Mykrox Tablets

MYKROX TABLETS- metolazone tablet
Celltech Pharmaceuticals, Inc.

DO NOT INTERCHANGE:

MYKROX TABLETS ARE A RAPIDLY AVAILABLE FORMULATION OF METOLAZONE FOR ORAL ADMINISTRATION. MYKROX TABLETS AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE ITS MORE RAPID AND COMPLETE BIOAVAILABILITY ARE NOT THERAPEUTICALLY EQUIVALENT TO ZAROXOLYN® TABLETS AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE ITS SLOW AND INCOMPLETE BIOAVAILABILITY. FORMULATIONS BIOEQUIVALENT TO MYKROX AND FORMULATIONS BIOEQUIVALENT TO ZAROXOLYN SHOULD NOT BE INTERCHANGED FOR ONE ANOTHER.

DESCRIPTION

MYKROX Tablets (metolazone tablets, USP) for oral administration contain ½ 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:

Image from Drug Label Content

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

Inactive Ingredients: Dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate.

CLINICAL PHARMACOLOGY

MYKROX (metolazone) is a quinazoline diuretic, with properties generally similar to the thiazide diuretics. The actions of MYKROX result from interference with the renal tubular mechanism of electrolyte reabsorption. MYKROX 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. MYKROX 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.

The antihypertensive mechanism of action of metolazone is not fully understood but is presumed to be related to its saluretic and diuretic properties.

In two double-blind, controlled clinical trials of MYKROX Tablets, the maximum effect on mean blood pressure was achieved within 2 weeks of treatment and showed some evidence of an increased response at 1 mg compared to ½ mg. There was no indication of an increased response with 2 mg.

After six weeks of treatment, the mean fall in serum potassium was 0.42 mEq/L at ½ mg, 0.66 mEq/L at 1 mg, and 0.7 mEq/L at 2 mg. Serum uric acid increased by 1.1 to 1.4 mg/dL at increasing doses. There were small falls in serum sodium and chloride and a 1.3-2.1 mg/dL increase in BUN at increasing doses.

The rate and extent of absorption of metolazone from MYKROX Tablets were equivalent to those from an oral solution of metolazone. Peak blood levels are obtained within 2 to 4 hours of oral administration with an elimination half-life of approximately 14 hours. MYKROX Tablets have been shown to produce blood levels that are dose proportional between ½ -2 mg. Steady state blood levels are usually reached in 4-5 days.

In contrast, other formulations of metolazone produce peak blood concentrations approximately 8 hours following oral administration; absorption continues for an additional 12 hours.

Mykrox Tablets Indications and Usage

MYKROX Tablets are indicated for the treatment of hypertension, alone or in combination with other antihypertensive drugs of a different class.

MYKROX TABLETS HAVE NOT BEEN EVALUATED FOR THE TREATMENT OF CONGESTIVE HEART FAILURE OR FLUID RETENTION DUE TO RENAL OR HEPATIC DISEASE AND THE CORRECT DOSAGE FOR THESE CONDITIONS AND OTHER EDEMA STATES HAS NOT BEEN ESTABLISHED.

SINCE A SAFE AND EFFECTIVE DIURETIC DOSE HAS NOT BEEN ESTABLISHED, MYKROX TABLETS SHOULD NOT BE USED WHEN DIURESIS IS DESIRED.

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 (see PRECAUTIONS).

Edema during pregnancy may arise from pathologic causes or from the physiologic and mechanical consequences of pregnancy. MYKROX is not indicated for the treatment of edema in pregnancy. 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.

In controlled clinical trials, 1.5% of patients taking ½ mg and 3.1% of patients taking 1 mg of MYKROX daily developed clinical hypokalemia (defined as hypokalemia accompanied by signs or symptoms); 21% of the patients taking ½ mg and 30% of the patients taking 1 mg of MYKROX daily developed hypokalemia (defined as a serum potassium concentration below 3.5 mEq/L); in another controlled clinical trial in which the patients started therapy with a serum potassium level greater than 4.0 mEq/L, 8% of patients taking ½ mg of MYKROX daily developed hypokalemia (defined as a serum potassium concentration below 3.5 mEq/L).

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

Other Antihypertensive Drugs

When MYKROX 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 MYKROX 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 MYKROX.

PRECAUTIONS

DO NOT INTERCHANGE

MYKROX TABLETS ARE A RAPIDLY AVAILABLE FORMULATION OF METOLAZONE FOR ORAL ADMINISTRATION. MYKROX TABLETS AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE ITS MORE RAPID AND COMPLETE BIOAVAILABILITY ARE NOT THERAPEUTICALLY EQUIVALENT TO ZAROXOLYN TABLETS AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE ITS SLOW AND INCOMPLETE BIOAVAILABILITY. FORMULATIONS BIOEQUIVALENT TO MYKROX AND FORMULATIONS BIOEQUIVALENT TO ZAROXOLYN SHOULD NOT BE INTERCHANGED FOR ONE ANOTHER.

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