PRECAUTIONS SECTION.

PRECAUTIONS. Laboratory ValuesPotassium: See WARNINGS Calcium Single doses of DEMADEX increased the urinary excretion of calcium by normal subjects, but serum calcium levels were slightly increased in 4- to 6-week hypertension trials. In long-term study of patients with congestive heart failure, the average 1-year change in serum calcium was decrease of 0.10 mg/dL (0.02 mmol/L). Among 426 patients treated with DEMADEX for an average of 11 months, hypocalcemia was not reported as an adverse event.Magnesium Single doses of DEMADEX caused healthy volunteers to increase their urinary excretion of magnesium, but serum magnesium levels were slightly increased in 4- to 6-week hypertension trials. In long-term hypertension studies, the average 1-year change in serum magnesium was an increase of 0.03 mg/dL (0.01 mmol/L). Among 426 patients treated with DEMADEX for an average of 11 months, one case of hypomagnesemia (1.3 mg/dL [0.53 mmol/L]) was reported as an adverse event.In long-term clinical study of DEMADEX in patients with congestive heart failure, the estimated annual change in serum magnesium was an increase of 0.2 mg/dL (0.08 mmol/L), but these data are confounded by the fact that many of these patients received magnesium supplements. In 4-week study in which magnesium supplementation was not given, the rate of occurrence of serum magnesium levels below 1.7 mg/dL (0.70 mmol/L) was 6% and 9% in the groups receiving mg and 10 mg of DEMADEX, respectively.Blood Urea Nitrogen (BUN), Creatinine and Uric Acid DEMADEX produces small dose-related increases in each of these laboratory values. In hypertensive patients who received 10 mg of DEMADEX daily for weeks, the mean increase in blood urea nitrogen was 1.8 mg/dL (0.6 mmol/L), the mean increase in serum creatinine was 0.05 mg/dL (4 mmol/L), and the mean increase in serum uric acid was 1.2 mg/dL (70 mmol/L). Little further change occurred with long-term treatment, and all changes reversed when treatment was discontinued.Symptomatic gout has been reported in patients receiving DEMADEX, but its incidence has been similar to that seen in patients receiving placebo.Glucose Hypertensive patients who received 10 mg of daily DEMADEX experienced mean increase in serum glucose concentration of 5.5 mg/dL (0.3 mmol/L) after weeks of therapy, with further increase of 1.8 mg/dL (0.1 mmol/L) during the subsequent year. In long-term studies in diabetics, mean fasting glucose values were not significantly changed from baseline. Cases of hyperglycemia have been reported but are uncommon.Serum Lipids In the controlled short-term hypertension studies in the United States, daily doses of mg, 10 mg, and 20 mg of DEMADEX were associated with increases in total plasma cholesterol of 4, 4, and mg/dL (0.10 to 0.20 mmol/L), respectively. The changes subsided during chronic therapy.In the same short-term hypertension studies, daily doses of mg, 10 mg and 20 mg of DEMADEX were associated with mean increases in plasma triglycerides of 16, 13 and 71 mg/dL (0.15 to 0.80 mmol/L), respectively.In long-term studies of mg to 20 mg of DEMADEX daily, no clinically significant differences from baseline lipid values were observed after year of therapy.OtherIn long-term studies in hypertensive patients, DEMADEX has been associated with small mean decreases in hemoglobin, hematocrit, and erythrocyte count and small mean increases in white blood cell count, platelet count, and serum alkaline phosphatase. Although statistically significant, all of these changes were medically inconsequential. No significant trends have been observed in any liver enzyme tests other than alkaline phosphatase.Drug InteractionsIn patients with essential hypertension, DEMADEX has been administered together with beta-blockers, ACE inhibitors, and calcium-channel blockers. In patients with congestive heart failure, DEMADEX has been administered together with digitalis glycosides, ACE inhibitors, and organic nitrates. None of these combined uses was associated with new or unexpected adverse events.Torsemide does not affect the protein binding of glyburide or of warfarin, the anticoagulant effect of phenprocoumon (a related coumarin derivative), or the pharmacokinetics of digoxin or carvedilol (a vasodilator/beta-blocker). In healthy subjects, coadministration of DEMADEX was associated with significant 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 DEMADEX and salicylates compete for secretion by renal tubules, patients receiving high doses of