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Mechanism of ActionMicropuncture studies in anima ls have shown that torsemide acts from within the lumen of the thickascending portion of the loop of Henle, where it inhibits the Na'JK'/2CI'-carrier system. Clinicalpharmacology studies have confirmed this site of action in humans, and effects in other segments ofthe nephron have not been demonstrated. Diuretic activity thus correlates better with the rate of drugexcretion in the urine than with the concentration in the blood.Torsemide increases the urinary excretion of sodium, chloride, and water, but it does not significantlyalterglomerular filtration rate, renal plasma flow, or acid-base balance.

Pharmacokinetics and MetabolismThe volume of distribution of torsemide is 12 liters to 15 liters in normal adults or in patients with mildto moderate renal failure or congestive heart failure. In patients with hepatic cirrhosis, the volume ofdistribution is approximately doubled.In normal subjects the elimination half- life of torsemide is approximately 3.5 hours. Torsemide is clearedfrom the circulation by both hepatic metabolism (approximately 80% of total clearance) and excretioninto the urine (approximately 20% of total clearance in patients w ith normal renal function). The majormetabolite in humans is the carboxylic acid derivative, which is biologically inactive. Two of the lessermetabolites possess some diuretic activity, but for practical purposes metabolism terminates the actionof the drug.Because torsemide is extensively bound to plasma protein (> 990/0), very little enters tubular urine viaglomerular filtration. Most renal clearance of torsemide occurs via active secretion of the drug by theproximal tubules into tubular urine.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 totalclearance of torsemide is approximately 50% of that seen in healthy volunteers, and the plasma half-lifeand AUG a re correspondingly increased. Because of reduced renal clearance, a smaller fraction of anygiven dose is delivered to the intraluminal site of action, so at any given dose there is less natriuresis inpatients with congestive heart failure than in normal subjects.In patients with renal failure, renal clearance of torsemide is markedly decreased but total plasmaclearance is not significantly altered. A smaller fraction of the administered dose is delivered to theintraluminal site of action, and the natriuretic action of any given dose of diuretic is reduced. A diureticresponse in renal failure may still be achieved if patients are given higher doses. The total plasmaclearance and elimination half-life of torsemide remain normal under the conditions of impaired renalfunction because metabolic elimination by the liver remains intact.In patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are allincreased, but total clearance is unchanged.The pharmacokinetic profile of torsemide in healthy elderly subjects is similar to that in young subjectsexcept for a decrease in renal clearance related to the decline in renal function that commonly occurswith aging. However, total plasma clearance and elimination half-life remain unchanged.

Clinical EffectsThe diuretic effect s of torsemide begin within 10 minutes of intravenous dosing and peak within the firsthour. With intravenous administration diuresis lasts about 6 to 8 h ours. In healthy subjects given singledoses, the dose-response relationship for sodium excretion is linear over the dose range o f 2.5 mg to 20mg. The increase in potassium excretion is negligible after a single dose of up to 10 mg and only slight(5 mEq to 15 mEq) after a single dose o f 20 mg.

Congestive Heart FailureTorsemide has been studied in controlled trials in patients with New York Heart Association Class II toClass IV congestive heart failure . Patients who received 10 mg to 20 mg o f daily torsemide in thesestudies achieved significantly greater reductions in weight and edema than did patients who receivedplacebo.

Nonanuric Renal FailureIn single-dose studies in patients with nonanuric renal failure, high doses of torsemide (20 mg to 200mg) caused marked increases in water and sodium excretion . In patients with nonanuric renal failure,severe enough to require hemodialys is, chronic treatment with up to 200 mg of daily torsemide hasnot been shown to change steady-state fluid retention . When patients in a study of acute renal failurereceived total daily doses of 520 mg to 1200 m g o f to rsemide, 1 9% experienced seizures. Ninety-sixpatients were treated in this study; 6/32 treated with torsemide experienced seizures, 6/32 treatedwith comparably high doses of furosemide experienced seizures, and 1/32 treated with placeboexperienced a seizure.

