Metolazone

Metolazone
Black Box Warning
Adult Indications & Dosage
Pediatric Indications & Dosage
Contraindications
Warnings & Precautions
Adverse Reactions
Drug Interactions
Use in Specific Populations
Administration & Monitoring
Overdosage
Pharmacology
Clinical Studies
How Supplied
Images
Patient Counseling Information
Precautions with Alcohol
Brand Names
Look-Alike Names

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Gerald Chi

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Black Box Warning

DO NOT INTERCHANGE: See full prescribing information for complete Boxed Warning. * Do not interchange Zaroxolyn tablets and other formulations of metolazone that share its slow and incomplete bioavailability and are not therapeutically equivalent at the same doses to Mykrox® tablets, a more rapidly available and completely bioavailable metolazone product. Formulations bioequivalent to Zaroxolyn and formulations bioequivalent to Mykrox should not be interchanged for one another.

Overview

Metolazone is a thiazide-like diuretic that is FDA approved for the {{{indicationType}}} of edema associated with congestive heart failure or renal disease. Metolazone is also indicated for the treatment of hypertension, alone or in combination with other antihypertensive agents. There is a Black Box Warning for this drug as shown here. Common adverse reactions include orthostatic hypotension, electrolyte disturbances, hyperuricemia, dizziness, and fatigue.

Adult Indications and Dosage

FDA-Labeled Indications and Dosage (Adult)

• Effective dosage of ZAROXOLYN should be individualized according to indication and patient response. A single daily dose is recommended. Therapy with ZAROXOLYN should be titrated to gain an initial therapeutic response and to determine the minimal dose possible to maintain the desired therapeutic response.

Edema

• Dosing Information

• 5–20 mg PO qd

• The time interval required for the initial dosage to produce an effect may vary. Diuresis and saluresis usually begin within one hour and persist for 24 hours or longer. When a desired therapeutic effect has been obtained, it may be advisable to reduce the dose if possible. The daily dose depends on the severity of the patient's condition, sodium intake, and responsiveness. A decision to change the daily dose should be based on the results of thorough clinical and laboratory evaluations. If antihypertensive drugs or diuretics are given concurrently with ZAROXOLYN, more careful dosage adjustment may be necessary. For patients who tend to experience paroxysmal nocturnal dyspnea, it may be advisable to employ a larger dose to ensure prolongation of diuresis and saluresis for a full 24-hour period.

Mild to Moderate Essential Hypertension

• Dosing Information

• 2.5–5 mg PO qd

• The time interval required for the initial dosage regimen to show effect may vary from three or four days to three to six weeks in the treatment of elevated blood pressure. Doses should be adjusted at appropriate intervals to achieve maximum therapeutic effect.

Off-Label Use and Dosage (Adult)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Metolazone in adult patients.

Non–Guideline-Supported Use

Calcium Renal Calculus

• Dosing Information

• 2.5–10 mg PO qd

Edema Associated with Liver Disease

• Dosing Information

• 5–20 mg PO qd

Pediatric Indications and Dosage

FDA-Labeled Indications and Dosage (Pediatric)

Edema

• Safety and effectiveness in pediatric patients have not been established in controlled clinical trials.
• There is limited experience with the use of ZAROXOLYN in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus.
• Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few days of treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended.

• Dosing Information

• 0.05–0.1 mg/kg qd

Off-Label Use and Dosage (Pediatric)

Guideline-Supported Use

There is limited information regarding Off-Label Guideline-Supported Use of Metolazone in pediatric patients.

Non–Guideline-Supported Use

There is limited information regarding Off-Label Non–Guideline-Supported Use of Metolazone in pediatric patients.

Contraindications

• Anuria
• Hepatic coma or precoma
• Allergy or hypersensitivity to metolazone

Warnings

DO NOT INTERCHANGE: See full prescribing information for complete Boxed Warning. * Do not interchange Zaroxolyn tablets and other formulations of metolazone that share its slow and incomplete bioavailability and are not therapeutically equivalent at the same doses to Mykrox® tablets, a more rapidly available and completely bioavailable metolazone product. Formulations bioequivalent to Zaroxolyn and formulations bioequivalent to Mykrox should not be interchanged for one another.

• Rapid Onset Hyponatremia And/Or Hypokalemia

• Rarely, the rapid onset of severe hyponatremia and/or hypokalemia has been reported following initial doses of thiazide and non-thiazide diuretics. When symptoms consistent with severe electrolyte imbalance appear rapidly, drug should be discontinued and supportive measures should be initiated immediately. Parenteral electrolytes may be required. Appropriateness of therapy with this class of drugs should be carefully reevaluated.

