Label: METOLAZONE- metolazone tablet

Metolazone tablets, USP, for oral administration contain 2.5 mg, 5 mg, or 10 mg of metolazone, USP, a diuretic/saluretic/antihypertensive drug of the quinazoline class.

Metolazone has the molecular formula C 16H 16ClN 3O 3S, 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:

Metolazone is only sparingly soluble in water, but more soluble in plasma, blood, alkali, and organic solvents.

Inactive Ingredients: colloidal silicon dioxide, magnesium stearate, microcrystalline cellulose and dye: 2.5 mg - D&C Red No. 30 and FD&C Blue No. 1; 5 mg - FD&C Blue No. 2; 10 mg - D&C Yellow No. 10 and FD&C Yellow No. 6.

Metolazone is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of metolazone result from interference with the renal tubular mechanism of electrolyte reabsorption. Metolazone 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. Metolazone 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 metolazone 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 metolazone tablets at maximum therapeutic dosage is approximately equal to thiazide diuretics. However, unlike thiazides, metolazone tablets may produce diuresis in patients with glomerular filtration rates below 20 mL/min.

Metolazone tablets 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 WARNINGSand 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.

Metolazone tablets are indicated for the treatment of salt and water retention including:

• edema accompanying congestive heart failure;
• edema accompanying renal diseases, including the nephrotic syndrome and states of diminished renal function.

Metolazone tablets are also indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class. MYKROX Tablets, a more rapidly available form of metolazone, are intended for the treatment of new patients with mild to moderate hypertension. A dose titration is necessary if MYKROX Tablets are to be substituted for metolazone tablets in the treatment of hypertension. See package circular for MYKROX Tablets.

Usage In Pregnancy

The routine use of diuretics in an otherwise healthy woman is inappropriate and exposes mother and fetus to unnecessary hazard. Diuretics do not prevent development of toxemia of pregnancy, and there is no evidence that they are useful in the treatment of developed toxemia.

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. Metolazone tablets are indicated in pregnancy when edema is due to pathologic causes, just as it is in the absence of pregnancy (see PRECAUTIONS). Dependent edema in pregnancy resulting from restriction of venous return by the expanded uterus is properly treated through elevation of the lower extremities and use of support hose; use of diuretics to lower intravascular volume in this case is illogical and unnecessary. There is hypervolemia during normal pregnancy which is harmful to neither the fetus nor the mother (in the absence of cardiovascular disease), but which is associated with edema, including generalized edema, in the majority of pregnant women. If this edema produces discomfort, increased recumbency will often provide relief. In rare instances, this edema may cause extreme discomfort which is not relieved by rest. In these cases, a short course of diuretics may be appropriate.

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

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 metolazone tablets are administered concomitantly to patients receiving furosemide (see PRECAUTIONS, Drug Interactions).

Other Antihypertensive Drugs

When metolazone tablets are 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 metolazone tablets are 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 metolazone tablets.

DO NOT INTERCHANGE

DO NOT INTERCHANGE METOLAZONE TABLETS, USP, ZAROXOLYN TABLETS, AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE THEIR 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.

General

Fluid And Electrolytes

All patients receiving therapy with metolazone 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

Metolazone tablets regularly cause 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 metolazone tablets. If azotemia and oliguria worsen during treatment of patients with severe renal disease, metolazone tablets should be discontinued.

Renal Impairment

Use caution when administering metolazone 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 metolazone tablets.

Metolazone tablets are usually well tolerated, and most reported adverse reactions have been mild and transient. Many of metolazone tablets 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.

Central And Peripheral Nervous System

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

Dermatologic/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.

Other

Transient blurred vision, chills, dry mouth.

In addition, adverse reactions reported with similar antihypertensive-diuretics, but which have not been reported to date for metolazone tablets include: bitter taste, sialadenitis, xanthopsia, respiratory distress (including pneumonitis), and anaphylactic reactions. These reactions should be considered as possible occurrences with clinical usage of metolazone tablets.

Whenever adverse reactions are moderate or severe, metolazone tablets dosage should be reduced or therapy withdrawn.

To report SUSPECTED ADVERSE REACTIONS, contact  Micro Labs USA, Inc. at 1-855-839-8195  or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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.

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

Usual Single Daily Dosage Schedules

Suitable initial dosages will usually fall in the ranges given.

Edema of cardiac failure:

Metolazone tablets 5 to 20 mg once daily.

Edema of renal disease:

Metolazone tablets 5 to 20 mg once daily.

Mild to moderate essential hypertension:

Metolazone tablets 2.5 to 5 mg once daily.

New patients – MYKROX Tablets (metolazone tablets, USP) (see MYKROX package circular). If considered desirable to switch patients currently on metolazone tablets, USP, to MYKROX, the dose should be determined by titration starting at one tablet (0.5 mg) once daily and increasing to two tablets (1 mg) once daily if needed.

Treatment Of Edematous States

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 metolazone tablets 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.

Treatment Of Hypertension

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.

Metolazone tablets, USP, are biconvex, round tablets, and are available in three strengths:

2.5 mg –pink colored mottled tablets debossed with “M1” on one side and plain on other side, free from physical defects. It is available as follows:

Bottles of 100 with child-resistant closure:                NDC 42571-416-01

Bottles of 1000:                                                          NDC 42571-416-10

5 mg –blue colored mottled tablets debossed with “M2” on one side and plain on other side, free from physical defects. It is available as follows:

Bottles of 100 with child-resistant closure:                NDC 42571-417-01

Bottles of 1000:                                                          NDC 42571-417-10

10 mg –yellow colored tablets debossed with “M3” on one side and plain on other side, free from physical defects. It is available as follows:

Bottles of 100 with child-resistant closure:                NDC 42571-418-01

Bottles of 1000:                                                          NDC 42571-418-10

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.
Dispense in a tight, light-resistant container as defined in the USP using a child-resistant closure.

For more information about Metolazone Tablets, USP call 1-855-839-8195.

All brand names are the trademarks of their respective owners.

Manufactured for:
Micro Labs USA, Inc.
Somerset, NJ 08873

Rev. 04/2023-01

NDC 42571-416-01
Metolazone Tablets, USP
2.5 mg
Rx Only
100 Tablets
Micro Labs Limited

NDC 42571-417-01
Metolazone Tablets, USP
5 mg
Rx Only
100 Tablets
Micro Labs Limited

NDC 42571-418-01
Metolazone Tablets, USP
10 mg
Rx Only
100 Tablets
Micro Labs Limited