Pronunciation: me-TOL-a-zone
Class: Thiazide diuretic

Trade Names

Zaroxolyn
- Tablets, oral 2.5 mg
- Tablets, oral 5 mg

Metolazone (generic)
- Tablets, oral 10 mg

Pharmacology

Increases urinary excretion of sodium and chloride by inhibiting reabsorption in ascending limb of loop of Henle and early distal tubules.

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Pharmacokinetics

Absorption

T _max is approximately 8 h.

Metabolism

A small fraction of metolazone is metabolized.

Elimination

Most is excreted in the unconverted form in urine.

Onset

Onset is 1 h.

Duration

Duration is 12 to 24 h.

Special Populations

Renal Function Impairment

May produce diuresis in patients with glomerular filtration rate less than 20 mL/min.

Indications and Usage

For the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class; for the treatment of salt and water retention, including the following: edema accompanying CHF; edema accompanying renal diseases, including the nephrotic syndrome and states of diminished renal function.

Unlabeled Uses

Diabetes insipidus; osteoporosis.

Contraindications

Anuria; hepatic coma or precoma; known allergy or hypersensitivity to metolazone.

Dosage and Administration

Hypertension
Adults

PO Initially, 2.5 to 5 mg once daily. Adjust doses at appropriate intervals to achieve maximum therapeutic effect.

Salt and water retention
Adults

PO Initially, 5 to 20 mg once daily. Base a decision to change the daily dose on the results of thorough clinical and laboratory evaluations. 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-h period.

General Advice

• Administer once daily without regard to food.
• When a desired therapeutic effect has been obtained, it may be advisable to reduce the dose if possible.
• If antihypertensive drugs or diuretics are given concurrently with metolazone, more careful dosage adjustment may be necessary.
• If considered desirable to switch patients currently on Zaroxolyn to Mykrox (no longer available in the US), the dose should be determined by titration started at 1 tablet (0.5 mg) once daily and increased to 2 tablets (1 mg) once daily if needed.
• Whenever adverse reactions are moderate or severe, metolazone dosage should be reduced or therapy withdrawn.

Storage/Stability

Store between 59° and 86°F. Protect from light.

Drug Interactions

Adrenocorticotropic hormone, corticosteroids

Corticosteroids or adrenocorticotropic hormone may increase the risk of hypokalemia and increase salt and water retention.

Alcohol, barbiturates, narcotics

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

Anticoagulants (eg, warfarin)

The hypoprothrombinemic response to anticoagulants may be decreased. Monitor anticoagulant activity and adjust the warfarin dose as needed.

Antihypertensive agents

When metolazone is used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary.

Antineoplastic agents

Risk of myelosuppression may be increased. Use with caution.

Cholestyramine, colestipol

May decrease effects of metolazone by decreasing absorption. Separate the administration times by as much as possible. An increased metolazone dose may still be needed.

Curariform drugs (eg, tubocurarine)

Diuretic-induced hypokalemia may enhance neuromuscular-blocking effects (eg, respiratory depression) of curariform drugs. Consider discontinuing metolazone 3 days before elective surgery.

Diazoxide

The pharmacologic effects of both drugs may be increased. Hyperglycemia, hyperuricemia, and hypotension may occur. If coadministration cannot be avoided, monitor blood glucose, serum uric acid, and BP, and make dosage adjustments as needed.

Digitalis glycosides (eg, digoxin)

Urinary loss of potassium and magnesium may predispose patient to digitalis-induced arrhythmia. Serious arrhythmias can result. Monitor potassium and magnesium levels, as well as for signs of digitalis toxicity.

Insulin, sulfonylureas (eg, tolbutamide)

Metolazone may decrease hypoglycemic effect of insulin or sulfonylureas by increasing blood glucose. Higher insulin or oral hypoglycemic doses may be needed. Monitor blood glucose and adjust the insulin or oral hypoglycemic agent dose as needed.

Lithium

Metolazone may decrease renal elimination of lithium, resulting in toxicity. If coadministration cannot be avoided, monitor lithium serum concentrations and the patient for symptoms of lithium toxicity. Adjust the lithium dose as needed.

Loop diuretics (eg, furosemide)

Concurrent use may produce profound diuresis and electrolyte abnormalities. Carefully titrate with small or intermittent doses. Monitor patients for dehydration and electrolyte abnormalities during combined therapy.

