Metolazone

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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[1]
Edema Associated with Liver Disease
  • Dosing Information
  • 5–20 mg PO qd[2]

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

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.
  • 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.
  • Concomitant Therapy
  • 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.
  • Unusually large or prolonged losses of fluids and electrolytes may result when Zaroxolyn is administered concomitantly to patients receiving furosemide.
  • 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
  • Sensitivity Reactions

Precautions

  • Fluid And Electrolytes
  • Glucose Tolerance
  • 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, 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.
  • 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.

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.

Drug Interactions

  • Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes.
  • 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.
  • The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy.
  • May increase the risk of hypokalemia and increase salt and water retention.
  • 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.
  • May decrease the antihypertensive effects of Zaroxolyn Tablets.
  • Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.
  • Efficacy may be decreased due to urinary alkalizing effect of metolazone.

Use in Specific Populations

Pregnancy

Pregnancy Category (FDA):

  • Pregnancy Category B
  • Teratogenic Effects
  • Reproduction studies performed in mice, rabbits, and rats treated during the appropriate period of gestation at doses up to 50 mg/kg/day have revealed no evidence of harm to the fetus due to metolazone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, Zaroxolyn Tablets (metolazone tablets, USP) should be used during pregnancy only if clearly needed. Metolazone crosses the placental barrier and appears in cord blood.
  • Non-Teratogenic Effects
  • The use of Zaroxolyn Tablets in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. It is not known what effect the use of the drug during pregnancy has on the later growth, development, and functional maturation of the child. No such effects have been reported with metolazone.


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

  • Based on clinical studies in which women received metolazone in late pregnancy until the time of delivery, there is no evidence that the drug has any adverse effects on the normal course of labor or delivery.

Nursing Mothers

  • Metolazone appears in breast milk. Because of the potential for serious adverse reactions in nursing infants from metolazone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

  • 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.
  • There is limited experience with the combination of Zaroxolyn and furosemide in pediatric patients with furosemide-resistant edema. Some benefited while others did not or had an exaggerated response with hypovolemia, tachycardia, and orthostatic hypotension requiring fluid replacement. Severe hypokalemia was reported and there was a tendency for diuresis to persist for up to 24 hours after Zaroxolyn was discontinued. Hyperbilirubinemia has been reported in 1 neonate. Close clinical and laboratory monitoring of all children treated with diuretics is indicated.

Geriatic Use

  • Clinical studies of Zaroxolyn did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.
  • This drug is known to be substantially excreted by the kidney, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

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

Monitoring

  • Close clinical and laboratory monitoring of all children treated with diuretics is indicated.
  • Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

IV Compatibility

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

Overdosage

Acute Overdose

Signs and Symptoms

  • Intentional overdosage has been reported rarely with metolazone and similar diuretic drugs.
  • Orthostatic hypotension, dizziness, drowsiness, syncope, electrolyte abnormalities, hemoconcentration and hemodynamic changes due to plasma volume depletion may occur. In some instances depressed respiration may be observed. At high doses, lethargy of varying degree may progress to coma within a few hours. The mechanism of CNS depression with thiazide overdosage is unknown. Also, GI irritation and hypermotility may occur. Temporary elevation of BUN has been reported, especially in patients with impairment of renal function. Serum electrolyte changes and cardiovascular and renal function should be closely monitored.

Management

  • There is no specific antidote available but immediate evacuation of stomach contents is advised. Dialysis is not likely to be effective. Care should be taken when evacuating the gastric contents to prevent aspiration, especially in the stuporous or comatose patient. Supportive measures should be initiated as required to maintain hydration, electrolyte balance, respiration, and cardiovascular and renal function.

Chronic Overdose

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

Pharmacology

Metolazone structure svg.png
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 C16H16ClN3O3S 
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

  • Zaroxolyn (metolazone) is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of Zaroxolyn result from interference with the renal tubular mechanism of electrolyte reabsorption. Zaroxolyn acts primarily to inhibit sodium reabsorption at the cortical diluting site and to a lesser extent in the proximal convoluted tubule. Sodium and chloride ions are excreted in approximately equivalent amounts. The increased delivery of sodium to the distal tubular exchange site results in increased potassium excretion. Zaroxolyn does not inhibit carbonic anhydrase. A proximal action of metolazone has been shown in humans by increased excretion of phosphate and magnesium ions and by a markedly increased fractional excretion of sodium in patients with severely compromised glomerular filtration. This action has been demonstrated in animals by micropuncture studies.

