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Demadex
Overview
What is Demadex?
DEMADEX (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:
Its empirical formula is CHNOS, 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.
What does Demadex look like?
What are the available doses of Demadex?
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What should I talk to my health care provider before I take Demadex?
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How should I use 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.
What interacts with Demadex?
DEMADEX is contraindicated in patients with known hypersensitivity to DEMADEX or to sulfonylureas.
DEMADEX is contraindicated in patients who are anuric.
What are the warnings of Demadex?
Concentrated extracts must be diluted with sterile diluent prior to first use on a patient for treatment or intradermal testing. All concentrates of glycerinated allergenic extracts have the ability to cause serious local and systemic reactions including death in sensitive patients. Sensitive patients may experience severe anaphylactic reactions resulting in respiratory obstruction, shock, coma and /or death.
An allergenic extract should be temporarily withheld from patients or the dose of the extract adjusted downward if any of the following conditions exist: (1) Severe symptoms of rhinitis and/or asthma (2) Infections or flu accompanied by fever and (3) Exposure to excessive amounts of clinically relevant allergen prior to a scheduled injection. When switching patients to a new lot of the same extract the initial dose should be reduced 3/4 so that 25% of previous dose is administered.
Hepatic Disease With Cirrhosis and
Ascites
Ototoxicity
Volume and Electrolyte Depletion
In controlled studies in the United States, DEMADEX 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
DEMADEX (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
DEMADEX 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 DEMADEX.
What are the precautions of Demadex?
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.
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.
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.
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 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.
The effect of DEMADEX on labor and delivery is unknown.
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.
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.
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.
What are the side effects of Demadex?
To report SUSPECTED ADVERSE REACTIONS, contact
Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or
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
| 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 |
What should I look out for while using Demadex?
DEMADEX is contraindicated in patients with known
hypersensitivity to DEMADEX or to sulfonylureas.
DEMADEX is contraindicated in patients who are anuric.
Hepatic Disease With Cirrhosis and
Ascites
Ototoxicity
Volume and Electrolyte Depletion
In controlled studies in the United States, DEMADEX 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
DEMADEX (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
DEMADEX 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 DEMADEX.
What might happen if I take too much Demadex?
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.
How should I store and handle Demadex?
Store at controlled room temperature 20° to 25°C (68° to 77°F) [see USP] .DEMADEX for oral administration is available as white, scored tablets containing 10 mg, 20 mg of torsemide. The tablets are supplied in: 10 mg Bottles of 30 NDC 54868-3835-020 mg Bottles of 10 NDC 54868-4687-120 mg Bottles of 30 NDC 54868-4687-020 mg Bottles of 90 NDC 54868-4687-320 mg Bottles of 100 NDC 54868-4687-2 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.StorageR onlyDEMADEX for oral administration is available as white, scored tablets containing 10 mg, 20 mg of torsemide. The tablets are supplied in: 10 mg Bottles of 30 NDC 54868-3835-020 mg Bottles of 10 NDC 54868-4687-120 mg Bottles of 30 NDC 54868-4687-020 mg Bottles of 90 NDC 54868-4687-320 mg Bottles of 100 NDC 54868-4687-2 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.StorageR onlyDEMADEX for oral administration is available as white, scored tablets containing 10 mg, 20 mg of torsemide. The tablets are supplied in: 10 mg Bottles of 30 NDC 54868-3835-020 mg Bottles of 10 NDC 54868-4687-120 mg Bottles of 30 NDC 54868-4687-020 mg Bottles of 90 NDC 54868-4687-320 mg Bottles of 100 NDC 54868-4687-2 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.StorageR onlyDEMADEX for oral administration is available as white, scored tablets containing 10 mg, 20 mg of torsemide. The tablets are supplied in: 10 mg Bottles of 30 NDC 54868-3835-020 mg Bottles of 10 NDC 54868-4687-120 mg Bottles of 30 NDC 54868-4687-020 mg Bottles of 90 NDC 54868-4687-320 mg Bottles of 100 NDC 54868-4687-2 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.StorageR onlyDEMADEX for oral administration is available as white, scored tablets containing 10 mg, 20 mg of torsemide. The tablets are supplied in: 10 mg Bottles of 30 NDC 54868-3835-020 mg Bottles of 10 NDC 54868-4687-120 mg Bottles of 30 NDC 54868-4687-020 mg Bottles of 90 NDC 54868-4687-320 mg Bottles of 100 NDC 54868-4687-2 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.StorageR onlyDEMADEX for oral administration is available as white, scored tablets containing 10 mg, 20 mg of torsemide. The tablets are supplied in: 10 mg Bottles of 30 NDC 54868-3835-020 mg Bottles of 10 NDC 54868-4687-120 mg Bottles of 30 NDC 54868-4687-020 mg Bottles of 90 NDC 54868-4687-320 mg Bottles of 100 NDC 54868-4687-2 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.StorageR onlyDEMADEX for oral administration is available as white, scored tablets containing 10 mg, 20 mg of torsemide. The tablets are supplied in: 10 mg Bottles of 30 NDC 54868-3835-020 mg Bottles of 10 NDC 54868-4687-120 mg Bottles of 30 NDC 54868-4687-020 mg Bottles of 90 NDC 54868-4687-320 mg Bottles of 100 NDC 54868-4687-2 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.StorageR only
Clinical Information
Chemical Structure
No Image foundClinical 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 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 (C) within 1 hour after oral
administration. C 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 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 (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.
Non-Clinical Toxicology
DEMADEX is contraindicated in patients with known hypersensitivity to DEMADEX or to sulfonylureas.DEMADEX is contraindicated in patients who are anuric.
Hepatic Disease With Cirrhosis and Ascites
Ototoxicity
Volume and Electrolyte Depletion
In controlled studies in the United States, DEMADEX 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 DEMADEX (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 DEMADEX 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 DEMADEX.
In vivo
In vitro
In vivo
Terbinafine decreases the clearance of caffeine by 19%. Terbinafine increases the clearance of cyclosporine by 15%.
There have been spontaneous reports of increase or decrease in prothrombin times in patients concomitantly taking oral terbinafine and warfarin, however, a causal relationship between Terbinafine Hydrochloride Tablets and these changes has not been established.
Terbinafine clearance is increased 100% by rifampin, a CYP450 enzyme inducer, and decreased 33% by cimetidine, a CYP450 enzyme inhibitor. Terbinafine clearance is unaffected by cyclosporine.
There is no information available from adequate drug-drug interaction studies with the following classes of drugs: oral contraceptives, hormone replacement therapies, hypoglycemics, theophyllines, phenytoins, thiazide diuretics, and calcium channel blockers.
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.
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.
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.
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 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.
The effect of DEMADEX on labor and delivery is unknown.
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.
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.
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.
To report SUSPECTED ADVERSE REACTIONS, contact Meda Pharmaceuticals Inc. at 1-800-526-3840 or FDA at 1-800-FDA-1088 or
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
Reference
This information is obtained from the National Institute of Health's Standard Packaging Label drug database.
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