Hepatic CirrhosisWhen given with aldosterone antagonists, torsemide also caused increases in sodium and fluidexcretion in patients with edema or ascites due to hepatic cirrhosis. Urinary sodium excretion raterelative 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 ofportal hypertension and ascites). However, because of the increased renal clearance of torsemide inpatients with hepatic cirrhosis, these factors tend to balance each other, and the result is an overallnatriuretic response that is similar to that seen in healthy subjects. Chronic use of any diuretic in hepaticdisease has not been studied in adequate and well-controlled trials.

Essential HypertensionIn patients with essential hypertenSion, torsemide has been shown in controlled studies to lower bloodpressure when administered once a day at doses of 5 mg to 10 mg. The antihypertensive effect is nearmaximal after 4 to 6 weeks of treatment, but it may continue to increase for up to 12 weeks. Systolic anddiastolicsupine and standing blood pressures are all reduced. There is no significant orthostatic effect,and there is only a minimal peak-trough difference in blood pressure reduction .The antihypertensive effects of torsemide are, like those of other diuretics, on the average greater inblack patients (a low-renin population) than in non black patients.When torsemide is first administered, daily urinary sodium excretion increases for a t least a week. Withchronic administration, however, daily sodium loss comes into balance with dietary sodium intake. Ifthe administration of torsemide is suddenly stopped, blood pressure returns to pretreatment levels overseveral days, without over shoot.Torsemide has been administered together with j3-adrenergic blocking agents, ACE inhibitors, andcalcium-channel blockers. Adverse drug inte rac tio n s have n o t been observed, and special dosageadjustment has not been necessary.

Torsemide Injection is indicated for the treatment of edema associated with congestive heart failure,renal disease, or hepatic disease. Use of torsemide has been found to be effective for the treatment ofedema associated w th chronic renal failure. Chronic use of any diuretic in hepatic disease has not beenstudied in adequate and well-controlled trials.Torsemide Injection is indicated when a rapid onset of diuresis is desired or when oral administrationis impractical.Torsemide Injection is indicated for the treatment of hypertension alone or in combination with otherantihypertensive agents.

Torsemide Injection is contraindicated in patients with known hypersensitivity to torsemide or tosulfonylureas.Torsemide Injection is contraindicated in patients who are anuric.

Hepatic Disease With Cirrhosis and Ascites

Laboratory ValuesPotassiumSee WARNINGS.

CalciumSingle doses of torsemide increased the urinary excretion of calcium by normal subjects, but serumcalcium levels were slightly increased in 4 to 6 week hypertension trials . In a long-term study of patientswith congestive heart failure, the average 1 year change in serum calcium was a decrease of 0 .1 mgJdL(0.02 mmoIlL). Among 426 patients treated with torsemide for an average o f 11 months, hypocalcemiawas not reported as an adverse event.

MagnesiumSingle doses of torsemide caused healthy volunteers to increase the ir urinary excretion of magnesium,but serum magnesium levels were slightly increased in 4 to 6 week hypertension trials. In long-termhypertension studies, the average 1 year change in serum magnesium was an increase of 0.03 mgJdL(0.01 mmoIlL). Among 426 patients treated with torsemide for an average of 11 months, one case ofhypomagnesemia (1 .3 m gJdL [0.53 mmollLJ) was reported as an adverse event .In a tong- term clinical study of torsemide in patients with congestive heart failure, the estimatedannual change in serum magnesium was an increase of 0.2 mg/dL (0.08 mmoI/L), but these data areconfounded by the fact that many of these patients received magnesium supplements. In a 4 weekstudy in which magnesium supplementation was not given, the rate of occurrence of serum magnesiumlevels below 1.7 mg/dL (0.7 mmollL) was 60/0 a nd 9% in the groups receiving 5 mg a nd 10 mg oftorsemide, respectively.

Blood Urea Nitrogen (BUN), C reatinin e a nd Uric AcidTorsemide produces small dose-related increases in each of these laboratory values. In hypertensivepatients who received 10 mg o f torsemide daily for 6 weeks, the mean increase in blood urea nitrogenwas 1 .8 mg/dL (0.6 mmo IJL) , the mean increase in serum creatinine was 0.05 mg/dL (4 mmo t/ L) , andthe mean increase in serum uric acid was 1 .2 m gJdL (70 mmoIJL). Little further change occurred withlong-term treatment, and all changes reversed when treatment was discontinued.Symptomatic gout has been reported in patients receiving torsemide, but its incidence has been similarto that seen in patients receiving placebo.