• Hypokalemia

• Hypokalemia may occur with consequent weakness, cramps, and cardiac dysrhythmias. Serum potassium should be determined at regular and appropriate intervals, and dose reduction, potassium supplementation or addition of a potassium-sparing diuretic instituted whenever indicated. Hypokalemia is a particular hazard in patients who are digitalized or who have or have had a ventricular arrhythmia; dangerous or fatal arrhythmias may be precipitated. Hypokalemia is dose related.

• Concomitant Therapy

• Lithium

• In general, diuretics should not be given concomitantly with lithium because they reduce its renal clearance and add a high risk of lithium toxicity. Read prescribing information for lithium preparations before use of such concomitant therapy.

• Furosemide

• Unusually large or prolonged losses of fluids and electrolytes may result when ZAROXOLYN is administered concomitantly to patients receiving furosemide.

• Other Antihypertensive Drugs

• When ZAROXOLYN is used with other antihypertensive drugs, particular care must be taken to avoid excessive reduction of blood pressure, especially during initial therapy.

• Cross-Allergy

• Cross-allergy may occur when ZAROXOLYN is given to patients known to be allergic to sulfonamide-derived drugs, thiazides, or quinethazone.

• Sensitivity Reactions

• Sensitivity reactions (e.g., angioedema, bronchospasm) may occur with or without a history of allergy or bronchial asthma and may occur with the first dose of ZAROXOLYN.

Precautions

• Fluid And Electrolytes

• All patients receiving therapy with ZAROXOLYN Tablets should have serum electrolyte measurements done at appropriate intervals and be observed for clinical signs of fluid and/or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. In patients with severe edema accompanying cardiac failure or renal disease, a low-salt syndrome may be produced, especially with hot weather and a low-salt diet. Serum and urine electrolyte determinations are particularly important when the patient has protracted vomiting, severe diarrhea, or is receiving parenteral fluids. Warning signs of imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyponatremia may occur at any time during long term therapy and, on rare occasions, may be life threatening.
• The risk of hypokalemia is increased when larger doses are used, when diuresis is rapid, when severe liver disease is present, when corticosteroids are given concomitantly, when oral intake is inadequate or when excess potassium is being lost extrarenally, such as with vomiting or diarrhea.
• Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.

• Glucose Tolerance

• Metolazone may raise blood glucose concentrations possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.

• Hyperuricemia

• ZAROXOLYN regularly causes an increase in serum uric acid and can occasionally precipitate gouty attacks even in patients without a prior history of them.

• Azotemia

• Azotemia, presumably prerenal azotemia, may be precipitated during the administration of ZAROXOLYN. If azotemia and oliguria worsen during treatment of patients with severe renal disease, ZAROXOLYN should be discontinued.

• Renal Impairment

• Use caution when administering ZAROXOLYN Tablets to patients with severely impaired renal function. As most of the drug is excreted by the renal route, accumulation may occur.

• Orthostatic Hypotension

• Orthostatic hypotension may occur; this may be potentiated by alcohol, barbiturates, narcotics, or concurrent therapy with other antihypertensive drugs.

• Hypercalcemia

• Hypercalcemia may infrequently occur with metolazone, especially in patients taking high doses of vitamin D or with high bone turnover states, and may signify hidden hyperparathyroidism. Metolazone should be discontinued before tests for parathyroid function are performed.

• Systemic Lupus Erythematosus

• Thiazide diuretics have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with ZAROXOLYN Tablets.

Adverse Reactions

Clinical Trials Experience

There is limited information regarding Clinical Trial Experience of Metolazone in the drug label.

Postmarketing Experience

• ZAROXOLYN is usually well tolerated, and most reported adverse reactions have been mild and transient. Many ZAROXOLYN related adverse reactions represent extensions of its expected pharmacologic activity and can be attributed to either its antihypertensive action or its renal/metabolic actions. The following adverse reactions have been reported. Several are single or comparably rare occurrences. Adverse reactions are listed in decreasing order of severity within body systems.

Cardiovascular

Chest pain/discomfort, orthostatic hypotension, excessive volume depletion, hemoconcentration, venous thrombosis, palpitations.

Neurologic

Syncope, neuropathy, vertigo, paresthesias, psychotic depression, impotence, dizziness/lightheadedness, drowsiness, fatigue, weakness, restlessness (sometimes resulting in insomnia), headache.

Hypersensitivity

Toxic epidermal necrolysis (TEN), Stevens-Johnson syndrome, necrotizing angiitis (cutaneous vasculitis), skin necrosis, purpura, petechiae, dermatitis (photosensitivity), urticaria, pruritus, skin rashes.

Gastrointestinal

Hepatitis, intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea, epigastric distress, diarrhea, constipation, anorexia, abdominal bloating, abdominal pain.

Hematologic

Aplastic/hypoplastic anemia, agranulocytosis, leukopenia, thrombocytopenia.

Metabolic

Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia, hypomagnesemia, hypercalcemia.