Methenamine

Methenamine efficacy may be decreased because of the urinary alkalizing effect of metolazone.

NSAIDs, salicylates

The antihypertensive effects of metolazone may be decreased. Monitor BP. Adjust the metolazone dose as needed or discontinue the NSAID.

Sympathomimetics

The arterial responsiveness to norepinephrine may be decreased, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Tretinoin

The risk of phototoxicity may be increased because of the additive photosensitizing properties of both drugs. Avoid coadministration.

Adverse Reactions

Cardiovascular

Excessive volume depletion; orthostatic hypotension; palpitations; syncope; venous thrombosis.

CNS

Dizziness; drowsiness; fatigue; headache; light-headedness; neuropathy; paresthesias; psychotic depression; restlessness (sometimes resulting in insomnia); vertigo; weakness.

Dermatologic

Cutaneous vasculitis; dermatitis; necrotizing angiitis; petechiae; photosensitivity; pruritus; purpura; rash; skin necrosis; Stevens-Johnson syndrome; TEN; urticaria.

GI

Abdominal bloating, abdominal pain; anorexia; constipation; diarrhea; dry mouth; epigastric distress; nausea; pancreatitis; vomiting.

Genitourinary

Glycosuria; impotence.

Hepatic

Hepatitis; intrahepatic cholestatic jaundice.

Hematologic

Agranulocytosis, aplastic/hypoplastic anemia, hemoconcentration, leukopenia, thrombocytopenia.

Metabolic

Hypercalcemia; hyperglycemia; hyperuricemia; hypochloremia; hypochloremic alkalosis; hypokalemia; hypomagnesemia; hyponatremia; hypophosphatemia; increased BUN or creatinine.

Musculoskeletal

Acute gouty attacks; joint pain; muscle cramps; spasm.

Miscellaneous

Chest pain/discomfort; chills; transient blurred vision.

Precautions

Monitor Monitor serum electrolyte at appropriate intervals and observe patients for clinical signs of fluid or electrolyte imbalance (eg, hyponatremia, hypochloremic alkalosis, hypokalemia). Monitor BP, reduction in edema, and blood glucose changes in patients with diabetes.

Pregnancy

Category B .

Lactation

Excreted in breast milk.

Children

Safety and effectiveness have not been established.

Elderly

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. Because elderly patients are more likely to have decreased renal function, take care in dose selection; it may be useful to monitor renal function.

Hypersensitivity

May occur; cross-sensitivity to sulfonamides or thiazides is possible.

Renal Function

Use caution when administering to patients with severely impaired renal function.

Hepatic Function

The risk of hypokalemia is increased when severe liver disease is present.

Fluid and/or electrolyte imbalance

Rarely, the rapid onset of severe hyponatremia or hypokalemia has been reported following initial doses of thiazide and non-thiazide diuretics. When symptoms consistent with severe electrolyte imbalance appear rapidly, discontinue the drug and initiate supportive measures immediately.

Glucose tolerance

May raise blood glucose concentrations, possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.

Hypercalcemia

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

Hyperuricemia

May increase serum uric acid and precipitate gout.

Interchangeability

Do not interchange Zaroxolyn and other formulations of metolazone that share its slow and incomplete bioavailability and are not therapeutically equivalent at the same doses to Mykrox (no longer available in the US), a more rapidly available and completely bioavailable metolazone product. Formulations bioequivalent to Zaroxolyn and formulations bioequivalent to Mykrox should not be interchanged.

Lupus erythematosus

May be activated or exacerbated.

Orthostatic hypotension

May occur.

Renal effects

Azotemia, presumably prerenal azotemia, may be precipitated.

Overdosage

Symptoms

Decreased respiration, dizziness, drowsiness, electrolyte abnormalities, GI irritation and hypermotility, hemoconcentration, hemodynamic changes due to plasma volume depletion, lethargy progressing to coma, orthostatic hypotension, syncope.

Patient Information

• Explain the significance of potential potassium loss, and identify appropriate supplemental food sources (eg, bananas, orange juice, dates, citrus fruits, apricots). Teach patient signs and symptoms of hypokalemia (muscle weakness, cramping).
• Inform patients that dizziness or light-headedness may occur if patient stands up too fast.
• Tell patient to avoid exposure to sunlight and to use sunscreen or wear protective clothing until tolerance to sunlight can be established.
• Explain that BP should be checked periodically by patient or family member.
• Review signs and symptoms of fluid imbalance.

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