GlucoseHypertensive patients who received 10 m g of daily torsemide experienced a mean increase in serumglucose concentration o f 5.5 mg/dL (0.3 mmot/L) after 6 weeks of therapy, with a further increase of1 .8 mgldL (0.1 mmollL) during the subsequent year. In long-term studies in diabetics, mean fastingglucose values were not significantly changed from baseline. Cases of hyperglycemia have beenreported but are uncommon.

Serum LipidsIn the controlled short-term hypertension studies in the United States, daily doses of 5 mg, 10 mg, and20 mg of torsemide were associated with increases in total plasma cholesterol of 4, 4 , and 8 mg/dL (0.1to 0.2 mmoIlL ), respectively. The changes subsided during chronic therapy.In the same short- term hypertension studies, daily doses of 5 mg, 10 m g and 20 mg of torsemide wereassociated with mean increases in plasma triglycerides of 16, 13, and 71 mg/dL (0. 15 to 0.8 mmoIlL) ,respectively.In long-term studies of 5 mg to 20 mg of torsemide daily, no clinically significant differences frombaseline lipid values were observed after 1 year of therapy.

OtherIn long-term studies in hypertensive patients, torsemide has been associated with small meandecreases in hemoglobin, hematocrit , and erythrocyte count and small mean increases in white bloodcell count, platelet count, and serum alkaline phosphatase. Although statistically significant, all of thesechanges were medically inconsequential. No significant trends have been observed in any liver enzymetests other than alkaline phosphatase.

In patients with essential hypertension, torsemide has been administered together with beta-blockers,ACE inhibitors, and calcium-channel blockers, In patients with congestive heart failure, torsemide hasbeen administered together with digitalis glycosides, ACE inhibitors, and o rganic nitrates. None of thesecombined uses was associated with new or unexpected adverse events.Torsemide does not affect the protein binding of glyburide or of wartarin, the anticoagulant effect ofphenprocoumon (a related coumarin derivative), or the pharmacokinetics of digoxin or carvedilol (avasodilator/beta-blocker). In hea lthy subjects, coadministration of torsemide was associated withsignificant reduction in the renal clearance of spironolactone, with corresponding increases in the AUC.However, clinical experience indicates that dosage adjustment of either agent is not required ,Because torsemide and salicylates compete fo r secretion by rena l tubules, patients receiving highdoses of salicylates may experience salicylate toxicity when torsemide is concomitantly administe red ,Also, although possible inte ractions between torsemide and nonsteroidal anti-inflammatory agents(including aspirin) have not been studied, coadministration of these agents with another loop diuretic(furosemide) has occasionally been associated with renal dysfunction,The natriuretic effect of torsemide (like that of many other diuretics) is partially inhibited by theconcomitant administration of indomethacin. This effect has been demonstrated for torsemide underconditions of dietary sodium restriction (50 mEq/day) but not in the presence of normal sodium intake(150 mEq/day).The pharmacokinetic profile and diuretic activity of torsemide are not altered by cimetidine ors pironolactone, Coadministration of digoxin is reported to increase the area under the curve fortorsemide by 50%, but dose adjustment of torsemide is not necessary.Concomitant use of torsemide and cholestyramine has not been studied in humans but, in a studyin animals, coadministration of cholestyramine decreased the absorption of orally administeredtorsemide. If torsemide and c holestyramine are used concomitantfy, simultaneous administration isnot recommended.Coadministration of probenecid reduces secretion of torsemide into the proximal tubule and therebydecreases the diuretic activity of torsemide.

