Zaroxolyn

In case of overdose, call your local poison control center at 1-800-222-1222. If the victim has collapsed or is not breathing, call local emergency services at 911.

Symptoms of overdose may include the following:

• dizziness
• drowsiness
• fainting
• slow or difficult breathing
• upset stomach
• coma

Metolazone is a thiazide diuretic (water pill) that helps prevent your body from absorbing too much salt, which can cause fluid retention.

Metolazone is used to treat fluid retention (edema) in people with congestive heart failure, or a kidney disorder such as nephrotic syndrome. Metolazone is also used to treat high blood pressure (hypertension).

Metolazone may also be used for purposes not listed in this medication guide.

You should not use metolazone if you are unable to urinate, or if you have severe liver disease.

Follow all directions on your prescription label. Your doctor may occasionally change your dose to make sure you get the best results. Do not use this medicine in larger or smaller amounts or for longer than recommended.

Metolazone is usually taken only once per day.

You may need to limit salt in your diet while taking this medicine. Follow your doctor's instructions carefully.

While using metolazone, you may need frequent blood tests. Your blood and urine may both be tested if you have been vomiting or are dehydrated.

Metolazone can cause unusual results with certain medical tests. Tell any doctor who treats you that you are using metolazone.

If you need surgery, tell the surgeon ahead of time that you are using metolazone. You may need to stop using the medicine for a short time.

If you are being treated for high blood pressure, keep using this medicine even if you feel well. High blood pressure often has no symptoms. You may need to use blood pressure medicine for the rest of your life.

Store the tablets at room temperature away from heat, light, and moisture.

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 Treatment Goals

• Carefully monitor BP during initial titration or subsequent upward adjustment in dosage.500 501

• When available, use evidence-based dosing information (i.e., dosages shown in randomized controlled trials to reduce complications of hypertension) to determine target dosages; target dosages usually can be achieved within 2–4 weeks but may take up to several months.501

• If adequate BP response not achieved with a single antihypertensive agent, add a second drug with demonstrated benefit; if goal BP still not achieved with optimal dosages of 2 antihypertensive agents, add a third drug.501 May maximize dosage of the first drug before adding a second drug, or add a second drug before maximizing dosage of the initial drug.501

• Consider initiating antihypertensive therapy with a combination of drugs if patient's BP exceeds goal BP by >20/10 mm Hg.500 501 503 504

• Goal is to achieve and maintain optimal control of BP; individualize specific target BP based on consideration of multiple factors, including patient age and comorbidities, and currently available evidence from clinical studies.500 501 (See Hypertension under Uses.)

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

For the management of fluid retention (e.g., edema) associated with heart failure, experts state that diuretics should be administered at a dosage sufficient to achieve optimal volume status and relieve congestion without inducing an excessively rapid reduction in intravascular volume, which could result in hypotension, renal dysfunction, or both.524

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

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

Initial dosage of 1.25–2.5 mg once daily has been suggested.a

Usual dosage range is 2.5–5 mg once daily.109 500 e

If adequate response is not achieved with monotherapy, add another antihypertensive agent.501

If intolerable adverse effects occur, consider dosage reduction; if adverse effects worsen or fail to resolve, may need to discontinue and switch to another antihypertensive drug class.501

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.524

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.)

For sequential nephron blockade in the management of fluid retention (e.g., edema) in heart failure, some experts recommend an initial dosage of 2.5–10 mg once daily in combination with a loop diuretic.524

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

Usual maximum is 5 mg daily.a

Maximum total daily dose recommended by ACCF/AHA: 20 mg.524

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

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 of severe hyponatremia and/or hypokalemia reported rarely following initial doses of thiazide and nonthiazide 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

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 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

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

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

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

Regularly increases serum uric acid concentrations and occasionally precipitates gouty attacks, including in patients without a prior history; generally avoid or use with caution in patients with history of gout or elevated uric acid concentrations.500 502 e

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

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

Consider possible exacerbation or activation of systemic lupus erythematosus.e

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

Category B.e

Diuretics are considered second-line agents for control of chronic hypertension in pregnant women;142 500 if initiation of antihypertensive therapy is necessary during pregnancy, other antihypertensives (i.e., methyldopa, nifedipine, labetalol) are preferred.142 540

Diuretics are not recommended for prevention or management of gestational hypertension or preeclampsia.141 539 540

Distributed into milk.a e Manufacturer states to discontinue nursing or the drug;e however, considered to be compatible with breast-feeding.141

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

Limited experience with use in pediatric patients with heart failure†, 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

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

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

Use with caution in patients with severe renal impairment.e (See Elimination 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

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.)

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.

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 (see WARNINGS and PRECAUTIONS, Drug Interactions).

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.

Intentional overdosage has been reported rarely with metolazone and similar diuretic drugs.

Signs And Symptoms

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.

Treatment

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.

Applies to metolazone: oral tablet

Along with its needed effects, metolazone (the active ingredient contained in Zaroxolyn) may cause some unwanted effects. Although not all of these side effects may occur, if they do occur they may need medical attention.

