agents (Second Generation [Atypical]): Blood Pressure Lowering Agents may enhance the hypotensive effect of Antipsychotic Agents (Second Generation [Atypical]). Monitor therapy

Barbiturates: May enhance the orthostatic hypotensive effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Barbiturates: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Beta2-Agonists: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Bile Acid Sequestrants: May decrease the absorption of Thiazide and Thiazide-Like Diuretics. The diuretic response is likewise decreased. Consider therapy modification

Brimonidine (Topical): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Calcium Salts: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Calcium Salts. Continued concomitant use can also result in metabolic alkalosis. Monitor therapy

CarBAMazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of CarBAMazepine. Specifically, there may be an increased risk for hyponatremia. Monitor therapy

Cardiac Glycosides: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cardiac Glycosides. Specifically, cardiac glycoside toxicity may be enhanced by the hypokalemic and hypomagnesemic effect of thiazide diuretics. Monitor therapy

Corticosteroids (Orally Inhaled): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Corticosteroids (Systemic): May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Cyclophosphamide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Cyclophosphamide. Specifically, granulocytopenia may be enhanced. Monitor therapy

Dexketoprofen: May enhance the adverse/toxic effect of Sulfonamides. Monitor therapy

Diazoxide: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Diazoxide. Monitor therapy

Diazoxide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Dofetilide: Thiazide and Thiazide-Like Diuretics may enhance the QTc-prolonging effect of Dofetilide. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Dofetilide. Avoid combination

DULoxetine: Blood Pressure Lowering Agents may enhance the hypotensive effect of DULoxetine. Monitor therapy

Herbs (Hypertensive Properties): May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Herbs (Hypotensive Properties): May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Hypotension-Associated Agents: Blood Pressure Lowering Agents may enhance the hypotensive effect of Hypotension-Associated Agents. Monitor therapy

Ivabradine: Thiazide and Thiazide-Like Diuretics may enhance the arrhythmogenic effect of Ivabradine. Monitor therapy

Levodopa: Blood Pressure Lowering Agents may enhance the hypotensive effect of Levodopa. Monitor therapy

Levosulpiride: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of Levosulpiride. Avoid combination

Licorice: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Lithium: Thiazide and Thiazide-Like Diuretics may decrease the excretion of Lithium. Consider therapy modification

Mecamylamine: Sulfonamides may enhance the adverse/toxic effect of Mecamylamine. Avoid combination

Methylphenidate: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Molsidomine: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Multivitamins/Fluoride (with ADE): May enhance the hypercalcemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Multivitamins/Minerals (with ADEK, Folate, Iron): Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Multivitamins/Minerals (with ADEK, Folate, Iron). Monitor therapy

Multivitamins/Minerals (with AE, No Iron): Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Multivitamins/Minerals (with AE, No Iron). Specifically, thiazide diuretics may decrease the excretion of calcium, and continued concomitant use can also result in metabolic alkalosis. Monitor therapy

Naftopidil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicergoline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nicorandil: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Nitroprusside: Blood Pressure Lowering Agents may enhance the hypotensive effect of Nitroprusside. Monitor therapy

Nonsteroidal Anti-Inflammatory Agents: Thiazide and Thiazide-Like Diuretics may enhance the nephrotoxic effect of Nonsteroidal Anti-Inflammatory Agents. Nonsteroidal Anti-Inflammatory Agents may diminish the therapeutic effect of Thiazide and Thiazide-Like Diuretics. 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. Consider therapy modification

OXcarbazepine: Thiazide and Thiazide-Like Diuretics may enhance the adverse/toxic effect of OXcarbazepine. Specifically, there may be an increased risk for hyponatremia. Monitor therapy

Pentoxifylline: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Phosphodiesterase 5 Inhibitors: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Porfimer: Photosensitizing Agents may enhance the photosensitizing effect of Porfimer. Monitor therapy

Prostacyclin Analogues: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Quinagolide: May enhance the hypotensive effect of Blood Pressure Lowering Agents. Monitor therapy

Reboxetine: May enhance the hypokalemic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Selective Serotonin Reuptake Inhibitors: May enhance the hyponatremic effect of Thiazide and Thiazide-Like Diuretics. Monitor therapy

Sodium Phosphates: Diuretics may enhance the nephrotoxic effect of Sodium Phosphates. Specifically, the risk of acute phosphate nephropathy may be enhanced. Management: Consider avoiding this combination by temporarily suspending treatment with diuretics, or seeking alternatives to oral sodium phosphate bowel preparation. If the combination cannot be avoided, hydrate adequately and monitor fluid and renal status. Consider therapy modification

Topiramate: Thiazide and Thiazide-Like Diuretics may enhance the hypokalemic effect of Topiramate. Thiazide and Thiazide-Like Diuretics may increase the serum concentration of Topiramate. Management: Monitor for increased topiramate levels/adverse effects (e.g., hypokalemia) with initiation/dose increase of a thiazide diuretic. Closely monitor serum potassium concentrations with concomitant therapy. Topiramate dose reductions may be necessary. Consider therapy modification

Toremifene: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Toremifene. Monitor therapy

Verteporfin: Photosensitizing Agents may enhance the photosensitizing effect of Verteporfin. Monitor therapy

Vitamin D Analogs: Thiazide and Thiazide-Like Diuretics may enhance the hypercalcemic effect of Vitamin D Analogs. Monitor therapy

Yohimbine: May diminish the antihypertensive effect of Antihypertensive Agents. Monitor therapy

Adverse Reactions

Frequency not defined.

