DO NOT INTERCHANGE
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DO NOT INTERCHANGE METOLAZONE TABLETS, USP, ZAROXOLYN® TABLETS, AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE THEIR SLOW AND INCOMPLETE BIOAVAILABILITY AND ARE NOT ...
DO NOT INTERCHANGE
DO NOT INTERCHANGE METOLAZONE TABLETS, USP, ZAROXOLYN® TABLETS, AND OTHER FORMULATIONS OF METOLAZONE THAT SHARE THEIR SLOW AND INCOMPLETE BIOAVAILABILITY AND ARE NOT THERAPEUTICALLY EQUIVALENT AT THE SAME DOSES TO MYKROX TABLETS, A MORE RAPIDLY AVAILABLE AND COMPLETELY BIOAVAILABLE METOLAZONE PRODUCT. FORMULATIONS BIOEQUIVALENT TO ZAROXOLYN AND FORMULATIONS BIOEQUIVALENT TO MYKROX SHOULD NOT BE INTERCHANGED FOR ONE ANOTHER.
General
Fluid and Electrolytes
All patients receiving therapy with metolazone tablets should have serum electrolyte measurements done at appropriate intervals and be observed for clinical signs of fluid and/or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia. In patients with severe edema accompanying cardiac failure or renal disease, a low-salt syndrome may be produced, especially with hot weather and a low-salt diet. Serum and urine electrolyte determinations are particularly important when the patient has protracted vomiting, severe diarrhea, or is receiving parenteral fluids. Warning signs of imbalance are: dryness of mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea and vomiting. Hyponatremia may occur at any time during long term therapy and, on rare occasions, may be life threatening.
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 is inadequate or when excess potassium is being lost extrarenally, such as with vomiting or diarrhea.
Thiazide-like diuretics have been shown to increase the urinary excretion of magnesium; this may result in hypomagnesemia.
Glucose Tolerance
Metolazone may raise blood glucose concentrations possibly causing hyperglycemia and glycosuria in patients with diabetes or latent diabetes.
Hyperuricemia
Metolazone regularly causes an increase in serum uric acid and can occasionally precipitate gouty attacks even in patients without a prior history of them.
Azotemia
Azotemia, presumably prerenal azotemia, may be precipitated during the administration of metolazone. If azotemia and oliguria worsen during treatment of patients with severe renal disease, metolazone should be discontinued.
Renal Impairment
Use caution when administering metolazone tablets to patients with severely impaired renal function. As most of the drug is excreted by the renal route, accumulation may occur.
Orthostatic Hypotension
Orthostatic hypotension may occur; this may be potentiated by alcohol, barbiturates, narcotics, or concurrent therapy with other antihypertensive drugs.
Hypercalcemia
Hypercalcemia may infrequently occur with metolazone, especially in patients taking high doses of vitamin D or with high bone turnover states, and may signify hidden hyperparathyroidism. Metolazone should be discontinued before tests for parathyroid function are performed.
Systemic Lupus Erythematosus
Thiazide diuretics have exacerbated or activated systemic lupus erythematosus and this possibility should be considered with metolazone tablets.
Information for Patients
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.
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 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 three days before elective surgery.
Salicylates and Other Non-Steroidal Anti-Inflammatory Drugs
May decrease the antihypertensive effects of metolazone tablets.
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.
Drug/Laboratory Test Interactions
None reported.
Carcinogenesis, Mutagenesis, Impairment of Fertility
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.
Pregnancy
Teratogenic Effects
Reproduction studies performed in mice, rabbits, and rats treated during the appropriate period of gestation at doses up to 50 mg/kg/day have revealed no evidence of harm to the fetus due to metolazone. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, metolazone tablets should be used during pregnancy only if clearly needed. Metolazone crosses the placental barrier and appears in cord blood.
Non-Teratogenic Effects
The use of metolazone tablets in pregnant women requires that the anticipated benefit be weighed against possible hazards to the fetus. These hazards include fetal or neonatal jaundice, thrombocytopenia, and possibly other adverse reactions which have occurred in the adult. It is not known what effect the use of the drug during pregnancy has on the later growth, development, and functional maturation of the child. No such effects have been reported with metolazone.
Labor and Delivery
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.
Nursing Mothers
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.
Pediatric Use
Safety and effectiveness in pediatric patients have not been established in controlled clinical trials. There is limited experience with the use of metolazone in pediatric patients with congestive heart failure, hypertension, bronchopulmonary dysplasia, nephrotic syndrome and nephrogenic diabetes insipidus. Doses used generally ranged from 0.05 to 0.1 mg/kg administered once daily and usually resulted in a 1 to 2.8 kg weight loss and 150 to 300 cc increase in urine output. Not all patients responded and some gained weight. Those patients who did respond did so in the first few days of treatment. Prolonged use (beyond a few days) was generally associated with no further beneficial effect or a return to baseline status and is not recommended.
There is limited experience with the combination of metolazone and furosemide in pediatric patients with furosemide-resistant edema. Some benefited while others did not or had an exaggerated response with hypovolemia, tachycardia, and orthostatic hypotension requiring fluid replacement. Severe hypokalemia was reported and there was a tendency for diuresis to persist for up to 24 hours after metolazone was discontinued. Hyperbilirubinemia has been reported in 1 neonate. Close clinical and laboratory monitoring of all children treated with diuretics is indicated. See CONTRAINDICATIONS, WARNINGS, PRECAUTIONS.
Geriatric Use
Clinical studies of metolazone 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.
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