ZAROXOLYN Tablet Ref.[9620] Active ingredients: Metolazone

Warnings

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, the drug should be discontinued and supportive measures should be initiated immediately. The appropriateness of therapy with this class of drug should be carefully re-evaluated.

Hypokalemia may occur, with consequent weakness, cramps, and cardiac arrhythmias. Hypokalemia is a particular hazard in digitalized patients or those who have had or have a ventricular arrhythmia; dangerous or fatal arrhythmias may be precipitated. Serum potassium should be determined at regular intervals, and dose reduction, potassium supplementation or addition of a potassium sparing diuretic instituted if indicated. Hypokalemia is dose related. (See PRECAUTIONS).

Azotemia and hyperuricemia may be noted or precipitated during the administration of ZAROXOLYN (metolazone). Infrequently, gouty attacks have been reported in persons with a history of gout. If azotemia and oliguria worsen during treatment of patients with severe renal disease, metolazone should be discontinued.

Unusually large or prolonged losses of fluid and electrolytes may result when metolazone is administered concomitantly to patients receiving furosemide.

Particular care must be taken, especially during initial therapy, when metolazone is used with other antihypertensive drugs of a different class to avoid excessive reduction in blood pressure. (See PRECAUTIONS, Drug Interactions).

Precautions

All patients receiving metolazone should have serum electrolytes measured at appropriate intervals and be observed for clinical signs of fluid and/or electrolyte imbalance; namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. Serum and urine electrolyte determinations are particularly important when the patient is vomiting excessively, has severe diarrhea, or is receiving parenteral fluids.

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 of potassium is inadequate or when excess potassium is being lost extrarenally; such as with vomiting or diarrhea.

Hyponatremia may occur at any time during long term therapy and, on rare occasions, may be life threatening (See WARNINGS).

Warning signs of electrolyte imbalance irrespective of cause are: dryness of mouth; thirst; weakness; lethargy; drowsiness; restlessness; muscle pains or cramps; muscular fatigue; hypotension; oliguria; tachycardia; and gastrointestinal disturbances such as nausea and vomiting.

Use of diuretics similar to metolazone have been associated, on rare occasions, with pathologic changes in the parathyroid glands. This possibility should be kept in mind with clinical use of metolazone. Hypercalcemia has been noted in a few patients.

Sulfonamide derivatives have been reported to exacerbate or activate systemic lupus erythematosus. Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) have been reported with sulfonamide derivatives such as metolazone (see ADVERSE REACTIONS).

Orthostatic hypotension may occur; this may be potentiated by alcohol, barbiturates, narcotics, or concurrent therapy with other antihypertensive drugs.

Special caution should be used in treating patients with severe hepatic disease since metolazone may induce metabolic alkalosis in cases of potassium depletion which may precipitate episodes of hepatic encephalopathy. (See CONTRAINDICATIONS).

Caution should be observed when administering metolazone to patients with severely impaired renal function. As most of the drug is excreted by the renal route, cumulative effects may be seen. (See CONTRAINDICATIONS).

Metolazone may raise blood glucose concentrations, possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.

Laboratory Tests: Periodic determination of serum electrolytes; blood urea nitrogen; uric acid, and glucose levels should be assessed at appropriate intervals during metolazone therapy. (See WARNINGS).

Drug Interactions

Alcohol, barbiturates, or narcotics: See PRECAUTIONS.

Antihypertensives: See WARNINGS and PRECAUTIONS. When metolazone is used with other antihypertensive drugs, particular care must be taken, especially during initial therapy. Dosage of other antihypertensive agents, especially the ganglionic blockers and quanethidine, should be reduced. Hydralazine in therapeutic doses may interfere with the natruretic action of metolazone.

Corticosteroids or ACTH Therapy: May increase the risk of hypokalemia and increase salt and water retention.

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 is advisable to discontinue metolazone tablets three days before elective surgery.

Digitalis: See WARNINGS.

Drugs Used to Treat Gout: See WARNINGS. Dosage adjustment of the gout medication may be necessary to control hyperuricemia and gout.

Furosemide and Other Loop Diuretics: See WARNINGS. Unusually large or prolonged losses of fluids and electrolytes may result.

Insulin and Oral Antidiabetic Agents: Adjustment of dosage may be necessary. See PRECAUTIONS.

Lithium: See WARNINGS.

Methenamine: Efficacy may be decreased due to urinary alkalizing effect of metolazone.

Salicylates and Other Nonsteroidal Anti-inflammatory Agents: May antagonize natruretic, diuretic and antihypertensive effects of metolazone. Patients should be monitored carefully.

Sympathomimetics: May decrease the antihypertensive effect of metolazone. Metolazone may decrease arterial responsiveness to norepinephrine, but this diminution is not sufficient to preclude effectiveness of the pressor agent for therapeutic use.

Use in Pregnancy

Since metolazone crosses the placenta and appears in cord blood, its administration to women of childbearing age requires that the potential benefits of the drug be weighed against its possible hazards to the fetus. The potential effects on the fetus include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. However, teratogenic studies in mice, rats and rabbits, have not shown teratologic effects in these animals.

Nursing Mothers

Metolazone appears in breast milk. Thus, it is possible that the effects of metolazone may occur in the newborn under these circumstances. If the use of metolazone is deemed essential for a nursing mother, the patient should stop nursing.

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: Necrotizing angitis (cutaneous vasculitis), Stevens-Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), purpura, dermatitis (photosensitivity), urticaria and skin rashes.

Gastrointestinal: Hepatitis: intrahepatic cholestatic jaundice, pancreatitis, vomiting, nausea, epigastric distress, diarrhea, constipation, anorexia, abdominal bloating.

Hematologic: Aplastic/hypolastic anemia, agranulocytosis, leukopenia.

Metabolic: Hypokalemia, hyponatremia, hyperuricemia, hypochloremia, hypochloremic alkalosis, hyperglycemia, glycosuria, increase in serum urea nitrogen (BUN) or creatinine, hypophosphatemia (See WARNINGS and PRECAUTIONS).

Musculoskeletal: Joint pain, acute gouty attacks, muscle cramps or spasm.

Other: Transient blurred vision, chills.

In addition, adverse reactions reported with similar antihypertensive diuretics, but which have not been reported to date for ZAROXOLYN include: bitter taste, dry mouth, sialadenitis, xanthopsia, respiratory distress (including pneumonitis), thrombocytopenia and anaphylactic reactions. These reactions should be considered as possible occurrences with clinical usage of ZAROXOLYN.

Whenever adverse reactions are moderate or severe, ZAROXOLYN dosage should be reduced or therapy withdrawn.