salicylates may experience salicylate toxicity when DEMADEX is concomitantly administered. Also, although possible interactions 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 DEMADEX (like that of many other diuretics) is partially inhibited by the concomitant administration of indomethacin. This effect has been demonstrated for DEMADEX under conditions 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 or spironolactone. Coadministration of digoxin is reported to increase the area under the curve for torsemide by 50%, but dose adjustment of DEMADEX is not necessary.Concomitant use of torsemide and cholestyramine has not been studied in humans but, in study in animals, coadministration of cholestyramine decreased the absorption of orally administered torsemide. If DEMADEX and cholestyramine are used concomitantly, simultaneous administration is not recommended.Coadministration of probenecid reduces secretion of DEMADEX into the proximal tubule and thereby decreases the diuretic activity of DEMADEX.Other diuretics are known to reduce the renal clearance of lithium, inducing high risk of lithium toxicity, so coadministration of lithium and diuretics should be undertaken with great caution, if at all. Coadministration of lithium and DEMADEX has not been studied.Other diuretics have been reported to increase the ototoxic potential of aminoglycoside antibiotics and of ethacrynic acid, especially in the presence of impaired renal function. These potential interactions with DEMADEX have not been studied.Carcinogenesis, Mutagenesis, Impairment of FertilityNo overall increase in tumor incidence was found when torsemide was given to rats and mice throughout their lives at doses up to mg/kg/day (rats) and 32 mg/kg/day (mice). On body-weight basis, these doses are 27 to 96 times human dose of 20 mg; on body-surface-area basis, they are to times this dose. In the rat study, the high-dose female group demonstrated renal tubular injury, interstitial inflammation, and statistically significant increase in renal adenomas and carcinomas. The tumor incidence in this group was, however, not much higher than the incidence sometimes seen in historical controls. Similar signs of chronic non-neoplastic renal injury have been reported in high-dose animal studies of other diuretics such as furosemide and hydrochlorothiazide.No mutagenic activity was detected in any of variety of in vivo and in vitro tests of torsemide and its major human metabolite. The tests 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 human dose of 20 mg on body-weight basis; 13 times this dose on body-surface-area basis), torsemide had no adverse effect on the reproductive performance of male or female rats.PregnancyPregnancy Category BThere was no fetotoxicity or teratogenicity in rats treated with up to mg/kg/day of torsemide (on mg/kg basis, this is 15 times human dose of 20 mg/day; on mg/m2 basis, the animal dose is 10 times the human dose), or in rabbits, treated with 1.6 mg/kg/day (on mg/kg basis, times the human dose of 20 mg/kg/day; on 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 (rabbits) and (rats) times larger. Adequate and well-controlled studies have not been carried out in pregnant women. Because animal reproduction studies are not always predictive of human response, this drug should be used during pregnancy only if clearly needed.Labor and DeliveryThe effect of DEMADEX on labor and delivery is unknown.Nursing MothersIt is not known whether DEMADEX is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when DEMADEX is administered to nursing woman.Pediatric UseSafety and effectiveness in pediatric patients have not been established.Administration of another loop diuretic to severely premature infants with edema due to patent ductus arteriosus and hyaline membrane disease has occasionally been associated with renal calcifications, sometimes barely visible on X-ray but sometimes in staghorn form, filling the renal pelves. Some of these calculi have been dissolved, and hypercalciuria has been reported to have decreased, when chlorothiazide has been coadministered along with the loop diuretic. In other premature neonates with hyaline membrane disease, another loop diuretic has been reported to increase the risk of persistent patent ductus arteriosus, possibly through prostaglandin-E-mediated process. The use of DEMADEX in such patients has not been studied.Geriatric useOf the total number of patients who received DEMADEX 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.