Structure

  • Zaroxolyn Tablets (metolazone tablets, USP) for oral administration contain 2½ or 5 mg of metolazone, USP, a diuretic/saluretic/antihypertensive drug of the quinazoline class.
  • Metolazone has the molecular formula C16H16ClN3S, the chemical name 7-chloro-1, 2, 3, 4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide, and a molecular weight of 365.83. The structural formula is:
This image is provided by the National Library of Medicine.
  • Metolazone is only sparingly soluble in water, but more soluble in plasma, blood, alkali, and organic solvents.
  • Inactive Ingredients: Magnesium stearate, microcrystalline cellulose and dye: 2½ mg-D&C Red No. 33; 5 mg-FD&C Blue No. 2.

Pharmacodynamics

  • When Zaroxolyn Tablets are given, diuresis and saluresis usually begin within one hour and may persist for 24 hours or more. For most patients, the duration of effect can be varied by adjusting the daily dose. High doses may prolong the effect. A single daily dose is recommended. When a desired therapeutic effect has been obtained, it may be possible to reduce dosage to a lower maintenance level.
  • The diuretic potency of Zaroxolyn at maximum therapeutic dosage is approximately equal to thiazide diuretics. However, unlike thiazides, Zaroxolyn may produce diuresis in patients with glomerular filtration rates below 20 mL/min.
  • Zaroxolyn and furosemide administered concurrently have produced marked diuresis in some patients where edema or ascites was refractory to treatment with maximum recommended doses of these or other diuretics administered alone. The mechanism of this interaction is unknown

Pharmacokinetics

  • Maximum blood levels of metolazone are found approximately eight hours after dosing. A small fraction of metolazone is metabolized. Most of the drug is excreted in the unconverted form in the urine.

Nonclinical Toxicology

  • Carcinogenesis, Mutagenesis, Impairment Of Fertility
  • Mice and rats administered metolazone 5 days/week for up to 18 and 24 months, respectively, at daily doses of 2, 10, and 50 mg/kg, exhibited no evidence of a tumorigenic effect of the drug. The small number of animals examined histologically and poor survival in the mice limit the conclusions that can be reached from these studies.
  • Metolazone was not mutagenic in vitro in the Ames Test using Salmonella typhimurium strains TA-97, TA-98, TA-100, TA-102, and TA-1535.
  • Reproductive performance has been evaluated in mice and rats. There is no evidence that metolazone possesses the potential for altering reproductive capacity in mice. In a rat study, in which males were treated orally with metolazone at doses of 2, 10, and 50 mg/kg for 127 days prior to mating with untreated females, an increased number of resorption sites was observed in dams mated with males from the 50 mg/kg group. In addition, the birth weight of offspring was decreased and the pregnancy rate was reduced in dams mated with males from the 10 and 50 mg/kg groups.

Clinical Studies

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

How Supplied

  • Zaroxolyn Tablets (metolazone tablets, USP) are shallow biconvex, round tablets, and are available in two strengths:
2½ mg, pink, debossed "Zaroxolyn" on one side, and "2½ " on reverse side.
NDC 53014-975-71 Bottle of 100's
5 mg, blue, debossed "Zaroxolyn" on one side, and "5" on reverse side.
NDC 53014-850-71 Bottle of 100's
  • Storage
  • Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature].
  • Protect from light. Keep out of the reach of children.

Storage

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

Images

Drug Images

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Drug Label Author:

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Package and Label Display Panel

Metolazone02.png
This image of the FDA label is provided by the National Library of Medicine.
Metolazone03.png
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This image of the FDA label is provided by the National Library of Medicine.

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®[3]

Look-Alike Drug Names

  • metolazone — methimazole[4]
  • metolazone — metoclopramide[4]

Drug Shortage Status

Price

References

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

  1. Cunningham, E. (1982-11). "Metolazone therapy of active calcium nephrolithiasis". Clinical Pharmacology and Therapeutics. 32 (5): 642–645. ISSN 0009-9236. PMID 7128005. Unknown parameter |coauthors= ignored (help); Check date values in: |date= (help)
  2. Hillenbrand, P. (1971-10-30). "Use of metolazone in the treatment of ascites due to liver disease". British Medical Journal. 4 (5782): 266–270. ISSN 0007-1447. PMC 1799533. PMID 5123909. Unknown parameter |coauthors= ignored (help)
  3. "Zaroxolyn (metolazone) tablet".
  4. 4.0 4.1 "http://www.ismp.org". External link in |title= (help)

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