Check with your doctor immediately if any of the following side effects occur while taking metolazone:

• Black, tarry stools
• bleeding gums
• blistering, peeling, or loosening of skin
• bloating
• blood in urine or stools
• blurred vision
• bone pain
• chest pain
• chills
• clay-colored stools
• cold sweats
• coma
• confusion
• constipation
• convulsions
• cough
• dark urine
• decreased urine
• diarrhea
• dizziness, faintness, or lightheadedness when getting up from lying or sitting position
• drowsiness
• dry mouth
• fast, irregular, pounding, or racing heartbeat or pulse
• fever
• flushed, dry skin
• fruit-like breath odor
• general tiredness and weakness
• headache
• incoherent speech
• increased hunger
• increased thirst
• increased urination
• indigestion
• irritability
• itching
• joint or muscle pain
• light-colored stools
• loss of appetite
• lower back or side pain
• metallic taste
• mood changes
• muscle pain or cramps
• nausea and vomiting
• numbness or tingling in hands, feet, or lips
• pain in lower legs
• painful or difficult urination
• pinpoint red spots on skin
• rash
• red irritated eyes
• red skin lesions, often with a purple center
• redness or swelling of lower leg
• shortness of breath
• sore throat
• sores, ulcers, or white spots in mouth or on lips
• sugar in the urine
• sweating
• swelling of face, ankles, or hands
• swollen or painful glands
• tightness in chest
• trembling
• troubled breathing
• unexplained weight loss
• unpleasant breath odor
• unusual bleeding or bruising
• unusual tiredness or weakness
• upper right abdominal pain
• vomiting of blood
• weak pulse
• wheezing
• yellow eyes and skin

Get emergency help immediately if any of the following symptoms of overdose occur while taking metolazone:

• Fainting
• irregular, fast or slow, or shallow breathing
• pale or blue lips, fingernails, or skin
• unusual drowsiness, dullness, tiredness, weakness, or feeling of sluggishness
• weakness and heaviness of legs

Some side effects of metolazone may occur that usually do not need medical attention. These side effects may go away during treatment as your body adjusts to the medicine. Also, your health care professional may be able to tell you about ways to prevent or reduce some of these side effects. Check with your health care professional if any of the following side effects continue or are bothersome or if you have any questions about them:

• Blue-green to black skin discoloration
• burning, tingling, numbness, or pain in the hands, arms, feet, or legs
• cracked, dry, or scaly skin
• decreased interest in sexual intercourse
• feeling of constant movement of self or surroundings
• hives or welts
• inability to have or keep an erection
• loss in sexual ability, desire, drive, or performance
• pain, redness, or sloughing of skin at place of injection
• restlessness
• sensation of pins and needles
• sensation of spinning
• stabbing pain

Applies to metolazone: oral tablet

Metabolic

A rare case of hyperosmolar nonketotic hyperglycemia is associated with metolazone (the active ingredient contained in Zaroxolyn) [Ref]

Metabolic side effects are the most common and profound. The rapid onset of hyponatremia or hypokalemia is often sudden and may be profound, particularly if metolazone is given with a loop diuretic. Hypokalemia may be important in patients with underlying cardiac arrhythmias. Metolazone may increase serum calcium and uric acid levels and lower serum magnesium and phosphate levels. Glucose intolerance is reported in rare cases.[Ref]

Cardiovascular

Cardiovascular side effects are uncommon. Postural hypotension is reported in less than 5% of patients. Rare cases of venous thrombosis are reported, thought to be due to metolazone-induced hypovolemia and increased serum concentrations of clotting factors. Rare cardiovascular side effects also include palpitations, hypovolemia, and chest pain.[Ref]

Renal

Renal insufficiency, manifest as a rise in serum creatinine and BUN, may occur, although, in most cases, creatinine clearance increases as a result of metolazone (the active ingredient contained in Zaroxolyn) therapy.[Ref]

Nervous system

Nervous system side effects include headache, dizziness, and fatigue. Two cases of syncope and seizures are reported. Metolazone-induced hypovolemia and electrolyte changes may induce hepatic encephalopathy in some patients.[Ref]

It is not clear whether the patients who developed syncope and seizure activity were hypotensive or hypovolemic at the time of the seizures or that metolazone can definitively be implicated. In one case the patient was also taking theophylline and had hypomagnesemia, which may be a complication of metolazone therapy.[Ref]

Hypersensitivity

Hypersensitivity reactions include rare case reports of necrotizing vasculitis, angiitis, and pruritic rashes.[Ref]

A case of cutaneous hypersensitivity angiitis has been reported in a patient who had previously tolerated thiazide diuretics, indicating that, despite the chemical similarity between thiazides and metolazone, there is not necessarily cross-reactivity.[Ref]

Hematologic

Hematologic abnormalities are rare. Cases of reversible hypoplastic anemia, aplastic anemia, agranulocytosis, and mild leukopenia are reported.[Ref]

Gastrointestinal

Gastrointestinal side effects are rare, and include a case of acute pancreatitis. Nausea, vomiting, anorexia, and abdominal bloating are also rare.[Ref]

Hepatic

Hepatic side effects include a rare case of cholestatic jaundice.[Ref]

Musculoskeletal

Musculoskeletal cramps are associated with metolazone (the active ingredient contained in Zaroxolyn) therapy, as with other diuretics, and may be associated with electrolyte disorders and rapid intravascular volume shifts.[Ref]

Some side effects of Zaroxolyn may not be reported. Always consult your doctor or healthcare specialist for medical advice. You may also report side effects to the FDA.