WARNINGS SECTION.

WARNINGS. Hepatic Disease With Cirrhosis and AscitesDEMADEX should be used with caution in patients with hepatic disease with cirrhosis and ascites, since sudden alterations of fluid and electrolyte balance may precipitate hepatic coma. In these patients, diuresis with DEMADEX (or any other diuretic) is best initiated in the hospital. To prevent hypokalemia and metabolic alkalosis, an aldosterone antagonist or potassium-sparing drug should be used concomitantly with DEMADEX.OtotoxicityTinnitus and hearing loss (usually reversible) have been observed after rapid intravenous injection of other loop diuretics and have also been observed after oral DEMADEX. It is not certain that these events were attributable to DEMADEX. Ototoxicity has also been seen in animal studies when very high plasma levels of torsemide were induced.Volume and Electrolyte DepletionPatients receiving diuretics should be observed for clinical evidence of electrolyte imbalance, hypovolemia, or prerenal azotemia. Symptoms of these disturbances may include one or more of the following: dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pains or cramps, muscular fatigue, hypotension, oliguria, tachycardia, nausea, and vomiting. Excessive diuresis may cause dehydration, blood-volume reduction, and possibly thrombosis and embolism, especially in elderly patients. In patients who develop fluid and electrolyte imbalances, hypovolemia, or prerenal azotemia, the observed laboratory changes may include hyper- or hyponatremia, hyper- or hypochloremia, hyper- or hypokalemia, acid-base abnormalities, and increased blood urea nitrogen (BUN). If any of these occur, DEMADEX should be discontinued until the situation is corrected; DEMADEX may be restarted at lower dose.In controlled studies in the United States, DEMADEX was administered to hypertensive patients at doses of mg or 10 mg daily. After weeks at these doses, the mean decrease in serum potassium was approximately 0.1 mEq/L. The percentage of patients who had serum potassium level below 3.5 mEq/L at any time during the studies was essentially the same in patients who received DEMADEX (1.5%) as in those who received placebo (3%). In patients followed for year, there was no further change in mean serum potassium levels. In patients with congestive heart failure, hepatic cirrhosis, or renal disease treated with DEMADEX at doses higher than those studied in United States antihypertensive trials, hypokalemia was observed with greater frequency, in dose-related manner.In patients with cardiovascular disease, especially those receiving digitalis glycosides, diuretic-induced hypokalemia may be risk factor for the development of arrhythmias. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes, and in patients receiving concomitant therapy with corticosteroids or ACTH.Periodic monitoring of serum potassium and other electrolytes is advised in patients treated with DEMADEX.

ADVERSE REACTIONS SECTION.

