Metolazone

METOLAZONE- metolazone tablet
Upstate Pharma, LLC

Rx Only

DO NOT INTERCHANGE

DO NOT INTERCHANGE UPSTATE’S 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.

DESCRIPTION

Upstate’s metolazone tablets, USP, for oral administration contain 2½, 5, or 10 mg of metolazone, USP, a diuretic/saluretic/antihypertensive drug of the quinazoline class.

Metolazone has the molecular formula C16 H16 ClN3 O3 S, 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:

Chemical Structure

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; 10 mg-D&C Yellow No. 10 and FD&C Yellow No. 6.

CLINICAL PHARMACOLOGY

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 Upstate’s metolazone tablets, USP, 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, USP, at maximum therapeutic dosage is approximately equal to thiazide diuretics. However, unlike thiazides, metolazone tablets, USP, may produce diuresis in patients with glomerular filtration rates below 20 mL/min.

Metolazone tablets, USP, 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.

INDICATIONS AND USAGE

Upstate’s metolazone tablets, USP, 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, USP, 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 Upstate’s metolazone tablets, USP, in the treatment of hypertension. See package circular for MYKROX Tablets (UCB).

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, USP, 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.

CONTRAINDICATIONS

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

WARNINGS

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

Other Antihypertensive Drugs

When metolazone tablets, USP, 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, USP, 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, USP.

PRECAUTIONS

DO NOT INTERCHANGE

DO NOT INTERCHANGE UPSTATE’S 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, USP, 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.

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