Metolazone

INDICATIONS AND USAGE 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 Zaroxolyn ® tablets and other formulations of metolazone that share its slow and incomplete bioavailability, in the treatment of hypertension. 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.

DOSAGE AND ADMINISTRATION Effective dosage of metolazone tablets, USP, should be individualized according to indication and patient response. A single daily dose is recommended. Therapy with metolazone tablets, USP, 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, USP, 5 to 20 mg once daily. Edema of renal disease: Metolazone tablets, USP, 5 to 20 mg once daily. Mild to moderate essential hypertension: Metolazone tablets, USP, 21⁄2 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 (1⁄2 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, USP, 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.

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

ADVERSE REACTIONS Metolazone tablets, USP, are usually well tolerated, and most reported adverse reactions have been mild and transient. Many of metolazone tablets, USP, 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, USP, 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, USP. Whenever adverse reactions are moderate or severe, metolazone tablets, USP, dosage should be reduced or therapy withdrawn. To report SUSPECTED ADVERSE REACTIONS, contact Innogenix, LLC. at 1-844-466-6469 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Drug Interactions Diuretics Furosemide and probably other loop diuretics given concomitantly with metolazone can cause unusually large or prolonged losses of fluid and electrolytes (see WARNINGS ). Other Antihypertensives When metolazone tablets, USP, are used with other antihypertensive drugs, care must be taken, especially during initial therapy. Dosage adjustments of other antihypertensives may be necessary. Alcohol, Barbiturates, And Narcotics The hypotensive effects of these drugs may be potentiated by the volume contraction that may be associated with metolazone therapy. Digitalis Glycosides Diuretic-induced hypokalemia can increase the sensitivity of the myocardium to digitalis. Serious arrhythmias can result. Corticosteroids Or ACTH May increase the risk of hypokalemia and increase salt and water retention. Lithium Serum lithium levels may increase (see WARNINGS ). Curariform Drugs Diuretic-induced hypokalemia may enhance neuromuscular blocking effects of curariform drugs (such as tubocurarine) – the most serious effect would be respiratory depression which could proceed to apnea. Accordingly, it may be advisable to discontinue metolazone tablets, USP, three days before elective surgery. Salicylates And Other Non-Steroidal Anti-Inflammatory Drugs May decrease the antihypertensive effects of metolazone tablets, USP. Sympathomimetics Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use. Insulin And Oral Antidiabetic Agents See Glucose Tolerance under PRECAUTIONS , General . Methenamine Efficacy may be decreased due to urinary alkalizing effect of metolazone. Anticoagulants Metolazone, as well as other thiazide-like diuretics, may affect the hypoprothrombinemic response to anticoagulants; dosage adjustments may be necessary.

DESCRIPTION Metolazone tablets, USP for oral administration contain 2.5, 5, or 10 mg of metolazone, USP, a diuretic/saluretic/antihypertensive drug of the quinazoline class. Metolazone has the molecular formula C 16 H 16 ClN 3 O 3 S, the chemical name 7-chloro-1, 2, 3, 4-tetrahydro-2-methyl-3-(2-methylphenyl)-4-oxo-6-quinazolinesulfonamide, and a molecular weight 365.83. The structural formula is: Metolazone is insoluble in water, sparingly soluble in methanol, slightly soluble in ethyl acetate, very slightly soluble in methylene chloride. Inactive Ingredients: Microcrystalline cellulose, magnesium stearate and colorants 2.5 mg -D&C Red No. 27 Aluminum Lake, 5 mg - FD&C Blue No. 2 Aluminum Lake and 10 mg - D&C Yellow No. 10 Aluminum Lake and FD&C Yellow No. 6 Aluminum Lake. Metolazone tablets, USP meets USP Dissolution Test 3 . structure

OVERDOSAGE 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.

HOW SUPPLIED Metolazone Tablets, USP are available containing 2.5 mg, 5 mg and 10 mg of metolazone, USP. The 2.5 mg tablets are pink, round tablets, with pink speckles, debossed with "M" on one side and "2 1⁄2" on reverse side. They are available as follows: NDC 76385-136-01 Bottle of 100's The 5 mg tablets are blue, round tablets, with blue speckles, debossed with "M" on one side and "5" on reverse side. They are available as follows: NDC 76385-137-01 Bottle of 100's The 10 mg tablets are yellow, round tablets, with yellow speckles, debossed with "M" on one side and "10" on reverse side. They are available as follows: NDC 76385-138-01 Bottle of 100's 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 contents in a tight, light-resistant container as defined in the USP with a child-resistant closure, as required. To report SUSPECTED ADVERSE REACTIONS, contact Unichem Pharmaceuticals (USA) Inc. at 1-866-562-4616 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch . MADE IN INDIA Distributed by: UNICHEM PHARMACEUTICALS (USA), INC. East Brunswick, NJ 08816 USA. All brand names are the trademarks of their respective owners. Rev. 10/2025 213944