A1,
A2,
B,
C1,
C2,
D,
E,
F,
G-H,
I-K,
L,
M,
N,
O,
P1,
P2,
Q-R,
S,
T,
U-V,
W-Z
Demadex Side Effects, and Drug Interactions - Torsemide
Demadex Side Effects, and Drug Interactions - Torsemide
SIDE EFFECTS
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 the table below.
|
Reactions Possibly or Probably
Drug-Related
United States Placebo-Controlled Studies Incidence (Percentages of Patients)
|
| |
DEMADEX
(N=564)
|
Placebo
(N=274)
|
Headache
Excessive Urination
Dizziness
Rhinitis
Asthenia
Diarrhea
ECG Abnormality
Cough Increase
Constipation
Nausea
Arthralgia
Dyspepsia
Sore Throat
Myalgia
Chest Pain
Insomnia
Edema
Nervousness |
7.3
6.7
3.2
2.8
2.0
2.0
2.0
2.0
1.8
1.8
1.8
1.6
1.6
1.6
1.2
1.2
1.1
1.1 |
9.1
2.2
4.0
2.2
1.5
1.1
0.4
1.5
0.7
0.4
0.7
0.7
0.7
1.5
0.4
1.8
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.
DRUG INTERACTIONS
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.
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.
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