8 USE IN SPECIFIC POPULATIONS See 17 for Patient Counseling Information 8.1 Pregnancy Risk Summary There are no available data on use of torsemide in pregnant women and the risk of major birth defects or miscarriage. In pregnant rats and rabbits dosed, on a mg/m2 basis, with 10 and 1.7 times a human dose of 20 mg/day, respectively, there was no fetotoxicity or teratogenicity. However, in pregnant rats and rabbits administered 50 and 6.8 times the human dose, respectively, decreases in body weight, decreased fetal resorption and delayed fetal ossification was observed. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major malformations and miscarriage in clinically recognized pregnancies is 2 to 4%, and 15 to 20%, respectively. Data There was no fetotoxicity or teratogenicity in rats treated with up to 5 mg/kg/day of torsemide (on a mg/kg basis, this is 15 times a human dose of 20 mg/day; on a mg/m2 basis, the animal dose is 10 times the human dose), or in rabbits, treated with 1.6 mg/kg/day (on a mg/kg basis, 5 times the human dose of 20 mg/kg/day; on a mg/m2 basis, 1.7 times this dose). Fetal and maternal toxicity (decrease in average body weight, increase in fetal resorption and delayed fetal ossification) occurred in rabbits and rats given doses 4 (rabbits) and 5 (rats) times larger. 8.2 Lactation Risk Summary There are no data regarding the presence of torsemide in human milk or the effects of torsemide on the breastfed child. Diuretics can suppress lactation. 8.4 Pediatric Use Safety and effectiveness in pediatric patients have not been established. Administration of another loop diuretic to premature infants has been associated with the precipitation of nephrocalcinosis/nephrolithiasis. Nephrocalcinosis/nephrolithiasis has also been observed in children under 4 years of age with no history of prematurity who have been treated chronically with the other loop diuretic. The other loop diuretic, when administered during the first weeks of life, has also been reported to increase the risk of persistent patent ductus arteriosus. The use of torsemide in such patients has not been studied. 8.5 Geriatric Use Of the total number of patients who received torsemide in United States clinical studies, 24% were 65 or older while about 4% were 75 or older. No specific age-related differences in effectiveness or safety were observed between younger patients and elderly patients. 8.6 Use in Renal Impairment In single-dose studies in patients with non-anuric renal failure, high doses of torsemide (20 mg to 200 mg) caused marked increases in water and sodium excretion. In patients with non-anuric renal failure, severe enough to require hemodialysis, chronic treatment with up to 200 mg of daily torsemide has not been shown to change steady-state fluid retention. When patients in a study of acute renal failure received total daily doses of 520 mg to 1200 mg of torsemide, 19% experienced seizures. Ninety-six patients were treated in this study; 6/32 treated with torsemide experienced seizures, 6/32 treated with comparably high doses of furosemide experienced seizures, and 1/32 treated with placebo experienced a seizure. 8.7 Use in Hepatic Impairment Torsemide can cause sudden alterations of fluid and electrolyte balance which may precipitate hepatic coma in patients with hepatic disease with cirrhosis and ascites. In these patients, diuresis with torsemide is best initiated in the hospital. Diuretic treatment can cause or contribute to the development of hypovolemia, hypokalemia, metabolic alkalosis, hyponatremia or azotemia which can lead to new or worsening hepatic encephalopathy. Consider suspending or discontinuing torsemide [see Contraindications (4 )]. To prevent hypokalemia and metabolic alkalosis, use an aldosterone antagonist or potassium-sparing drug with torsemide in patients with hepatic disease. When given with aldosterone antagonists, torsemide also caused increases in sodium and fluid excretion in patients with edema or ascites due to hepatic cirrhosis. Urinary sodium excretion rate relative to the urinary excretion rate of torsemide is less in cirrhotic patients than in healthy subjects (possibly because of the hyperaldosteronism and resultant sodium retention that are characteristic of portal hypertension and ascites). However, because of the increased renal clearance of torsemide in patients with hepatic cirrhosis, these factors tend to balance each other, and the result is an overall natriuretic response that is similar to that seen in healthy subjects. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials.