nz is concomitantly administered. concomitant use of nonsteroidal anti-inflammatory drugs (nsaids) and torsemide has been associated with the development of acute renal failure. the diuretic effects of torsemide can be reduced by nsaids. partial inhibition of the natriuretic effect of torsemide by concomitant administration of indomethacin has been demonstrated for torsemide under conditions of dietary sodium restriction (50 meq/day) but not in the presence of normal sodium intake (150 meq/day). 7.2 cytochrome p450 2c9 inhibitors and inducers torsemide is a substrate of cyp2c9. concomitant use of cyp2c9 inhibitors (e.g., amiodarone, fluconazole, miconazole, oxandrolone) can decrease torsemide clearance and increase torsemide plasma concentrations. concomitant use of cyp2c9 inducers (e.g., rifampin) increase torsemide clearance and decrease plasma torsemide concentrations. monitor diuretic effect and blood pressure when used in combination with cyp2c9 inhibitor or inducer. adjust soaanz dose, if necessary. because of its inhibition of cyp2c9 metabolism, torsemide may affect the efficacy and safety of sensitive cyp2c9 substrates, such as celecoxib, or of substrates with a narrow therapeutic range, such as warfarin or phenytoin. monitor patients and adjust dosages if necessary. 7.3 cholestyramine concomitant use of torsemide and cholestyramine has not been studied in humans but, in a study in animals, coadministration of cholestyramine decreased the absorption of orally administered torsemide. if soaanz and cholestyramine should be coadministered, administer soaanz at least one hour before or 4 to 6 h after cholestyramine administration. 7.4 organic anion drugs coadministration of organic anion drugs (e.g., probenecid) that undergo significant renal tubular secretion have the potential to reduce secretion of torsemide into the proximal tubule which thereby decreases the diuretic activity of soaanz. monitor diuretic effect and blood pressure during coadministration. 7.5 lithium like other diuretics, torsemide reduces the renal clearance of lithium, inducing a high risk of lithium toxicity. monitor lithium levels periodically when soaanz is coadministered. 7.6 ototoxic drugs loop diuretics increase the ototoxic potential of other ototoxic drugs, including aminoglycoside antibiotics and ethacrynic acid. this effect has been reported with concomitant use of torsemide and gentamycin. avoid concomitant use of soaanz and aminoglycoside antibiotics, if possible. 7.7 renin-angiotensin inhibitors coadministration of soaanz with ace inhibitors or angiotensin receptor blockers can increase the risk of hypotension and renal impairment. 7.8 radiocontrast agents soaanz can increase the risk of renal toxicity related to administration of radiocontrast agents. 7.9 corticosteroids and acth concomitant use with soaanz may increase risk of hypokalemia.

n occur, and gout may rarely be precipitated. monitor serum electrolytes and blood glucose periodically. 5.3 ototoxicity tinnitus and hearing loss (usually reversible) have been observed with loop diuretics, including torsemide. higher than recommended doses, severe renal impairment, and hypoproteinemia, appear to increase the risk of ototoxicity.

of subjects (6%) treated with soaanz. 6.2 postmarketing experience the following adverse reactions have been identified during the post-approval use of torsemide. because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to estimate their frequency reliably or establish a causal relationship to drug exposure. gastrointestinal system: pancreatitis, abdominal pain nervous system: paresthesia, confusion, visual impairment, loss of appetite hematologic: leucopenia, thrombocytopenia, anemia hepatobiliary: increase in liver transaminases, gamma-glutamyltransferase metabolism: thiamine (vitamin b1) deficiency skin/hypersensitivity: stevens-johnson syndrome, toxic epidermal necrolysis, photosensitivity reaction, pruritus urogenital: acute urinary retention

nz is concomitantly administered. concomitant use of nonsteroidal anti-inflammatory drugs (nsaids) and torsemide has been associated with the development of acute renal failure. the diuretic effects of torsemide can be reduced by nsaids. partial inhibition of the natriuretic effect of torsemide by concomitant administration of indomethacin has been demonstrated for torsemide under conditions of dietary sodium restriction (50 meq/day) but not in the presence of normal sodium intake (150 meq/day). 7.2 cytochrome p450 2c9 inhibitors and inducers torsemide is a substrate of cyp2c9. concomitant use of cyp2c9 inhibitors (e.g., amiodarone, fluconazole, miconazole, oxandrolone) can decrease torsemide clearance and increase torsemide plasma concentrations. concomitant use of cyp2c9 inducers (e.g., rifampin) increase torsemide clearance and decrease plasma torsemide concentrations. monitor diuretic effect and blood pressure when used in combination with cyp2c9 inhibitor or inducer. adjust soaanz dose, if necessary. because of its inhibition of cyp2c9 metabolism, torsemide may affect the efficacy and safety of sensitive cyp2c9 substrates, such as celecoxib, or of substrates with a narrow therapeutic range, such as warfarin or phenytoin. monitor patients and adjust dosages if necessary. 7.3 cholestyramine concomitant use of torsemide and cholestyramine has not been studied in humans but, in a study in animals, coadministration of cholestyramine decreased the absorption of orally administered torsemide. if soaanz and cholestyramine should be coadministered, administer soaanz at least one hour before or 4 to 6 h after cholestyramine administration. 7.4 organic anion drugs coadministration of organic anion drugs (e.g., probenecid) that undergo significant renal tubular secretion have the potential to reduce secretion of torsemide into the proximal tubule which thereby decreases the diuretic activity of soaanz. monitor diuretic effect and blood pressure during coadministration. 7.5 lithium like other diuretics, torsemide reduces the renal clearance of lithium, inducing a high risk of lithium toxicity. monitor lithium levels periodically when soaanz is coadministered. 7.6 ototoxic drugs loop diuretics increase the ototoxic potential of other ototoxic drugs, including aminoglycoside antibiotics and ethacrynic acid. this effect has been reported with concomitant use of torsemide and gentamycin. avoid concomitant use of soaanz and aminoglycoside antibiotics, if possible. 7.7 renin-angiotensin inhibitors coadministration of soaanz with ace inhibitors or angiotensin receptor blockers can increase the risk of hypotension and renal impairment. 7.8 radiocontrast agents soaanz can increase the risk of renal toxicity related to administration of radiocontrast agents. 7.9 corticosteroids and acth concomitant use with soaanz may increase risk of hypokalemia.

/kg/day of torsemide (on a mg/m 2 basis, the animal dose is 2.4 times the human starting dose of 20 mg/day), or in rabbits, treated with 1.6 mg/kg/day (on a mg/m 2 basis, the animal dose is 1.6 times the human starting dose of 20 mg/day 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 the safety and effectiveness of soaanz in pediatric patients have not been established. administration of a 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 a loop diuretic. a loop diuretic, when administered during the first weeks of life, has also been reported to increase the risk of persistent patent ductus arteriosus. 8.5 geriatric use of the total number of patients who received torsemide in united states clinical studies, 24% were 65 or older and 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 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. [see dosage and administration (2.1)].

m 2 basis, the animal dose is 2.4 times the human starting dose of 20 mg/day), or in rabbits, treated with 1.6 mg/kg/day (on a mg/m 2 basis, the animal dose is 1.6 times the human starting dose of 20 mg/day 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.

as 12.7 meq. edema torsemide has been studied in controlled trials in patients with new york heart association class ii to class iv heart failure. patients who received 10 mg to 20 mg of daily torsemide in these studies achieved significantly greater reductions in weight and edema than did patients who received placebo. when torsemide is first administered, daily urinary sodium excretion increases for at least a week. with chronic administration, however, daily sodium loss comes into balance with dietary sodium intake. if the administration of torsemide is suddenly stopped, blood pressure returns to pretreatment levels over several days, without overshoot. torsemide has been administered together with β-adrenergic blocking agents, ace inhibitors, and calcium-channel blockers. adverse drug interactions have not been observed, and special dosage adjustment has not been necessary. 12.3 pharmacokinetics absorption torsemide reaches peak plasma concentration (c max ) within 2.5 hours after oral administration of soaanz. c max and area under the serum concentration-time curve (auc) of torsemide after oral administration are proportional to dose over the range of 2.5 mg to 200 mg. effect of food administration of soaanz with a high fat, high calorie meal in healthy adults delays the time to c max by about 45 minutes, increases c max by 100% and increases area under the plasma concentration over time curve (auc) by 48%. no clinically significant change in overall diuretic activity was observed. distribution the volume of distribution of torsemide is 12 to 15 liters in normal adults or in patients with mild to moderate renal failure or congestive heart failure. in patients with hepatic cirrhosis, the volume of distribution is approximately doubled. torsemide is extensively bound to plasma protein (>99%). metabolism torsemide is metabolized by the hepatic cytochrome cyp2c9 and, to a minor extent, cyp2c8 and cyp2c18. three main metabolites have been identified in humans. metabolite m1 is formed by methylhydroxylation of torsemide, metabolite m3 is formed by ring hydroxylation of torsemide, and metabolite m5 is formed by oxidation of m1. the major metabolite in humans is the carboxylic acid derivative m5, which is biologically inactive. metabolites m1 and m3 possess some pharmacological activity; however, their systemic exposures are much lower when compared to torsemide. elimination in normal subjects the elimination half-life of torsemide is approximately 3.5 hours. torsemide is cleared from the circulation by both hepatic metabolism (approximately 80% of total clearance) and excretion into the urine (approximately 20% of total clearance in patients with normal renal function). because torsemide is extensively bound to plasma protein (>99%), very little enters tubular urine via glomerular filtration. most renal clearance of torsemide occurs via active secretion of the drug by the proximal tubules into tubular urine. after a single oral dose, the amounts recovered in urine were: torsemide 21%, metabolite m1 12%, metabolite m3 2%, and metabolite m5 34%. renal impairment in patients with renal failure, renal clearance of torsemide is markedly decreased but total plasma clearance is not significantly altered. a smaller fraction of the administered dose is delivered to the intraluminal site of action, and the natriuretic action of any given dose of diuretic is reduced. hepatic impairment in patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are all increased, but total clearance is unchanged. geriatric patients the renal clearance of torsemide is lower in elderly subjects as compared to younger adults, which is related to the decline in renal function that commonly occurs with aging. however, total plasma clearance and elimination half-life remain unchanged. heart failure in patients with decompensated congestive heart failure, hepatic and renal clearance are both reduced, probably because of hepatic congestion and decreased renal plasma flow, respectively. the total clearance of torsemide is approximately 50% of that seen in healthy volunteers, and the plasma half-life and auc are correspondingly increased. because of reduced renal clearance, a smaller fraction of any given dose is delivered to the intraluminal site of action, so at any given dose there is less natriuresis in patients with heart failure than in normal subjects. drug interactions digoxin : coadministration of digoxin is reported to increase the auc for torsemide by 50%, but dose adjustment of soaanz is not necessary. torsemide does not affect the pharmacokinetics of digoxin. spironolactone : in healthy subjects, coadministration of torsemide was associated with significant reduction in the renal clearance of spironolactone, with corresponding increases in the auc. however, the pharmacokinetic profile and diuretic activity of torsemide are not altered by spironolactone. torsemide does not affect the protein binding of glyburide or warfarin. cimetidine : the pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine.

p2c9 and, to a minor extent, cyp2c8 and cyp2c18. three main metabolites have been identified in humans. metabolite m1 is formed by methylhydroxylation of torsemide, metabolite m3 is formed by ring hydroxylation of torsemide, and metabolite m5 is formed by oxidation of m1. the major metabolite in humans is the carboxylic acid derivative m5, which is biologically inactive. metabolites m1 and m3 possess some pharmacological activity; however, their systemic exposures are much lower when compared to torsemide. elimination in normal subjects the elimination half-life of torsemide is approximately 3.5 hours. torsemide is cleared from the circulation by both hepatic metabolism (approximately 80% of total clearance) and excretion into the urine (approximately 20% of total clearance in patients with normal renal function). because torsemide is extensively bound to plasma protein (>99%), very little enters tubular urine via glomerular filtration. most renal clearance of torsemide occurs via active secretion of the drug by the proximal tubules into tubular urine. after a single oral dose, the amounts recovered in urine were: torsemide 21%, metabolite m1 12%, metabolite m3 2%, and metabolite m5 34%. renal impairment in patients with renal failure, renal clearance of torsemide is markedly decreased but total plasma clearance is not significantly altered. a smaller fraction of the administered dose is delivered to the intraluminal site of action, and the natriuretic action of any given dose of diuretic is reduced. hepatic impairment in patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are all increased, but total clearance is unchanged. geriatric patients the renal clearance of torsemide is lower in elderly subjects as compared to younger adults, which is related to the decline in renal function that commonly occurs with aging. however, total plasma clearance and elimination half-life remain unchanged. heart failure in patients with decompensated congestive heart failure, hepatic and renal clearance are both reduced, probably because of hepatic congestion and decreased renal plasma flow, respectively. the total clearance of torsemide is approximately 50% of that seen in healthy volunteers, and the plasma half-life and auc are correspondingly increased. because of reduced renal clearance, a smaller fraction of any given dose is delivered to the intraluminal site of action, so at any given dose there is less natriuresis in patients with heart failure than in normal subjects. drug interactions digoxin : coadministration of digoxin is reported to increase the auc for torsemide by 50%, but dose adjustment of soaanz is not necessary. torsemide does not affect the pharmacokinetics of digoxin. spironolactone : in healthy subjects, coadministration of torsemide was associated with significant reduction in the renal clearance of spironolactone, with corresponding increases in the auc. however, the pharmacokinetic profile and diuretic activity of torsemide are not altered by spironolactone. torsemide does not affect the protein binding of glyburide or warfarin. cimetidine : the pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine.

ests included the ames test in bacteria (with and without metabolic activation), tests for chromosome aberrations and sister-chromatid exchanges in human lymphocytes, tests for various nuclear anomalies in cells found in hamster and murine bone marrow, tests for unscheduled dna synthesis in mice and rats, and others. in doses up to 25 mg/kg/day (75 times a human dose of 20 mg on a body-weight basis; 13 times this dose on a body-surface-area basis), torsemide had no adverse effect on the reproductive performance of male or female rats.

t in bacteria (with and without metabolic activation), tests for chromosome aberrations and sister-chromatid exchanges in human lymphocytes, tests for various nuclear anomalies in cells found in hamster and murine bone marrow, tests for unscheduled dna synthesis in mice and rats, and others. in doses up to 25 mg/kg/day (75 times a human dose of 20 mg on a body-weight basis; 13 times this dose on a body-surface-area basis), torsemide had no adverse effect on the reproductive performance of male or female rats.