Demadex

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.

DEMADEX tablets may be given at any time in relation to a meal, as convenient. Special dosage adjustment in the elderly is not necessary.

The usual initial dose of DEMADEX 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.

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.

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.

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.

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 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.

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

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.

Micropuncture 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.

The 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 1 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, 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 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. 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. A 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 a 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.