Mykrox® Tablets

(metolazone tablets, USP)

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 C₁₆H₁₆ClN₃O₃S, 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: Dibasic calcium phosphate, magnesium stearate, microcrystalline cellulose, pregelatinized starch, sodium starch glycolate.

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 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.

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.

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

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 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).

Cross-allergy may occur when MYKROX Tablets are given to patients known to be allergic to sulfonamide-derived drugs, thiazides, or quinethazone.

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.

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.

Patients should be informed of possible adverse effects, advised to take the medication as directed, and promptly report any possible adverse reactions to the treating physician.

None reported.

Mice and rats administered metolazone 5 days/week for up to 18 and 24 months, respectively, at daily doses of 2, 10, and 50 mg/kg, exhibited no evidence of a tumorigenic effect of the drug. The small number of animals examined histologically and poor survival in the mice limit the conclusions that can be reached from these studies.

Metolazone was not mutagenic in vitro in the Ames Test using Salmonella typhimurium strains TA-97, TA-98, TA-100, TA-102, and TA-1535.

Reproductive performance has been evaluated in mice and rats. There is no evidence that metolazone possesses the potential for altering reproductive capacity in mice. In a rat study, in which males were treated orally with metolazone at doses of 2, 10, and 50 mg/kg for 127 days prior to mating with untreated females, an increased number of resorption sites was observed in dams mated with males from the 50 mg/kg group. In addition, the birth weight of offspring was decreased and the pregnancy rate was reduced in dams mated with males from the 10 and 50 mg/kg groups.

Based on clinical studies in which women received metolazone in late pregnancy until the time of delivery, there is no evidence that the drug has any adverse effects on the normal course of labor or delivery.

Metolazone appears in breast milk. Because of the potential for serious adverse reactions in nursing infants from metolazone, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Safety and effectiveness of MYKROX Tablets in pediatric patients have not been established, and such use is not recommended.

Clinical studies of MYKROX did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects. Other reported clinical experience has not identified differences in responses between the elderly and younger patients. In general, 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, and the risk of toxic reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.

Adverse experience information is available from more than 14 years of accumulated marketing experience with other formulations of metolazone for which reliable quantitative information is lacking and from controlled clinical trials with MYKROX from which incidences can be calculated.

In controlled clinical trials with MYKROX, adverse experiences resulted in discontinuation of therapy in 6.7-6.8% of patients given ½ to 1 mg of MYKROX.

Adverse experiences occurring in controlled clinical trials with MYKROX with an incidence of >2%, whether or not considered drug-related, are summarized in the following table.

Some of the adverse effects reported in association with MYKROX also occur frequently in untreated hypertensive patients, such as headache and dizziness, which occurred in 14.8 and 7.4% of patients in a smaller parallel placebo group.

The following adverse effects were reported in less than 2% of the MYKROX treated patients.

Cold extremities, edema, orthostatic hypotension, palpitations.

Anxiety, depression, dry mouth, impotence, nervousness, neuropathy, weakness, “weird” feeling.

Pruritus, rash, skin dryness.

Cough, epistaxis, eye itching, sinus congestion, sore throat, tinnitus.

Abdominal discomfort (pain, bloating), bitter taste, constipation, diarrhea, nausea, vomiting.

Nocturia.

Back pain.

Adverse experiences reported with other marketed metolazone formulations and most thiazide diuretics, for which quantitative data are not available, are uled in decreasing order of severity within body systems. Several are single or rare occurrences.

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

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.

There is no specific antidote available but immediate evacuation of stomach spans is advised. Dialysis is not likely to be effective. Care should be taken when evacuating the gastric spans 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.

Therapy should be individualized according to patient response.

For initial treatment of mild to moderate hypertension, the recommended dose is one MYKROX Tablet (½ mg) once daily, usually in the morning. If patients are inadequately controlled with one ½ mg tablet, the dose can be increased to two MYKROX Tablets (1 mg) once a day. An increase in hypokalemia may occur. Doses larger than 1 mg do not give increased effectiveness.

The same dose titration is necessary if MYKROX Tablets are to be substituted for other dosage forms of metolazone in the treatment of hypertension.

If blood pressure is not adequately controlled with two MYKROX Tablets alone, the dose should not be increased; rather, another antihypertensive agent with a different mechanism of action should be added to therapy with MYKROX Tablets.

MYKROX Tablets (metolazone tablets, USP), ½ mg are white, flat-faced, round tablets, debossed “MYKROX” on one side, and “½” on reverse side.

NDC 53014-847-71        Bottle of 100’s

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [See USP Controlled Room Temperature]. Protect from light. Keep out of the reach of children.