At the time of approval, torsemide had been eva luated for safety in approximately 4000 subjects: over800 of these subjects received torsemide for at least 6 months, and over 380 were treated for morethan 1 year. Among these subjects were 564 who received torsemide during United States-based trialsin which 274 other subjects received placebo.The reported side effects of torsemide were generally transient, and there was no relationship betweenside effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effectsoccurred in 3.5% of United States patients treated with torsemide and in 4.4% of patients treated withplacebo. In studies conducted in the United States and Europe, discontinuation rates due to side effectswere 3% (38/1250) with torsemide and 3.4% (13/380) with furosemide in patients with congestive heartfailure, 2% (81409) with torsemide and 4.8% (11/230) with furosemide in patients with renal insufficiency,and 7.6% (13/170) with torsemide and 0% (0/33) with furosemide in patients with cirrhosis.The most common reasons for discontinuation of therapy with torsemide were (in descending orderof frequency) dizziness, headache, nausea, weakness, vomiting, hyperglycemia, excessive urination,hyperuricemia, hypokalemia, excessive thirst, hypovolemia, impotence, esophageal hemorrhage, anddyspepsia. Dropout rates for these adverse events ranged from 0.1 % to 0.5%.The side effects considered possibly or probably related to study drug that occurred in United Statesplacebo-controlled trials in more than 1% of patients treated with torsemide are shown in Table 1.Table 1 Reactions Possibly or Probably Drug-Related United States Placebo-Controlled

There is no human experience with overdoses of torsemide, but the signs and symptoms of overdosagecan be anticipated to be those of excessive pharmacologic effect: dehydration, hypovolemia,hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and hemoconcentration. Treatmentof overdosage should consist of fluid and electrolyte replacement.Laboratory determinations of serum levels of torsemide and its metabolites are not widely available.No data are available to suggest physiological maneuvers (e.g., maneuvers to change the pH of theurine) that might accelerate elimination of torsemide and its metabolites. Torsemide is not dialyzable,so hemodialysis will not accelerate elimination.

General: Special dosage adjustment in the elderly is not necessary.Because of the high bioavailability of torsemide, oral and intravenous doses are therapeuticallyequivalent, so patients may be switched to and from the intravenous form with no change in dose.Torsemide injection should be administered either slowly as a bolus over a period of 2 minutes oradministered as a continuous infusion.If torsemide is administered through an IV line, it is recommended that, as with other IV injections,the IV line be flushed with Normal Saline (Sodium Chloride Injection) before and after administration.Torsemide injection is formulated above pH 8.3. Flushing the line is recommended to avoid the potentialfor incompatibilities caused by differences in pH which could be indicated by color change, haziness orthe formation of a precipitate in the solution.If torsemide injection is administered as a continuous infusion, stability has been demonstrated through24 hours at room temperature in plastic containers for the following fluids and concentrations:200 mg torsemide (10 mg/mL) added to:250 mL Dextrose 5% in water250 mL 0.9% Sodium Chloride500 mL 0.45% Sodium Chloride50 mg torsemide (10 mg/mL) added to:500 mL Dextrose 5% in water500 mL 0.9% Sodium Chloride500 mL 0.45% Sodium ChlorideBefore administration, the solution of torsemide injection should be visually inspected for discolorationand particulate matter. If either is found, the vial should not be used.Congestive Heart FailureThe usual initial dose is 10 mg or 20 mg of intravenous torsemide. II the diuretic response is inadequate,the dose should be titrated upward by approximately doubling until the desired diuretic response isobtained. Single doses higher than 200 mg have not been adequately studied.Chronic Renal FailureThe usual initial dose of torsemide is 20 mg of intravenous torsemide. If the diuretic response isinadequate, the dose should be titrated upward by approximately doubling until the desired diureticresponse is obtained. Single doses higher than 200 mg have not been adequately studied.Hepatic CirrhosisThe usual initial dose is 5 mg or 10 mg of intravenous torsemide, administered together with analdosterone antagonist or a potassium·sparing diuretic. If the diuretic response is inadequate, the doseshould be titrated upward by approximately doubling until the desired diuretic response is obtained.Single doses higher than 40 mg have not been adequately studied.Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlledtrials.HypertenSionThe usual initial dose is 5 mg daily. If the 5 mg dose does not provide adequate reduction in bloodpressure within 4 to 6 weeks, the dose may be increased to 10 mg daily. If the response to 10 mg isinsufficient, an additional anti-hypertensive agent should be added to the treatment regimen.

Torsemide Injection 10 mg/mL, is available as follows:2 mL single dose vials in cartons of 10 - NDC# is 0517-0770-105 mL single dose vials in cartons of 10 - NDC# is 0517-0771-10StorageStore at 200 to 250 C (680 to 7]0 F) (See USP Controlled Room Temperature). DO NOT FREEZE.