ADVERSE REACTIONS. To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. At the time of approval, DEMADEX had been evaluated for safety in approximately 4000 subjects: over 800 of these subjects received DEMADEX for at least months, and over 380 were treated for more than year. Among these subjects were 564 who received DEMADEX during United States-based trials in which 274 other subjects received placebo.The reported side effects of DEMADEX were generally transient, and there was no relationship between side effects and age, sex, race, or duration of therapy. Discontinuation of therapy due to side effects occurred in 3.5% of United States patients treated with DEMADEX and in 4.4% of patients treated with placebo. In studies conducted in the United States and Europe, discontinuation rates due to side effects were 3.0% (38/1250) with DEMADEX and 3.4% (13/380) with furosemide in patients with congestive heart failure, 2.0% (8/409) with DEMADEX and 4.8% (11/230) with furosemide in patients with renal insufficiency, and 7.6% (13/170) with DEMADEX and 0% (0/33) with furosemide in patients with cirrhosis.The most common reasons for discontinuation of therapy with DEMADEX were (in descending order of frequency) dizziness, headache, nausea, weakness, vomiting, hyperglycemia, excessive urination, hyperuricemia, hypokalemia, excessive thirst, hypovolemia, impotence, esophageal hemorrhage, and dyspepsia. 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 States placebo-controlled trials in more than 1% of patients treated with DEMADEX are shown in Table 1.Table Reactions Possibly or Probably Drug-Related United States Placebo-Controlled Studies Incidence (Percentages of Patients)DEMADEX(N=564)Placebo(N=274)Headache7.39.1Excessive Urination6.72.2Dizziness3.24.0Rhinitis2.82.2Asthenia2.01.5Diarrhea2.01.1ECG Abnormality2.00.4Cough Increase2.01.5Constipation1.80.7Nausea1.80.4Arthralgia1.80.7Dyspepsia1.60.7Sore Throat1.60.7Myalgia1.61.5Chest Pain1.20.4Insomnia1.21.8Edema1.11.1Nervousness1.10.4The daily doses of DEMADEX used in these trials ranged from 1.25 mg to 20 mg, with most patients receiving mg to 10 mg; the duration of treatment ranged from to 52 days, with median of 41 days. Of the side effects listed in the table, only excessive urination occurred significantly more frequently in patients treated with DEMADEX than in patients treated with placebo. In the placebo-controlled hypertension studies whose design allowed side-effect rates to be attributed to dose, excessive urination was reported by 1% of patients receiving placebo, 4% of those treated with mg of daily DEMADEX, and 15% of those treated with 10 mg. The complaint of excessive urination was generally not reported as an adverse event among patients who received DEMADEX for cardiac, renal, or hepatic failure.Serious adverse events reported in the clinical studies for which drug relationship could not be excluded were atrial fibrillation, chest pain, diarrhea, digitalis intoxication, gastrointestinal hemorrhage, hyperglycemia, hyperuricemia, hypokalemia, hypotension, hypovolemia, shunt thrombosis, rash, rectal bleeding, syncope, and ventricular tachycardia.Angioedema has been reported in patient exposed to DEMADEX who was later found to be allergic to sulfa drugs.Of the adverse reactions during placebo-controlled trials listed without taking into account assessment of relatedness to drug therapy, arthritis and various other nonspecific musculoskeletal problems were more frequently reported in association with DEMADEX than with placebo, even though gout was somewhat more frequently associated with placebo. These reactions did not increase in frequency or severity with the dose of DEMADEX. One patient in the group treated with DEMADEX withdrew due to myalgia, and one in the placebo group withdrew due to gout.Hypokalemia: See WARNINGS.

CLINICAL PHARMACOLOGY SECTION.

CLINICAL PHARMACOLOGY. Mechanism of ActionMicropuncture studies in animals have shown that torsemide acts from within the lumen of the thick ascending portion of the loop of Henle, where it inhibits the Na+/K+/2CI--carrier system. Clinical pharmacology studies have confirmed this site of action in humans, and effects in other segments of the nephron have not been demonstrated. Diuretic activity thus correlates better with the rate of drug excretion in the urine than with the concentration in the blood.Torsemide increases the urinary excretion of sodium, chloride, and water, but it does not significantly alter glomerular filtration rate, renal plasma flow, or acid-base balance.Pharmacokinetics and MetabolismThe bioavailability of DEMADEX tablets is approximately 80%, with little intersubject variation; the 90% confidence interval is 75% to 89%. The drug is absorbed with little first-pass metabolism, and the serum concentration reaches its peak (Cmax) within hour after oral administration. Cmax and area under the serum concentration-time curve (AUC) after oral administration are proportional to dose over the range of 2.5 mg to 200 mg. Simultaneous food intake delays the time to Cmax by about 30 minutes, but overall bioavailability (AUC) and diuretic activity are unchanged. Absorption is essentially unaffected by renal or hepatic dysfunction.The volume of distribution of torsemide is 12 liters 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.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). The major metabolite in humans is the carboxylic acid derivative, which is biologically inactive. Two of the lesser metabolites possess some diuretic activity, but for practical purposes metabolism terminates the action of the drug.Because torsemide is extensively bound to plasma protein (greater than 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.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, 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 congestive heart failure than in normal subjects.In patients with renal failure, renal clearance of torsemide is markedly decreased but total plasma clearance is not significantly altered. 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. diuretic response in renal failure may still be achieved if patients are given higher doses. The total plasma clearance and elimination half-life of torsemide remain normal under the conditions of impaired renal function because metabolic elimination by the liver remains intact.In patients with hepatic cirrhosis, the volume of distribution, plasma half-life, and renal clearance are all increased, but total clearance is unchanged.The pharmacokinetic profile of torsemide in healthy elderly subjects is similar to that in young subjects except for decrease in renal clearance related to the decline in renal function that commonly occurs with aging. However, total plasma clearance and elimination half-life remain unchanged.