"The European Medicines Agency's Committee for Medicinal Products for Human Use (CHMP) has recommended the marketing of selexipag (Uptravi, Actelion Registration Ltd) for the treatment of adults with pulmonary arterial hypertension (PAH)./"...
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 nonthiazide 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 (metolazone) 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 (metolazone) 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 (metolazone) daily developed hypokalemia (defined as a serum potassium concentration below 3.5 mEq/L).
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.
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 (metolazone) 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 may occur when MYKROX (metolazone) 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 (metolazone) .
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 (metolazone) AND FORMULATIONS BIOEQUIVALENT TO ZAROXOLYN SHOULD NOT BE INTERCHANGED FOR ONE ANOTHER.
Fluid and Electrolytes
All patients receiving therapy with MYKROX (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.
MYKROX (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, presumably prerenal azotemia, may be precipitated during the administration of MYKROX (metolazone) Tablets. If azotemia and oliguria worsen during treatment of patients with severe renal disease, MYKROX (metolazone) Tablets should be discontinued.
Use caution when administering MYKROX (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 may occur; this may be potentiated by alcohol, barbiturates, narcotics, or concurrent therapy with other antihypertensive drugs. In controlled clinical trials, 1.4% of patients treated with MYKROX (metolazone) Tablets (½ mg) had orthostatic hypotension; this effect was not reported in the placebo group.
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 MYKROX (metolazone) Tablets.
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.
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.
Teratogenic Effects: Pregnancy Category B
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, MYKROX (metolazone) Tablets should be used during pregnancy only if clearly needed. Metolazone crosses the placental barrier and appears in cord blood.
The use of MYKROX (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.
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 (metolazone) Tablets in pediatric patients have not been established, and such use is not recommended.
Clinical studies of MYKROX (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.This monograph has been modified to include the generic and brand name in many instances.
Last reviewed on RxList: 5/4/2009
Additional Mykrox Information
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