Drug: Demadex

DEMADEX (torsemide) is a diuretic of the pyridine-sulfonylurea class. Its chemical name is 1-isopropyl-3-[(4-m-toluidino-3-pyridyl) sulfonyl] urea and its structural formula is: Its empirical formula is C16H20N4O3S, its pKa is 7.1, and its molecular weight is 348.43. Torsemide is a white to off-white crystalline powder. The tablets for oral administration also contain lactose NF, crospovidone NF, povidone USP, microcrystalline cellulose NF, and magnesium stearate NF.

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To report SUSPECTED ADVERSE REACTIONS, contact Meda PharmaceuticalsInc. 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 6 months, and over 380 were treated for more than 1 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 1 : Reactions Possibly or Probably Drug-Related
United States Placebo-Controlled Studies Incidence (Percentages of Patients)
  DEMADEX
(N=564) Placebo
(N=274) Headache 7.3 9.1 Excessive Urination 6.7 2.2 Dizziness 3.2 4.0 Rhinitis 2.8 2.2 Asthenia 2.0 1.5 Diarrhea 2.0 1.1 ECG Abnormality 2.0 0.4 Cough Increase 2.0 1.5 Constipation 1.8 0.7 Nausea 1.8 0.4 Arthralgia 1.8 0.7 Dyspepsia 1.6 0.7 Sore Throat 1.6 0.7 Myalgia 1.6 1.5 Chest Pain 1.2 0.4 Insomnia 1.2 1.8 Edema 1.1 1.1 Nervousness 1.1 0.4 The daily doses of DEMADEX used in these trials ranged from 1.25 mg to 20 mg, with most patients receiving 5 mg to 10 mg; the duration of treatment ranged from 1 to 52 days, with a 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 5 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 a 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 a 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. Postmarketing Experience The following adverse reactions have been identified during the post approval use of Demadex. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Adverse reactions reported include the following: leucopenia, thrombocytopenia. Serious skin reactions (i.e., Stevens-Johnson syndrome, toxic epidermal necrolysis) have been reported in association with torsemide use. Pancreatitis has been reported in association with torsemide use. Read the Demadex (torsemide) Side Effects Center for a complete guide to possible side effectsLearn More »

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General DEMADEX tablets may be given at any time in relation to a meal, as convenient. Special dosage adjustment in the elderly is not necessary. Congestive Heart Failure The usual initial dose is 10 mg or 20 mg of once-daily oral DEMADEX. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied. Chronic Renal Failure The usual initial dose of DEMADEX is 20 mg of once-daily oral DEMADEX. If the diuretic response is inadequate, the dose should be titrated upward by approximately doubling until the desired diuretic response is obtained. Single doses higher than 200 mg have not been adequately studied. Hepatic Cirrhosis The usual initial dose is 5 mg or 10 mg of once-daily oral DEMADEX, administered together with an aldosterone antagonist or a potassium-sparing diuretic. If the diuretic response is inadequate, the dose should 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- controlled trials. Hypertension The usual initial dose is 5 mg once daily. If the 5 mg dose does not provide adequate reduction in blood pressure within 4 to 6 weeks, the dose may be increased to 10 mg once daily. If the response to 10 mg is insufficient, an additional antihypertensive agent should be added to the treatment regimen.

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In 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 a 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 a 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. Read the Demadex Drug Interactions Center for a complete guide to possible interactions Learn More »

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DEMADEX 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 of edema associated with chronic renal failure. Chronic use of any diuretic in hepatic disease has not been studied in adequate and well-controlled trials. DEMADEX is indicated for the treatment of hypertension alone or in combination with other antihypertensive agents.

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DEMADEX is contraindicated in patients with known hypersensitivity to DEMADEX or to sulfonylureas. DEMADEX is contraindicated in patients who are anuric. Last reviewed on RxList: 8/27/2012
This monograph has been modified to include the generic and brand name in many instances.

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There is no human experience with overdoses of DEMADEX, but the signs and symptoms of overdosage can be anticipated to be those of excessive pharmacologic effect: dehydration, hypovolemia, hypotension, hyponatremia, hypokalemia, hypochloremic alkalosis, and hemoconcentration. Treatment of 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 the urine) that might accelerate elimination of torsemide and its metabolites. Torsemide is not dialyzable, so hemodialysis will not accelerate elimination.

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DEMADEX for oral administration is available as white, scored tablets containing 5 mg, 10 mg, 20 mg, or 100 mg of torsemide. The tablets are supplied in bottles of 100 as follows: Dose Shape Bottle 5 mg elliptical NDC 0037-5005-01 10 mg elliptical NDC 0037-5010-01 20 mg elliptical NDC 0037-5020-01 100 mg capsule shaped NDC 0037-5001-01 Each tablet is debossed on the scored side with the logo BM and 102, 103, 104, or 105 (for 5 mg, 10 mg, 20 mg, or 100 mg, respectively). On the opposite side, the tablet is debossed with 5, 10, 20, or 100 to indicate the dose. Storage Store at 15° to 30°C (59° to 86°F). Manufactured By: Roche Farma S.A., Leganes, Spain. For: Meda Pharmaceuticals, Meda Pharmaceuticals Inc. Somerset, NJ 08873-4120. Rev. 08/12 Last reviewed on RxList: 8/27/2012
This monograph has been modified to include the generic and brand name in many instances.

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Laboratory Values Potassium: 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 a long-term study of patients with congestive heart failure, the average 1-year change in serum calcium was a 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 a 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 a 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 5 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 6 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 a mean increase in serum glucose concentration of 5.5 mg/dL (0.3 mmol/L) after 6 weeks of therapy, with a 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 5 mg, 10 mg, and 20 mg of DEMADEX were associated with increases in total plasma cholesterol of 4, 4, and 8 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 5 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 5 mg to 20 mg of DEMADEX daily, no clinically significant differences from baseline lipid values were observed after 1 year of therapy. Other In 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. Carcinogenesis, Mutagenesis and Impairment of Fertility No overall increase in tumor incidence was found when torsemide was given to rats and mice throughout their lives at doses up to 9 mg/kg/day (rats) and 32 mg/kg/day (mice). On a body-weight basis, these doses are 27 to 96 times a human dose of 20 mg; on a body-surface-area basis, they are 5 to 8 times this dose. In the rat study, the high-dose female group demonstrated renal tubular injury, interstitial inflammation, and a 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 a 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 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. Pregnancy Pregnancy Category B 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. 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 Delivery The effect of DEMADEX on labor and delivery is unknown. Nursing Mothers It 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 a nursing woman. Pediatric Use Safety 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 a prostaglandin-E-mediated process. The use of DEMADEX in such patients has not been studied. Geriatric Use Of 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. Last reviewed on RxList: 8/27/2012
This monograph has been modified to include the generic and brand name in many instances.

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