Musculoskeletal

Joint pain, acute gouty attacks, muscle cramps or spasm.

Miscellaneous

Transient blurred vision, chills, dry mouth.

• In addition, adverse reactions reported with similar antihypertensive-diuretics, but which have not been reported to date for ZAROXOLYN include: bitter taste, sialadenitis, xanthopsia, respiratory distress (including pneumonitis), and anaphylactic reactions. These reactions should be considered as possible occurrences with clinical usage of ZAROXOLYN.
• Whenever adverse reactions are moderate or severe, ZAROXOLYN dosage should be reduced or therapy withdrawn.

Drug Interactions

• Diuretics

• Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes.

• Other Antihypertensives

• When ZAROXOLYN Tablets are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary.

• Alcohol, Barbiturates, And Narcotics

• The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy.

• Digitalis Glycosides

• Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result.

• Corticosteroids Or ACTH

• May increase the risk of hypokalemia and increase salt and water retention.

• Lithium

• Serum lithium levels may increase.

• Curariform Drugs

• Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) – the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue ZAROXOLYN three days before elective surgery.

• Salicylates And Other Non-Steroidal Anti-Inflammatory Drugs

• May decrease the antihypertensive effects of ZAROXOLYN Tablets.

• Sympathomimetics

• Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

• Insulin And Oral Antidiabetic Agents
• Methenamine

• Efficacy may be decreased due to urinary alkalizing effect of metolazone.

• Anticoagulants

• Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

• Pregnancy Category

Pregnancy Category (AUS):

• Australian Drug Evaluation Committee (ADEC) Pregnancy Category

There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Metolazone in women who are pregnant.

Labor and Delivery

There is no FDA guidance on use of Metolazone during labor and delivery.

Nursing Mothers

There is no FDA guidance on the use of Metolazone with respect to nursing mothers.

Pediatric Use

There is no FDA guidance on the use of Metolazone with respect to pediatric patients.

Geriatic Use

There is no FDA guidance on the use of Metolazone with respect to geriatric patients.

Gender

There is no FDA guidance on the use of Metolazone with respect to specific gender populations.

Race

There is no FDA guidance on the use of Metolazone with respect to specific racial populations.

Renal Impairment

There is no FDA guidance on the use of Metolazone in patients with renal impairment.

Hepatic Impairment

There is no FDA guidance on the use of Metolazone in patients with hepatic impairment.

Females of Reproductive Potential and Males

There is no FDA guidance on the use of Metolazone in women of reproductive potentials and males.

Immunocompromised Patients

There is no FDA guidance one the use of Metolazone in patients who are immunocompromised.

Administration and Monitoring

Administration

• Oral

• Intravenous

Monitoring

There is limited information regarding Monitoring of Metolazone in the drug label.

Condition1

• Description

IV Compatibility

There is limited information regarding IV Compatibility of Metolazone in the drug label.

Overdosage

Acute Overdose

Signs and Symptoms

• Description

Management

• Description

Chronic Overdose

There is limited information regarding Chronic Overdose of Metolazone in the drug label.

Pharmacology

Metolazone
Systematic (IUPAC) name
7-chloro-2-methyl-3-(2-methylphenyl)- 4-oxo-1,2-dihydroquinazoline-6-sulfonamide
Identifiers
CAS number	17560-51-9
ATC code	C03BA08
PubChem	4170
DrugBank	APRD01109
Chemical data
Formula	Template:OrganicBox atomTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox atomTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBoxTemplate:OrganicBox
Mol. mass	365.835 g/mol
Pharmacokinetic data
Bioavailability	~65%
Metabolism	minimal
Half life	14 hours
Excretion	primarily urine
Therapeutic considerations
Pregnancy cat.	B
Legal status	Prescription only
Routes	Oral

Mechanism of Action

Structure

This image is provided by the National Library of Medicine.

Pharmacodynamics

There is limited information regarding Pharmacodynamics of Metolazone in the drug label.

Pharmacokinetics

There is limited information regarding Pharmacokinetics of Metolazone in the drug label.

Nonclinical Toxicology

There is limited information regarding Nonclinical Toxicology of Metolazone in the drug label.

Clinical Studies

There is limited information regarding Clinical Studies of Metolazone in the drug label.

How Supplied

Storage

There is limited information regarding Metolazone Storage in the drug label.

Images

Drug Images

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Patient Counseling Information

• Patients should be informed of possible adverse effects, advised to take the medication as directed, and promptly report any possible adverse reactions to the treating physician.

Precautions with Alcohol

• The hypotensive effects of alcohol may be potentiated by the volume contraction associated with metolazone therapy.

Brand Names

• Mykrox®
• Zaroxolyn®

Look-Alike Drug Names

• metolazone — methimazole
• metolazone — metoclopramide

Drug Shortage Status

Price

References

The contents of this FDA label are provided by the National Library of Medicine.

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