Cardiovascular: Chest pain/discomfort, necrotizing angiitis, orthostatic hypotension, palpitation, syncope, venous thrombosis, vertigo, volume depletion

Central nervous system: Chills, depression, dizziness, drowsiness, fatigue, headache, lightheadedness, restlessness

Dermatologic: Petechiae, photosensitivity, pruritus, purpura, rash, skin necrosis, Stevens-Johnson syndrome, toxic epidermal necrolysis, urticaria

Endocrine & metabolic: Gout attacks, hypercalcemia, hyperglycemia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hypokalemia, hypomagnesemia, hyponatremia, hypophosphatemia

Gastrointestinal: Abdominal bloating, abdominal pain, anorexia, constipation, diarrhea, epigastric distress, nausea, pancreatitis, vomiting, xerostomia

Genitourinary: Impotence

Hematologic: Agranulocytosis, aplastic/hypoplastic anemia, hemoconcentration, leukopenia, thrombocytopenia

Hepatic: Cholestatic jaundice, hepatitis

Neuromuscular & skeletal: Joint pain, muscle cramps/spasm, neuropathy, paresthesia, weakness

Ocular: Blurred vision (transient)

Renal: BUN increased, glucosuria

Warnings/Precautions

Concerns related to adverse effects:

• Electrolyte disturbances: Severe hypokalemia and/or hyponatremia can occur rapidly following initial doses. Hypercalcemia, hypochloremic alkalosis, and/or hypomagnesemia can also occur.

• Hypersensitivity: Sensitivity reactions, including angioedema and bronchospasm, may occur.

• Orthostatic hypotension: Orthostatic hypotension may occur. Ethanol may potentiate orthostatic hypotensive effect of metolazone. Instruct patients to avoid ethanol during therapy. If taken concurrently, monitor for hypotensive effects.

• Photosensitivity: Photosensitization may occur.

• Renal effects: Azotemia and oliguria may occur.

• Sulfonamide (“sulfa”) allergy: The FDA-approved product labeling for many medications containing a sulfonamide chemical group includes a broad contraindication in patients with a prior allergic reaction to sulfonamides. There is a potential for cross-reactivity between members of a specific class (eg, two antibiotic sulfonamides). However, concerns for cross-reactivity have previously extended to all compounds containing the sulfonamide structure (SO2NH2). An expanded understanding of allergic mechanisms indicates cross-reactivity between antibiotic sulfonamides and nonantibiotic sulfonamides may not occur or at the very least this potential is extremely low (Brackett 2004; Johnson 2005; Slatore 2004; Tornero 2004). In particular, mechanisms of cross-reaction due to antibody production (anaphylaxis) are unlikely to occur with nonantibiotic sulfonamides. T-cell-mediated (type IV) reactions (eg, maculopapular rash) are less well understood and it is not possible to completely exclude this potential based on current insights. In cases where prior reactions were severe (Stevens-Johnson syndrome/TEN), some clinicians choose to avoid exposure to these classes.

Disease-related concerns:

• Diabetes: Use with caution in patients with prediabetes or diabetes mellitus; may see a change in glucose control.

• Gout: Hyperuricemia can occur and gout can be precipitated.

• Hepatic impairment: Use with caution in patients with severe hepatic dysfunction.

• Hypokalemia: Use with caution in patients with hypokalemia; correct before initiating therapy.

• Renal impairment: Use caution in severe renal disease. If azotemia and oliguria worsen during treatment in these patients, discontinue therapy.

• Systemic lupus erythematosus (SLE): Can cause SLE exacerbation or activation.

Concurrent drug therapy issues:

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

• Interchangeability: Do not interchange Zaroxolyn with other formulations of metolazone that are not therapeutically equivalent at the same doses (eg, Mykrox, no longer available in the US).

Special populations:

• Surgical patients: If given the morning of surgery, metolazone may render the patient volume depleted and blood pressure may be labile during general anesthesia.

Monitoring Parameters

Serum electrolytes, uric acid, fluid balance, renal function, blood pressure (standing, sitting/supine)

Pregnancy Risk Factor

B

Pregnancy Considerations

Adverse events have not been observed in animal reproduction studies. Metolazone crosses the placenta and appears in cord blood. Hypoglycemia, hypokalemia, hyponatremia, jaundice, and thrombocytopenia are reported as complications to the fetus or newborn following maternal use of thiazide diuretics.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience constipation, diarrhea, fatigue, headache, joint pain, lack of appetite, nausea, vomiting, bloating, or abdominal pain. Have patient report immediately to prescriber signs of fluid and electrolyte problems (mood changes, confusion, muscle pain or weakness, abnormal heartbeat, very bad dizziness or passing out, fast heartbeat, more thirst, seizures, feeling very tired or weak, not hungry, unable to pass urine or change in the amount of urine produced, dry mouth, dry eyes, or nausea or vomiting), signs of kidney problems (urinary retention, blood in urine, change in amount of urine passed, or weight gain), signs of high blood sugar (confusion, feeling sleepy, more thirst, hunger, passing urine more often, flushing, fast breathing, or breath that smells like fruit), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), signs of pancreatitis (severe abdominal pain, severe back pain, severe nausea, or vomiting), severe dizziness, passing out, burning or numbness feeling, angina, sexual dysfunction, bruising, bleeding, severe loss of strength and energy, chills, pharyngitis, agitation, or depression (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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