FDA label dffb4544-0e47-40cd-9baa-d622075838cc

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.

ADVERSE REACTIONS 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. Incidence of Adverse Experiences Volunteered or Elicited (by Patient in Percent)* * Percent of patients reporting an adverse experience one or more times. † All doses combined (½, 1, and 2 mg). MYKROX n = 226† Dizziness (lightheadedness) 10.2 Headaches 9.3 Muscle Cramps 5.8 Fatigue (malaise, lethargy, lassitude) 4.4 Joint Pain, swelling 3.1 Chest Pain (precordial discomfort) 2.7 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. Cardiovascular Cold extremities, edema, orthostatic hypotension, palpitations. Central and Peripheral Nervous System Anxiety, depression, dry mouth, impotence, nervousness, neuropathy, weakness, “weird” feeling. Dermatological Pruritus, rash, skin dryness. Eyes, Ears, Nose, Throat Cough, epistaxis, eye itching, sinus congestion, sore throat, tinnitus. Gastrointestinal Abdominal discomfort (pain, bloating), bitter taste, constipation, diarrhea, nausea, vomiting. Genitourinary Nocturia. Musculoskeletal Back pain. Other Adverse Experiences Adverse experiences reported with other marketed metolazone formulations and most thiazide diuretics, for which quantitative data are not available, are listed in decreasing order of severity within body systems. Several are single or rare occurrences. Cardiovascular excessive volume depletion, hemoconcentration, venous thrombosis. Central and Peripheral Nervous System syncope, paresthesias, drowsiness, restlessness (sometimes resulting in insomnia). 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, anorexia, nausea, diarrhea, abdominal pain. Hematologic aplastic (hypoplastic) anemia, agranulocytosis, leukopenia, thrombocytopenia. Metabolic hypokalemia (see WARNINGS, Hypokalemia ), hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia, hypomagnesemia, hypercalcemia. Musculoskeletal acute gouty attacks. Other transient blurred vision, chills. In addition, rare adverse experiences reported in association with similar antihypertensive-diuretics but not reported to date for metolazone include: sialadenitis, xanthopsia, respiratory distress (including pneumonitis), and anaphylactic reactions. These experiences could occur with clinical use of metolazone.

<table width="90%"> <caption>Incidence of Adverse Experiences Volunteered or Elicited (by Patient in Percent)*</caption> <col align="left"/> <col align="center"/> <tfoot> <tr> <td align="left" colspan="2">* Percent of patients reporting an adverse experience one or more times.</td> </tr> <tr> <td align="left" colspan="2">&#x2020; All doses combined (&#xBD;, 1, and 2 mg).</td> </tr> </tfoot> <tbody> <tr> <td/> <td> <content styleCode="bold">MYKROX</content> <content styleCode="bold underline">n = 226&#x2020;</content> </td> </tr> <tr> <td> <content styleCode="bold">Dizziness (lightheadedness)</content> </td> <td>10.2</td> </tr> <tr> <td> <content styleCode="bold">Headaches </content> </td> <td>9.3</td> </tr> <tr> <td> <content styleCode="bold">Muscle Cramps</content> </td> <td>5.8</td> </tr> <tr> <td> <content styleCode="bold">Fatigue (malaise, lethargy, lassitude)</content> </td> <td>4.4</td> </tr> <tr> <td> <content styleCode="bold">Joint Pain, swelling</content> </td> <td>3.1</td> </tr> <tr> <td> <content styleCode="bold">Chest Pain (precordial discomfort)</content> </td> <td>2.7</td> </tr> </tbody> </table>