Torsemide Information
Torsemide () Description
Torsemide () is a diuretic of the pyridine-sulfonylurea class. Its chemical name is 1-isopropyl-3-[(4--toluidino-3-pyridyl)sulfonyl]urea and its structural formula is:
CHNOS M.W. 348.43
Torsemide () has a pKa of 7.1.
Torsemide () is a white to off-white crystalline powder. The tablets for oral administration also contain crospovidone, lactose anhydrous, magnesium stearate, microcrystalline cellulose and povidone.
Torsemide () Clinical Pharmacology
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 Torsemide () 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 (C) within 1 hour after oral administration. Cand 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 C 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 (> 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.
Torsemide () Indications And Usage
Torsemide () tablets are 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.
Torsemide () tablets are indicated for the treatment of hypertension alone or in combination with other antihypertensive agents.
Torsemide () Contraindications
Torsemide () tablets are contraindicated in patients with known hypersensitivity to Torsemide () or to sulfonylureas.
Torsemide () tablets are contraindicated in patients who are anuric.
Torsemide () Warnings
Patients 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, Torsemide () should be discontinued until the situation is corrected; Torsemide () may be restarted at a lower dose.
In controlled studies in the United States, Torsemide () was administered to hypertensive patients at doses of 5 mg or 10 mg daily. After 6 weeks at these doses, the mean decrease in serum potassium was approximately 0.1 mEq/L. The percentage of patients who had a serum potassium level below 3.5 mEq/L at any time during the studies was essentially the same in patients who received Torsemide () (1.5%) as in those who received placebo (3%). In patients followed for 1 year, there was no further change in mean serum potassium levels. In patients with congestive heart failure, hepatic cirrhosis, or renal disease treated with Torsemide () at doses higher than those studied in United States antihypertensive trials, hypokalemia was observed with greater frequency, in a dose-related manner.
In patients with cardiovascular disease, especially those receiving digitalis glycosides, diuretic-induced hypokalemia may be a risk factor for the development of arrhythmias. The risk of hypokalemia is greatest in patients with cirrhosis of the liver, in patients experiencing a 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 Torsemide () .
Torsemide () Precautions
Potassium:
WARNINGS
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 () 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 or of , the anticoagulant effect of (a related coumarin derivative), or the pharmacokinetics of or (a vasodilator/beta-blocker). In healthy subjects, coadministration of Torsemide () was associated with significant reduction in the renal clearance of , with corresponding increases in the AUC. However, clinical experience indicates that dosage adjustment of either agent is not required.
Because Torsemide () and compete for secretion by renal tubules, patients receiving high doses of may experience salicylate toxicity when Torsemide () is concomitantly administered. Also, although possible interactions between Torsemide () and 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 the concomitant administration of . This effect 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).
The pharmacokinetic profile and diuretic activity of Torsemide () are not altered by or . Coadministration of is reported to increase the area under the curve for Torsemide () 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 study in animals, coadministration of cholestyramine decreased the absorption of orally administered Torsemide () . If Torsemide () and cholestyramine are used concomitantly, simultaneous administration is not recommended.
Coadministration of reduces secretion of Torsemide () into the proximal tubule and thereby decreases the diuretic activity of Torsemide () .
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 Torsemide () has not been studied.
Other diuretics have been reported to increase the ototoxic potential of and of , especially in the presence of impaired renal function. These potential interactions with Torsemide () have not been studied.
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 and 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.
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 Torsemide () in such patients has not been studied.
Torsemide () Adverse Reactions
At the time of approval, Torsemide () had been evaluated for safety in approximately 4000 subjects: over 800 of these subjects received Torsemide () for at least 6 months, and over 380 were treated for more than 1 year. Among these subjects were 564 who received Torsemide () during United States-based trials in which 274 other subjects received placebo.
The reported side effects of Torsemide () 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 Torsemide () 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 Torsemide () and 3.4% (13/380) with furosemide in patients with congestive heart failure, 2.0% (8/409) 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 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 Torsemide () are shown in the table below.
The daily doses of Torsemide () 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 Torsemide () 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 Torsemide () , 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 Torsemide () 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 Torsemide () 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 Torsemide () 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 Torsemide () . One patient in the group treated with Torsemide () withdrew due to myalgia, and one in the placebo group withdrew due to gout.
Torsemide () Overdosage
There is no human experience with overdoses of Torsemide () , 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.
Torsemide () Dosage And Administration
Torsemide () tablets may be given at any time in relation to a meal, as convenient. Special dosage adjustment in the elderly is not necessary.
Because of the high bioavailability of Torsemide () , oral and intravenous doses are therapeutically equivalent, so patients may be switched to and from the intravenous form with no change in dose.
The usual initial dose is 5 mg or 10 mg of once-daily oral Torsemide () , 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.
Torsemide () How Supplied:
Torsemide () Tablets for oral administration are available as:
10 mg – white to off-white, oval shaped tablet, scored and debossed “9” and “3” on each side of the score, and debossed “7128” on the other side. They are available as follows:
NDC 51079-025-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
20 mg – white to off-white, oval shaped tablet, scored and debossed “9” and “3” on each side of the score, and debossed “7129” on the other side. They are available as follows:
NDC 51079-026-20 - Unit dose blister packages of 100 (10 cards of 10 tablets each).
Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Do not freeze.Protect from light.
Manufactured in Israel by:TEVA PHARMACEUTICAL IND. LTD.Jerusalem, 91010, Israel
Manufactured in Ireland by:IVAX Pharmaceuticals IrelandWaterford, Ireland
Manufactured for:TEVA PHARMACEUTICALS USASellersville, PA 18960
Distributed by:UDL Laboratories, Inc.Rockford, IL 61103
S-8213 R29/07
Torsemide () Principal Display Panel Mg
NDC 51079-025-20
100 Tablets (10 x 10)
Each tablet contains:Torsemide () 10 mg
Store at 20° to 25°C (68° to 77°F) [See USPControlled Room Temperature]. Do notfreeze. Protect from light.
Packaged and Distributed by:UDL LABORATORIES, INC.ROCKFORD, IL 61103
This unit dose package is not child resistant.
For institutional use only.
Keep this and all drugs out of the reach of children.
This container provides light-resistance.
See window for lot number and expiration date.
Torsemide () Principal Display Panel Mg
NDC 51079-026-20
100 Tablets (10 x 10)
Each tablet contains:Torsemide () 20 mg
Store at 20° to 25°C (68° to 77°F) [See USPControlled Room Temperature]. Do notfreeze. Protect from light.
Packaged and Distributed by:UDL LABORATORIES, INC.ROCKFORD, IL 61103
This unit dose package is not child resistant.
For institutional use only.
Keep this and all drugs out of the reach of children.
This container provides light-resistance.
See window for lot number and expiration date.
